A Phase 3, Randomized, Double-Blind Study of Adjuvant Immunotherapy With Nivolumab Versus Placebo After Complete Resection of Stage IIB/C Melanoma
Phase: PHASE3
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 3, Randomized, Double-Blind Study of Adjuvant Immunotherapy with Nivolumab 
versus Placebo after Complete Resection of Stage IIB/C Melanoma 
(CheckMate 76K: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 76K) 
 
NCT Number: NCT04099251 
Document Date (Date in which document was last revised): 28-Apr-2022 

Page:
1
Protocol Number:
CA20976K
IND Number:
115,195
EUDRACT Number:
2019-001230-34
Date:
13-May-2019
Revised Date:
28-Apr-2022
CLINICAL PROTOCOL CA20976K
A Phase 3, Randomized, Double-Blind Study of Adjuvant Immunotherapy with Nivolumab 
versus Placebo after Complete Resection of Stage IIB/C Melanoma
(CheckMate 76K: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 76K)
Short Title:
Efficacy Study of Nivolumab Compared to Placebo in Prevention of Recurrence of Melanoma 
After Complete Resection of Stage IIB/C Melanoma (CheckMate 76K)
Protocol Amendment Number: 03
Clinical Trial Physician - Medical Monitor
Clinical Scientist
Uxbridge Business Park, Sanderson Road
Uxbridge, UB8 1DH, UK
86 Morris Ave
Summit-East, NJ 07901
Telephone (office):
Telephone (mobile): 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
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be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Date: 28-Apr-2022
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol Amendment 03
28-Apr-2022
•
Study personnel updated.
•
Definition of progression-free survival through next-line
therapy (PFS2) was rephrased.
•
Revised overall survival (OS) estimates and added
formal OS interim analysis.
•
Edited text throughout to refer to the number of
Recurrence-free Survival and OS events to be observed
as “approximately” instead of “at least.”
•
Other clarifications and administrative/editorial updates
made throughout the protocol.
Protocol Amendment 02
15-Oct-2021
•
Protocol updated to align the management of adverse
events (AEs) in trial participants, as well as the
reporting of such AEs, per the Common Terminology
Criteria for Adverse Events (CTCAE) version 5.0.
•
Language was inserted to provide descriptive OS data
at the time of positive read out of the primary endpoint
(recurrence-free survival [RFS]), as well as the
projected number of deaths at the time of interim and
final RFS analysis.
•
Clarifications to eligibility criteria regarding: (a)
handling of indeterminate nodules found during
screening; (b) deletion of requirement for male
contraception, and appropriate adjustments to text
under the Age and Reproductive Status criteria; (c)
extension of pregnancy testing window up to 72 hours
prior to treatment start in situations where results
cannot be obtained within 24 hours; and (d) flexibility
in allowing enrollment of participants who may not
have completed the full dosing schedule of coronavirus
disease 2019 (COVID-19) vaccines.
•
Appendices 1, 2, 3, 4, and 5 were updated.
•
Other clarifications and administrative/editorial updates
made throughout the protocol.
Administrative Letter 02
12-Jul-2021
•
Study personnel updated.
Revised Protocol 01
16-Oct-2020
•
Revised accrual rate assumptions. Updated the Interim
Analysis for Recurrence-Free Survival (RFS) analysis
to be conducted at increased number of events (80%
Information Fraction). Inserted condition for final RFS
analysis to be conducted at 90% of planned events in
case event rate is slower than anticipated.
•
Adjusted the sample size from 
 to 
 patients to
align with revised statistical parameters.
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Date: 28-Apr-2022
Document
Date of Issue
Summary of Change
•
Clarified body imaging language regarding imaging of 
extremities.
•
Inserted rationale for continued adjuvant study therapy 
for participants diagnosed with melanoma in situ.
•
Inserted text for criteria to resume study treatment in 
participants with confirmed or suspected SARS-CoV-2 
infection.
•
Inserted text requiring cytological/histological 
confirmation of melanoma recurrence when clinically 
feasible and safe.
•
Inserted text regarding determination of date of 
recurrence of melanoma regardless of method used to 
determine recurrence.
•
Pharmacokinetics: clarified timing of sample draw for 
End of Infusion timepoint.
•
Updated the management algorithms and added 
myocarditis algorithm to Appendix 5. Clarified that 
reporting of AEs is per CTCAE v5, however, 
management of AEs is per CTCAE v4.
•
Clarified the reporting of AEs/SAEs in the blinded and 
open-label portions of the trial. Introduced text on the 
collection of AEs/SAEs related to SARS-CoV-2 
infection.
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Protocol Amendment No.: 03
Date: 28-Apr-2022
Document
Date of Issue
Summary of Change
•
Changes as per Amendment 03 (for sites in Norway) 
were added as part of this revision.
•
Other typographical/editorial changes throughout.
Administrative Letter 01
04-Oct-2019
Page 159 – Appendix 9 – Country-Specific Appendix
Previously written:
Criteria for exclusion of HIV-positive subjects in 
Argentina, Czech Republic, France, Germany, Italy, Spain, 
and any other countries where exclusion of HIV-positive 
participants is locally mandated.
Changed to:
Criteria for exclusion of HIV-positive subjects in 
Argentina, Czech Republic, Germany, and any other 
countries where exclusion of HIV-positive participants is 
locally mandated.
Original Protocol
13-May-2019
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03:
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number and 
Title
Description of Change
Brief Rationale
Title Page
Changed the name and 
contact information of 
the Clinical Scientist.
Updated Clinical Scientist per study 
personnel change.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number and 
Title
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities
Table 2-2: On-Treatment 
Assessments CA20976K 
(Applies to All 
Participants: Blinded or 
Open-label Treatment)
Biopsy of affected organs
Dispense Study 
Treatment
Included a statement 
regarding the optional 
procedure to biopsy
affected organs “Upon 
occurrence of ≥ Grade 3 
drug-related AE and/or 
lab abnormalities 
regarded as a drug-
related SAE.”
Included statement to 
use Interactive Response 
Technology (IRT) to 
dispense study 
treatment.
Text added in the “On-Treatment” table
(Table2-2), since a ≥ Grade 3 drug-
related adverse event (AE) and/or lab 
abnormality regarded as a drug-related 
serious adverse event (SAE) could 
happen during treatment as well as 
post-treatment discontinuation 
(optional biopsy text reflecting the 
post-treatment discontinuation period is 
already present in the long-term follow-
up table [Table2-3]).
Text was inserted to serve as a 
reminder for the site to use the IRT to 
dispense study treatment.
Section 2: Schedule of 
Activities
Table 2-3: Long-Term 
Follow-Up CA20976K 
(Applies to All 
Participants: Blinded or 
Open-label Treatment)
Survival Status
Modified the length of 
follow-up from “5 
years” to “until the OS 
final analysis.”
Modification of follow-up visits was 
completed for consistency with other 
sections.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number and 
Title
Description of Change
Brief Rationale
Section 4: Objectives and 
Endpoints
Table 4-1: Objectives 
and Endpoints
Definition of 
progression-free 
survival through next-
line therapy (PFS2) was 
rephrased.
Definition was editorially rephrased for 
better clarity.
Section 5.1.1: Nivolumab 
or Placebo Blinded 
Treatment
Survival Status Follow-
Up (in-person or by 
telephone)
Section 8.1.1: Post Study 
Treatment Study Follow-
up
Changed survival status
follow-up from “up to 5 
years” to “until the OS 
final analysis.”
Update was made to align with the 
anticipated timing of the final OS 
analysis 
 
Section 10.1.1: RFS
Edited text throughout 
to refer to the number of 
RFS events to be 
observed as 
“approximately” instead 
of “at least.”
Changes were made to consistently 
refer to the number of RFS events to be 
observed as the “approximate: number 
of events. Previously, text was 
inconsistently listed in some places 
referring to the number of events to be 
observed as “at least” and in some 
other places as “approximately.”
Section 10.1.2: Overall 
Survival
 
Edited text throughout 
to refer to the number of 
OS events to be 
observed as 
“approximately” instead 
of “at least.”
Changes were made to consistently 
refer to the number of OS events to be 
observed as the “approximate: number 
of events. Previously, text was 
inconsistently listed in some places 
referring to the number of events to be 
observed as “at least” and in some 
other places as “approximately.”
Protocol Amendment No.: 03
Date: 28-Apr-2022
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number and 
Title
Description of Change
Brief Rationale
Section 10.3.1.2 
Secondary Endpoint 
Analyses
Investigator-Assessed 
Outcomes on Next-Line 
Therapies
Definition of PFS2 was 
rephrased.
Definition was editorially rephrased for 
better clarity.
Section 10.3.4: Interim 
Analysis
Updated statistical 
parameters (number of 
events, power, cHR, and 
projected number of 
deaths at the time of the 
OS interim analyses).
Updates were made based on real-word 
survival data in the Stage IIB/C study 
population, and accounting additionally 
for the impact of post-recurrence anti-
cancer therapy.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number and 
Title
Description of Change
Brief Rationale
All
Edited minor formatting 
and typographical 
corrections throughout 
protocol.
Minor, therefore, have not been 
summarized.
Protocol Amendment No.: 03
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03: ............................ 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03 ................ 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Overview .................................................................................................. 
3.1.2 Research Hypothesis ................................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Pediatric Melanoma ................................................................................. 
3.2.2 The Adjuvant Treatment of Patients with Stage IIB/C Melanoma with 
Nivolumab is a Promising Strategy ............................................................ 
3.2.2.1 Harnessing the Success of Immunotherapy in Patients with Late 
Stage Melanoma to Patients with Stage IIB/C Melanoma .................... 
3.2.3 Nivolumab Mechanism of Action ............................................................. 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Nivolumab or Placebo Blinded Treatment .............................................. 
5.1.2 Optional On-Protocol Open-Label Nivolumab Treatment After First 
Recurrence .................................................................................................. 
5.1.3 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Treatment with Blinded Nivolumab ................................... 
5.4.5 Rationale for Blinding (Nivolumab Versus Placebo) .............................. 
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5.5 Justification for Dose ........................................................................................ 
5.5.1 Rationale for 480 mg Flat Dose Every 4 Weeks ...................................... 
5.5.3 Rationale for Nivolumab 30-Minute Infusion Duration .......................... 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.1.1 Inclusion Criteria - Blinded Nivolumab or Placebo Treatment .............. 
6.1.2 Inclusion Criteria for Participants Receiving Treatment after Recurrence
..................................................................................................................... 
6.2 Exclusion Criteria ............................................................................................. 
6.2.1 Exclusion Criteria - Blinded Nivolumab or Placebo Treatment ............. 
6.2.2 Exclusion Criteria for Participants Receiving Treatment After 
Recurrence .................................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 Treatment with Nivolumab or Placebo .................................................... 
7.1.2 General Treatment Administration Considerations................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.2.1 Blinded Nivolumab or Placebo Treatment .............................................. 
7.2.2 Optional Open-Label Nivolumab Treatment After First Recurrence ...... 
7.3 Blinding............................................................................................................. 
7.3.1 Unblinding: Emergency, Accidental, and in the Event of Disease 
Recurrence .................................................................................................. 
7.3.2 Unblinding in the Event of Disease Recurrence ...................................... 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Criteria to Delay, Resume, or Discontinue Nivolumab or Nivolumab-
Placebo ....................................................................................................... 
7.4.1.1 Additional Dose Delay Criteria/Details ......................................... 
7.4.1.2 Additional Dose Resumption Criteria/Details ................................ 
7.4.1.3 Additional Dose Discontinuation Criteria/Details ......................... 
7.4.2 Treatment of Nivolumab-Related Infusion Reactions .............................. 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence / Biocomparability
..................................................................................................................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.3 Imaging Restriction and Precautions ...................................................... 
7.7.4 Permitted Therapy ................................................................................... 
7.8 Treatment After the End of the Study ............................................................... 
7.8.1 Treatment Beyond Disease Progression .................................................. 
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7.8.1.1 Participants Receiving Optional Open-Label Nivolumab with 
Unresectable/Metastatic Disease (Arm 2) ............................................ 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.1.1 Methods of Measurement ................................................................ 
9.1.2 Investigator Assessment of Baseline Disease Status ................................ 
9.1.2.1 General Considerations for Determining Recurrence .................... 
9.1.2.2 Investigator Assessment of Recurrence (Nivolumab/Placebo-
Blinded Treatment and Open-Label Nivolumab - Arm 1) .................... 
9.1.2.3 Definitions ....................................................................................... 
9.1.2.4 Date of Recurrence ......................................................................... 
9.1.2.5 Investigator Assessment of Progression for Participants Receiving 
Open-Label Nivolumab (Arm 2: Unresectable/Metastatic Disease) .... 
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 ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8.1 Additional Research Collection ............................................................... 
9.8.2 Tissue Specimens ..................................................................................... 
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9.10 Other Assessments .......................................................................................... 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.1.1 RFS ......................................................................................................... 
10.1.2 Overall Survival ..................................................................................... 
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....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.3.3 Pharmacokinetic Analyses ............................................................ 
10.3.3.5 Immunogenicity Analyses.............................................................. 
10.3.3.6 Analyses of Follow-Up Data from Participants Receiving Optional 
Open-Label Nivolumab Treatment ....................................................... 
10.3.4 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING ....................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0 ......................................................................................................... 
APPENDIX 6 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 7 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
APPENDIX 8 AJCC MELANOMA STAGING .......................................................... 
APPENDIX 9 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
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APPENDIX 10 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
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Clinical Protocol
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1
SYNOPSIS
Protocol Title: A Phase 3, Randomized, Double-Blind Study of Adjuvant Immunotherapy 
with Nivolumab versus Placebo after Complete Resection of Stage IIB/C Melanoma
Short Title:
Efficacy Study of Nivolumab Compared to Placebo in Prevention of Recurrence of Melanoma 
After Complete Resection of Stage IIB/C Melanoma (CheckMate 76K)
Study Phase: 3
Study Overview:
CA20976K is a Phase 3, randomized, double-blind study designed to evaluate the use of adjuvant 
immunotherapy with nivolumab versus placebo after complete resection of Stage IIB/C melanoma 
in adults and pediatric participants ≥12 years old. 
In this study, participants with resected Stage IIB/C melanoma and no evidence of disease will be 
randomized to treatment with either nivolumab or placebo for a duration of 12 months. Results 
from this study will help to define the role of nivolumab as an adjuvant immunotherapy in patients 
with resected Stage IIB and IIC cutaneous melanoma. In the event of disease recurrence, 
participants will have the option to receive on-study open-label nivolumab treatment. Placebo-
treated participants who experience disease recurrence within 3 years after the last dose of placebo, 
and nivolumab-treated participants who experience recurrence greater than 6 months and within 3 
years after completing treatment, will be eligible to participate in on study unblinded /open-label 
nivolumab treatment. Participants with resectable / recurrent disease will be offered nivolumab for 
a maximum duration of 12 months, whereas participants with unresectable or metastatic disease 
will be offered nivolumab monotherapy for a maximum of 24 months. Participants with disease 
recurrence who do not participate in the optional open-label nivolumab treatment portion of the 
study will be treated per standard of care as recommended by their treating physician. 
Overall Study Rationale:
There is currently an unmet medical need for effective adjuvant therapies for patients diagnosed 
with Stage IIB and IIC cutaneous melanoma. Results from this study will help to define the role 
of nivolumab as an adjuvant immunotherapy in patients with Stage IIB and IIC cutaneous 
melanoma.
Cutaneous malignant melanomas are staged according to the American Joint Committee on Cancer 
(AJCC) tumor/node/metastasis (TNM) classification and staging system. The AJCC 8th edition 
tumor staging for patients presenting with Stage II cutaneous malignant melanomas is shown 
below.1
Protocol Amendment No.: 03
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When T is…
And N is…
And M is….
The pathological stage 
is….
T2b/T3a
N0
M0
IIA
T3b/T4a
N0
M0
IIB
T4b
N0
M0
IIC
T2: >1.0–2.0 mm; T3: >2.0–4.0 mm; T4: >4.0 mm; a: without ulceration; b: with ulceration; N0: No regional 
metastases detected; M0: No evidence of distant metastasis
Stage IIB (T3b/T4a, N0, M0) and IIC (T4b, N0, M0) melanomas are classified as localized Stage 
IIB (T3b/T4a, N0, M0) and IIC (T4b, N0, M0) melanomas are classified as localized melanomas 
without nodal involvement but are a higher risk category compared to Stage I and IIA melanomas 
due to a relatively worse prognosis. Patients diagnosed with Stage IIB and IIC melanoma have 5-
year melanoma-specific survival (MSS) reported as 87% and 82%, respectively. The 
corresponding 10-year survival rates have been reported as 82% and 75%, respectively.
The relatively similar prognosis of patients with Stage IIB/C melanoma and patients with Stage
IIIB melanoma (5-year MSS for Stage IIIB = 83%), the poorer prognosis for these patients after 
relapse, underscore the need to prevent local or systemic relapses and provide support for the study 
of new systemic interventions to prevent metastases in the Stage IIB/C adjuvant melanoma 
setting.2 The demonstrated efficacy and acceptable benefit-risk profiles of immunotherapies such 
as nivolumab in Stage III and IV unresectable/metastatic melanoma, as well as in resected Stage 
III and IV melanoma, make nivolumab a suitable candidate to study in Stage IIB/C melanoma 
where the tumor burden is lower and immunotherapies may have a better chance of curing the 
patient. 
In this trial, the effect of re-introducing open-label nivolumab in the event of disease recurrence in
participants undergoing initial treatment with nivolumab will be explored. Anecdotal evidence 
exists for the re-introduction of immunotherapy in similar settings. In addition, placebo 
participants will also be provided with the opportunity to crossover and receive active treatment 
in the event of disease recurrence. The open-label component may also increase understanding of 
the impact of treating with nivolumab in earlier stage disease on subsequent treatment with 
nivolumab when patients develop more advanced disease. 
Study Population:
Male and female participants (≥12 years of age) with completely resected Stage IIB or IIC 
melanoma, with no evidence of disease (NED). Note: Where local regulations and/or institutional 
policies do not allow for participants < 18 years of age, the eligible participant population is ≥18 
years of age.
Key Inclusion Criteria:
a) Participants must have been diagnosed with Stage IIB/C cutaneous melanoma (AJCC
Staging, 8th edition) and have histologically confirmed melanoma that is completely
surgically resected, with documented negative margins (per local standard) for disease on
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resected specimens. All melanomas, except ocular and mucosal melanoma, regardless of 
primary site of disease will be allowed. 
b) Complete resection with documented negative margins (per local standard) and sentinel
lymph node assessment for presence/absence of disease, must be performed within 12
weeks prior to randomization. Note: In case of delays exceeding 12 weeks due to
unforeseen circumstances, the eligibility should be discussed with the Medical Monitor or
designee. Participants must have had a negative sentinel lymph node biopsy. Participants
in whom a sentinel lymph node biopsy procedure could not be done or a sentinel lymph
node was not detected are not eligible.
c) Participants must have disease-free status documented by a complete physical examination
(within 14 days) and imaging studies within 4 weeks (28 days) prior to randomization.
Imaging studies must include CT scans of the chest/abdomen/pelvis or CT scan of the chest
and MRI scans of the abdomen and pelvis, and all known sites of resected disease (imaging
of extremities for resected melanomas located in the extremities is not a requirement). The
evaluation of extremities may be conducted, and documented, per local standard of care.
Participants with signs and symptoms consistent with brain metastases should have
imaging studies done to rule out the presence of brain metastases.
d) Participant has not been previously treated for melanoma beyond complete surgical
resection of the melanoma lesion.
e) Participant has recovered adequately from toxicity and/or complications from surgery prior
to study start.
f)
ECOG performance status of 0 or 1 at the time of enrollment.
g) Tumor tissue (minimum of 15 unstained slides, preferably freshly cut, or 1 FFPE block to
contain sufficient tissue for at least 15 sections) from the primary diagnostic biopsy must
be shipped to the central laboratory prior to randomization. If the required tumor tissue
content cannot be provided, the eligibility should be discussed with the Medical Monitor
or designee.
Key Exclusion Criteria
1) Medical Conditions
a) History of ocular and mucosal melanoma.
b) 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.
c) 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.
d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days
of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10
mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
e) Women who are pregnant or breastfeeding.
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f)
Participants with serious or uncontrolled medical disorders. Additionally, in the case of
prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptoms
must have completely resolved and based on investigator assessment in consultation with
the BMS Medical Monitor or designee, there are no sequelae that would place the
participant at a higher risk of receiving investigational treatment.
2) Prior/Concomitant Therapy
a) Use of an investigational agent or an investigational device within 28 days before
administration of first dose of study drug.
b) Treatment directed against the resected melanoma (eg, chemotherapy, radiation therapy,
targeted agents, biotherapy, or limb perfusion) that is administered after the complete
resection.
c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4
antibody, or agents that target IL-2 pathway any other antibody or drug specifically
targeting T-cell co-stimulation or checkpoint pathways. Exception: Prior adjuvant
treatment with interferon (for melanoma other than study entry melanoma) is allowed if
completed ≥ 6 months prior to randomization.
d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese
medicines) 
to 
treat 
the 
disease 
under 
study 
within 
2 weeks 
prior 
to
randomization/treatment. Such medications are permitted if they are used as supportive
care.
e) Participants who have received a live / attenuated vaccine within 30 days of first treatment.
Male and female participants with disease recurrence within 3 years of discontinuation of 
blinded-study treatment (nivolumab or placebo) may be eligible for additional treatment with 
nivolumab monotherapy. In addition, for nivolumab participants, disease recurrence should be 
greater than 6 months following 1 year of treatment completion. Detailed eligibility criteria for 
enrollment to open-label nivolumab are in the main body of the protocol.
Objectives and Endpoints:
Table 1:
Objectives and Endpointsa
Objectives
Endpoints
Primary
To compare the efficacy, as measured by recurrence-
free survival (RFS), provided by nivolumab 
monotherapy versus placebo in participants with 
completely resected Stage IIB/C melanoma with no 
evidence of disease who are at high risk for 
recurrence.
RFS
Secondary
To compare the overall survival (OS) provided by 
nivolumab monotherapy versus placebo in 
participants with completely resected Stage IIB/C 
OS
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Table 1:
Objectives and Endpointsa
Objectives
Endpoints
melanoma with no evidence of disease who are at 
high risk for recurrence.
To assess safety and toxicity of nivolumab 
monotherapy in participants with completely resected 
Stage IIB/C melanoma with no evidence of disease.
Occurrence and severity of AEs as defined by NCI 
CTCAE v5.
To evaluate distant metastases-free survival (DMFS)
DMFS
To evaluate investigator-assessed outcomes on next-
line therapies.
•
Objective response rates (if applicable)
•
Duration of treatment on next-line therapies
•
Progression-free survival through next-line therapy
(PFS2) is defined as the time from randomization to
recurrence/objective disease progression after the
start of the next-line of systemic anti-cancer therapy,
or to the start of a second next-line systemic therapy,
or to 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.
Exploratory
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Table 1:
Objectives and Endpointsa
Objectives
Endpoints
To characterize the pharmacokinetics (PK) and 
explore exposure-response relationships with respect 
to safety and efficacy.
PK parameters and exposure metrics calculated from 
serum concentration-time data and characterization of 
exposure-response relationships
To characterize the immunogenicity of nivolumab.
Detection of anti-nivolumab antibodies
Abbreviations: AE, adverse events;
 
 
 
IgG, immunoglobulin G; 
 
NCI CTCAE, National Cancer Institute Common Terminology for Adverse Events; OS, overall survival; 
PFS2, progression-free survival through next line therapy; PK, pharmacokinetics;
 
 
a Objectives and endpoints for participants entering the optional open-label nivolumab are very similar to blinded
nivolumab/placebo participants with some subtle differences in endpoints to account for the open-label non-
randomized nature of treatment and for participants presenting with recurrent unresectable/metastatic disease in the 
event of recurrence.
 
Study Design:
In this study, participants with completely resected Stage IIB/C melanoma with no evidence of 
disease, will be randomized (2:1), stratified by T stage, to receive nivolumab (480 mg IV every 
4 weeks), or nivolumab-matched placebo until recurrence, unacceptability toxicity, withdrawal of 
consent, or a maximum of 12 months from the first dose of study treatment, which occurs first. 
Following first recurrence (Placebo participants: within 3 years after the last dose; Nivolumab 
participants: greater than 6 months from completion of 12 months of nivolumab, but within 3 years 
after completing 12 months of treatment), participants may be eligible to receive optional open-
label nivolumab for a maximum of 12 months (resectable disease) or 24 months (for 
unresectable/metastatic disease). The 12 or 24 months is calculated from the first dose of open-
label study treatment. 
The study design schematic is presented in Figure 1 below.
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Figure 1:
Study Design Schematic (applicable To Adult and Pediatric 
Participants ≥12 years old)
Abbreviations: IV, intravenous; Nivo, nivolumab; Q4W, every 4 weeks; SLN, sentinel lymph node; WLE, wide local 
excision.
a Pediatric dosing weight-based under 40 kg and for sites preferring weight-based dosing in pediatrics
b Tumor material obtained from surgery or biopsy
c Recurrence > 6 months after completion of 1 year of nivolumab treatment
d After recurrence, participants assigned to placebo arm will be offered to cross-over to nivolumab
e Resectable disease (Arm 1): Nivo 480 mg IV Q4W for 12 months
Unresectable disease (Arm 2): Nivo 480 mg IV Q4W for 24 months
During both blinded and open-label treatment, assessments of pharmacokinetics, 
 
 and imaging will be conducted at the schedules defined in the full 
protocol. During follow-up of blinded-treatment, participants will continue in-person assessment 
visits through 1-year post treatment (12 months from Follow-Up Visit 2). Participants will 
continue to be followed for survival status until the OS final analysis. 
Number of Participants:
Approximately 
participants, stratified by AJCC 8th edition T-stage (T3b vs. T4a vs. T4b) will 
be randomized in a 2:1 ratio to nivolumab 480 mg intravenously (IV) every 4 weeks (Q4W) or 
nivolumab-matched placebo. 
Treatment Arms and Treatment Duration Details: 
All participants on nivolumab or placebo will be treated until recurrence, unacceptable toxicity, 
participant withdrawal of consent, or a maximum of 12 months from first dose of study treatment, 
whichever occurs first. Dosing details for nivolumab and placebo are provided below.
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•
Arm A (Nivolumab):
−
Adult Dosing:
♦Nivolumab 480 mg IV flat dose over approximately 30 minutes every 4 weeks (Q4W).
−Pediatric Dosing:
♦12-17 years of age and weighing ≥40 kgs: Nivolumab 480 mg IV Q4W.
♦12-17 years of age and weighing < 40 kgs: 6 mg/kg Q4W up to a maximum of 240 mg.
♦For centers that do not prefer to use flat dosing: 6 mg/kg Q4W (maximum of 240 mg
for weight < 40 kgs; maximum of 480 mg for weight ≥40 kgs).
♦All nivolumab infusions to be administered over approximately 30 minutes.
•
Arm B: Adults and Pediatrics: Nivolumab matched placebo (0.9% Sodium Chloride for
Injection/5% Dextrose for Injection) IV over approximately 30 minutes Q4W.
Optional open-label nivolumab will be administered for pediatrics and adults at the dosages 
described for blinded-treatment above (480 mg IV flat dose Q4 weeks). For centers that do not 
prefer to use flat dosing, weight-based dosing can be used as mentioned above. Participants will 
be treated until progression, unacceptable toxicity, withdrawal of consent or a maximum treatment 
duration defined as 12 months for participants with resectable disease, or 24 months for those with 
unresectable/metastatic disease (calculated from the first dose of open-label treatment) whichever 
is first. 
Study Treatments:
Medication 
Potency 
IP/Non-IP 
BMS-936558 (Nivolumab) Solution 
for Injection
10 mg/mL
IP
0.9% Sodium Chloride for Injection
N/A
IP
5% Dextrose for Injection
N/A
IP
Statistical Considerations: 
The sample size of the study 
 is based on a comparison of the RFS distribution between 
participants randomized to nivolumab and participants randomized to placebo. 
 
 
 
 
Sample size calculations for this study design were performed using EAST 
(v 6.4.1).
For this comparison of RFS between nivolumab and placebo in all randomized participants, 
approximately 154 RFS events would be required for a two-sided experiment-wise alpha = 0.05 
log-rank test to show a statistically significant difference in RFS between the treatment arms with 
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at least 90% power when the average hazard ratio (HR) of the nivolumab arm to the placebo arm 
is 
 
 An observed HR of 
or less would result in a statistically 
significant improvement at the final analysis of RFS. 
Data Monitoring Committee: Yes 
References: 
1
Gershenwald J, Scolyer R, Hess K, et al. Melanoma Staging: Evidence-Based Changes in the American Joint 
Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin. 2017;67(6):472–492.
2
Grob J, Garbe C, Ascierto P, et al. Adjuvant melanoma therapy with new drugs: should physicians continue to 
focus on metastatic disease or use it earlier in primary melanoma? Lancet Oncol. 2018;19:e720-25.
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2
SCHEDULE OF ACTIVITIES
The following schedules of activities are provided:
Table 2-1:
Screening Procedural Outline CA20976K (Applies to All Participants: Blinded or 
Open-label Treatment)
Table 2-2:
On-Treatment Assessments CA20976K (Applies to All Participants: Blinded or 
Open-label Treatment)
Table 2-3: 
Long-Term Follow-Up CA20976K (Applies to All Participants: Blinded or Open-
label Treatment)
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Table 2-1:
Screening Procedural Outline CA20976K (Applies to All Participants: Blinded or Open-label 
Treatment)
Procedurea
Screening Visit
(Before Day 1, 
prior to Randomization)b
Notes
Eligibility Assessments
Informed Consent
X
Must be obtained prior to performing any screening procedures. 
Register in IRT to obtain the participant number (See Section 7.2)
If participant meets the criteria for re-enrollment (Section 6.4), the 
participant must be re-consented and assigned a new participant 
number from IRT.
For optional open-label nivolumab treatment after first 
recurrence: 
Participant will maintain the same participant ID assigned for 
randomized blinded treatment, but the ID must be assigned again via 
IRT for open-label nivolumab treatment (See Section 7.2)
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria (See Section 6.1 and 6.2) will be 
assessed during Screening (and reenrollment if applicable), and must 
be confirmed prior to randomization.b
Medical History
X
All medical history related to the disease under study.
•
Include: Smoking history (including e-cigarettes), and alcohol
history.
Concomitant Medication Collection
X
Within 14 days prior to randomizationb
Review of Pathology Report
X
The pathology report must be reviewed, and the review documented 
by the investigator prior to randomization.b
Copies of de-identified pathology reports must be sent to the central 
laboratory vendor prior to randomization.b
•
Refer to inclusion criteria in Section 6.1 and 6.2.
Tumor Tissue Samples
X
Prior to randomizationb: Tumor tissue from the primary diagnostic
biopsy (minimum 15 unstained slides, preferably freshly cut, or 1 
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Table 2-1:
Screening Procedural Outline CA20976K (Applies to All Participants: Blinded or Open-label 
Treatment)
Procedurea
Screening Visit
(Before Day 1, 
prior to Randomization)b
Notes
FFPE block to contain sufficient tissue for at least 15 sections) must 
be shipped to central laboratory. Refer to Section 6.1 (Inclusion 
Criteria) and Section 9.8.2 (Tissue Specimens). 
Safety Assessments
Complete Physical Examination
X
Include height and weight, within 14 days prior to randomization.b 
Pay special attention to skin and nodal examination.
Vital Signs, Oxygen Saturation
X
Include blood pressure (BP), heart rate, and temperature. Oxygen 
saturation by pulse oximetry at screening only. Perform assessments 
at the screening visit within 14 days prior to randomization.b
Performance Status (ECOG)
X
Within 14 days prior to randomizationb
Serious Adverse Event Assessment
X
Collected from the time of consent, including all SAEs associated 
with SARS-CoV-2 infection.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomizationb
Electrocardiogram (ECG)
X
Within 14 days prior to randomizationb
Laboratory Tests
X
On site/local laboratory testing to be completed within 14 days prior 
to randomization,b except for viral testing, which is to be completed
within 28 days prior to randomization.b
See Section 9.4.4 for a list of laboratory tests to be conducted.
Pregnancy Test
X
WOCBP only. Serum or urine to be done at screening visit and 
repeated within 24 hours prior to first dose of study therapy. 
For females under the age of 55, FSH > 40 mIU/mL is required to 
confirm menopause. See Appendix 4.
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Table 2-1:
Screening Procedural Outline CA20976K (Applies to All Participants: Blinded or Open-label 
Treatment)
Procedurea
Screening Visit
(Before Day 1, 
prior to Randomization)b
Notes
Efficacy assessment
Body Imaging
X
Within 4 weeks (28 days) prior to randomization:b Contrast-
enhanced (CE) CT of the chest, CE CT/MRI of the abdomen/pelvis, 
and all other known and/or suspected sites of disease (imaging of 
extremities for resected melanomas located in the extremities is not a 
requirement and may be conducted per local standard of care). See 
Section 9.1.1.1 for further details.
Brain Imaging
X
Within 4 weeks (28 days) prior to randomizationb: MRI of the brain
(brain CT allowable if MRI is contraindicated) without and with 
contrast, to be performed only if participant has signs and symptoms 
consistent with metastases to the brain. See Section 9.1.1.1 for 
further details.
Other
IRT Call/Assignment 
X
Abbreviations: CT, computed tomography; eCRF, electronic Case Report Form; FFPE, formalin-fixed paraffin embedded; FSH, follicle-stimulating hormone; 
ID, 
 IRT, Interactive Response Technology; MRI, magnetic resonance imaging; SAE, serious adverse events; SAR-CoV-2, severe acute 
respiratory syndrome coronoavirus 2; WOCBP, women of childbearing potential.
a 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.
b For participants who opt for open-label on-protocol nivolumab treatment after first disease recurrence, Screening assessments will occur prior to assignment
to optional on-protocol open-label nivolumab treatment. 
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Table 2-2:
On-Treatment Assessments CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedurea,b
Each cycle = 4 
weeks)c
Notes
Day 1 of Each 
Cycle
Cycle 1 is to be initiated within 3 calendar days (72 hours) of randomization.d
Subsequent cycles can be initiated within ± 3 days of the target visit date. See Section 7
(Treatment) for further details.
Safety Assessments
Targeted Physical Examination
X
To be performed within 72 hours prior to dosing. Pay special attention to skin and 
nodal examination.
Vital Signs
X
Include BP, heart rate, temperature.
Weight and Performance Status
X
Within 72 hours prior to dosing.
Adverse Event Assessment (including SAE 
assessment)
X
Continuously during treatment (including AEs/SAEs associated with SARS-CoV-2 
infection). All AEs/SAEs are to be graded and managed per NCI CTCAE v5. 
Review of concomitant medications
X
Laboratory Tests
X 
See full list of assessments in Section 9.4.4.
On site/local labs to be performed within 72 hours prior to dosing.
Note: Cycle 1 Day 1 laboratory tests are not required to be repeated if performed 
within 14 days prior to first dose.
Amylase, lipase, albumin, ACTH, and cortisol as clinically indicated.
Pregnancy Test
X
A negative pregnancy test should be documented within 24 hours prior to the initial 
administration of study drug. For subsequent cycles, a negative pregnancy test should 
be documented within 72 hours prior to dosing with study drug. Serum or Urine.
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Table 2-2:
On-Treatment Assessments CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedurea,b
Each cycle = 4 
weeks)c
Notes
Efficacy Assessments
Body Imaging
See note
Contrast-enhanced (CE) CT of the chest, CE CT/MRI of the abdomen/pelvis, and all 
other known and/or suspected sites of disease. Imaging of extremities for resected 
melanomas located in the extremities is not a requirement and may be conducted per 
local standard of care. Extremity imaging should be conducted in the event of a 
suspected locoregional relapse that is not clinically unequivocal.
Participants with Stage IIB/C melanoma (Nivolumab or Placebo blinded portion): 
•
Every 26 weeks (± 14 days) during the treatment phase of 12 months.e
For optional open-label nivolumab treatment after first recurrence:
ARM 1 (Resectable disease)
Participants enrolled with recurrent Stage III/IV resected disease
•
Every 12 weeks (± 7 days) from first dose of open-label study treatment through 12
months.e
ARM 2 (Unresectable/metastatic disease)
•
Every 12 weeks (± 7 days) from first dose of open-label study treatment through 24
months.e
Brain Imaging
See note
Participants with signs or symptoms consistent with brain metastases should have an 
MRI of the brain (without and with contrast) as clinically indicated. CT of the brain 
without and with contrast can be performed if MRI is contraindicated. See Section 
9.1.1.1 for further details.
Pharmacokinetic /Immunogenicity Assessments
PK and Immunogenicity samples
See note
Details regarding specific sample timing are specified in Table 9.5-1.
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Table 2-2:
On-Treatment Assessments CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedurea,b
Each cycle = 4 
weeks)c
Notes
Biopsy of affected organs
See note
Optional. Upon occurrence of ≥ Grade 3 drug-related AE and/or lab abnormality
regarded as a drug-related SAE. (See Section 9.8.2 and Table 2-3 for additional 
information).
Clinical Drug Supplies
IRT Randomization
X
Details regarding randomization of participants to receive nivolumab or placebo are 
described in Section 7.2.1. 
For details on treatment assignment for participants in the open-label nivolumab 
monotherapy portion of the trial, see Section 7.2.2.
Dispense Study Treatment 
X
Please use the IRT to dispense study treatment. First dose of study treatment to be 
administered within 3 calendar days (72 hours) of randomization.d Refer to Section
7.1.1 for details.
Abbreviations: ACTH, adrenocorticotropic hormone; AE, adverse events, BP, blood pressure, CE, contrast enhanced; CT, computed tomography; eCRF, electronic 
Case Report Form;
 
FFPE, formalin-fixed paraffin embedded; FSH, follicle-
stimulating hormone;
 IRT, Interactive Response Technology; MRI, magnetic resonance imaging; NCI CTCAE v5, National Cancer Institute 
Common Terminology Criteria for Adverse Events version 5; PK, pharmacokinetics; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2; WOCBP, Women of childbearing potential.
a 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.
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b If a dose is delayed, the procedures (except imaging procedures) scheduled for that same time point should also be delayed to coincide with when that time 
point’s dosing actually occurs.
c Participants receiving blinded study treatment, and those receiving open-label nivolumab in Arm 1 (resectable disease) will be treated until unacceptable toxicity, 
withdrawal of consent, completion of 12 months of treatment, disease recurrence, or the study ends, whichever occurs first. Participants receiving open-label 
nivolumab after first recurrence in Arm 2 (unresectable/metastatic disease) will be treated until unacceptable toxicity, withdrawal of consent, completion of 24 
months of treatment, disease recurrence, or the study ends, whichever occurs first. 
d Prior to assignment to open-label nivolumab for participants who opt for open-label on-protocol nivolumab treatment after first disease recurrence.
e Timing is calculated from the first dose of blinded study treatment or open-label treatment, whichever is applicable. 
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Table 2-3:
Long-Term Follow-Up CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedure
Follow-up
Visit 1a
Follow-up
Visit 2a
After 
Follow-up 
Visit 2 
Notes
Safety Assessments
Targeted Physical Examination, Vital Signs, and 
Performance Status
X
X
X (see Note)
Only for participants with Stage IIB/C melanoma 
(Nivolumab or Placebo blinded portion): 
After Follow-up Visit 2 (FU2), participants continue in-
person assessment approximately every 12 weeks for 12 
months (12 months calculated from FU2). Pay special 
attention to skin and nodal examination.
For participants initiating subsequent systemic anti-
cancer therapy for a melanoma recurrence, other than 
participation in optional open-label nivolumab 
monotherapy or for a non-melanoma cancer, follow-up 
assessments can be done per local standard of care.
Adverse Event Assessment
X
X
X (see Note)
Please refer to Section 9.2 and Appendix 3 for further 
details regarding the collection and follow-up of 
AEs/SAEs (including AEs/SAEs associated with SARS-
CoV-2-related infection) following study treatment 
discontinuation.
All AEs/SAEs are to be graded and managed per NCI
CTCAE v5. 
Only for participants with Stage IIB/C melanoma 
(Nivolumab or Placebo-blinded portion):
After FU2, participants continue in-person assessment 
approximately every 12 weeks for an additional 12 
months (12 months calculated from FU2) b.
SAEs
X
X
Laboratory Tests 
X
X 
For Follow-up Visit 1 (FU1), onsite/local labs to include 
hematology and chemistry testing. See Section 9.4.4 for 
panel requirements. Repeat at Follow-up Visit 2 if study 
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Table 2-3:
Long-Term Follow-Up CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedure
Follow-up
Visit 1a
Follow-up
Visit 2a
After 
Follow-up 
Visit 2 
Notes
treatment-related toxicity persists, or as clinically 
indicated.
Laboratory toxicities (eg, suspected drug induced liver 
enzyme elevations) will be monitored during the follow-
up phase, based on results from on-site/local labs, until 
all study drug related toxicities resolve, return to 
baseline, or are deemed irreversible.
Pregnancy Test
X
X
Serum or urine.b Pregnancy testing is only required at 
FU1 and FU2, unless increased frequency and duration 
is required per local regulations.
Review of Concomitant Medication
X
X
Long-term use of corticosteroids and other immune-
modulating medications will be reported.b
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Table 2-3:
Long-Term Follow-Up CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedure
Follow-up
Visit 1a
Follow-up
Visit 2a
After 
Follow-up 
Visit 2 
Notes
Efficacy Assessments
Body Imaging
See note
Contrast-enhanced (CE) CT of the chest, CE CT/MRI of 
the abdomen/pelvis, and all other known and/or 
suspected sites of disease. Imaging of extremities for 
resected melanomas located in the extremities is not a 
requirement and may be conducted per local standard of 
care. Extremity imaging should be conducted in the 
event of a suspected locoregional relapse that is not 
clinically unequivocal.
For participants with Stage IIB/C melanoma (Nivo 
or Placebo blinded portion):
•
Years 1, 2, and 3: Every 26 weeks (± 14 days)
•
Years 4 and 5: Every 52 weeks (± 28 days)
•
Participants who develop a loco-regional recurrence 
only, must be followed by surveillance imaging 
until the development of distant metastases.
•
If a participant starts systemic anti-cancer therapy 
for melanoma recurrence after study drug 
discontinuation, other than optional open-label on-
protocol nivolumab systemic therapy, or for a new 
non-melanoma tumor, follow-up scans can be done 
as per local standard of care. 
For optional open-label nivolumab treatment after 
first recurrence: 
ARM 1 (Resectable Disease)d
Participants enrolled with recurrent Stage III/IV 
resected disease
•
Years 1, 2, and 3: Every 12 weeks (± 7 days)
•
Years 4 and 5: Every 26 weeks (± 14 days)c
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Table 2-3:
Long-Term Follow-Up CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedure
Follow-up
Visit 1a
Follow-up
Visit 2a
After 
Follow-up 
Visit 2 
Notes
ARM 2 (Unresectable/Metastatic Disease)e
Every 12 weeks (± 7 days) until disease progression, or 
treatment discontinuation, whichever occurs later.
Brain Imaging
MRI (brain CT allowable if MRI is 
contraindicated) of the brain without and 
with contrast, as clinically indicated. See 
Section 9.1.1.
Survival status
Survival status
X
X
X
Every 12 weeks (± 14 days) from FU2 until the OS final 
analysis.e
May be accomplished by visit or phone contact, to 
include subsequent anti-cancer therapy.
BMS may request that survival data be collected on all 
treated participants outside of the 12-week window. At 
the time of this request each participant will be 
contacted to determine their survival status unless the 
participant has withdrawn consent for all contact.
Pharmacokinetic and Immunogenicity Samples
PK and Immunogenicity 
Details regarding specific sample timing are specified in Table 9.5-1.
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Table 2-3:
Long-Term Follow-Up CA20976K (Applies to All Participants: Blinded or Open-label Treatment)
Procedure
Follow-up
Visit 1a
Follow-up
Visit 2a
After 
Follow-up 
Visit 2 
Notes
Label Arm 1: resectable disease)/progression (Open-
Label Arm 2: unresectable/metastatic disease)
recurrence/progression (either surgery or biopsy) is 
strongly recommended for all participants except when 
risk of procedure to obtain such material is too high or 
not feasible. Refer to Section 9.8.2
Biopsy of affected organs
Upon occurrence of ≥ Grade 3 drug-
related AE and/or lab abnormalities 
regarded as a drug- related SAE
Optional
Abbreviations: AE, adverse event; BMS, Bristol-Myers Squibb; CR, complete response ; CT, computed tomography; 
 
 
FU1, Follow-Up Visit 1; FU2, Follow-Up Visit 2; MRI, magnetic resonance imaging; NCI 
CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events version 5; OS, overall survival; PK, pharmacokinetics; PR, partial 
response; SAE, serious adverse event; 
; SD, stable disease.
a Participants must be followed for at least 100 days after the last dose of study treatment. FU1  should occur 30 days from the last dose (± 7 days) or can be 
performed on the date of discontinuation if that date is greater than 37 days from the last dose. FU2 occurs approximately 100 days (± 7 days) from the last dose 
of study treatment. Both follow-up visits should be conducted in person. 
b If a participant on the placebo arm experiences recurrence, and opts to receive open-label nivolumab monotherapy (Arm 1 or 2), participants may or may not 
have completed the two follow-up visits (FU1 and FU2) on blinded treatment. Assessments from FU1 and FU2, if conducted, may contribute to satisfying 
screening/Cycle 1 Day 1 requirements prior to treatment assignment (please check Screening Schedule of Activities requirements). If the participant (nivolumab-
or placebo-treated) does not opt to receive open-label nivolumab treatment, the assessments/assessment frequency described in this table apply. For optional 
open-label nivolumab treatment after first recurrence, visits after FU2, may be accomplished by visit (eg, examination, laboratory tests) OR by phone 
contact.
c Timing is calculated from the date of the first dose of blinded study treatment, or open-label nivolumab treatment, whichever is applicable. 
 
 
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d Efficacy Assessments (Arm 1: Resectable disease): If a participant starts systemic therapy for melanoma recurrence or for a new non-melanoma cancer after 
study drug discontinuation, follow-up scans can be done as per standard of care. Participants who did not have Stage IV resected disease on entry in the open-
label treatment portion of the trial who develop a loco-regional recurrence only and have not initiated subsequent anticancer systemic therapy, must be followed 
by surveillance imaging until the development of distant metastases.
e Efficacy Assessments (Arm 2: Unresectable/Metastatic disease): For responders (CR, PR or SD) who received open-label nivolumab and remain on study 
beyond 2 years, an extension of the frequency of scans from every 12 weeks to every 26 weeks (± 14 days) until disease progression is permitted. Participants 
who discontinue study therapy for reasons other than progression should continue to be scanned until progression is documented. Note: All imaging activities 
will continue until Year 5 (Year 5 is calculated from first dose of open-label on-protocol nivolumab study treatment). 
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3
INTRODUCTION
3.1
Study Rationale
3.1.1
Overview
CA20976K is a Phase 3, randomized, double-blind study designed to evaluate the use of adjuvant 
immunotherapy with nivolumab versus placebo after complete resection of Stage IIB/C melanoma 
in adults and pediatric participants ≥12 years old. 
In this study, participants with resected Stage IIB/C melanoma and no evidence of disease will be 
randomized to treatment with either nivolumab or placebo for a duration of 12 months. Results 
from this study will help to define the role of nivolumab as an adjuvant immunotherapy in patients 
with resected Stage IIB and IIC cutaneous melanoma. In the event of disease recurrence, 
participants will have the option to receive on-study open-label nivolumab treatment. Placebo-
treated participants who experience disease recurrence within 3 years after the last dose of placebo, 
and nivolumab-treated participants who experience recurrence greater than 6 months and within 3 
years after completing treatment, will be eligible to participate in on study unblinded /open-label 
nivolumab treatment. Participants with resectable / recurrent disease will be offered nivolumab for 
a maximum duration of 12 months, whereas participants with unresectable or metastatic disease 
will be offered nivolumab monotherapy for a maximum of 24 months. Participants with disease 
recurrence who do not participate in the optional open-label nivolumab treatment portion of the 
study will be treated per standard of care as recommended by their treating physician. 
3.1.2
Research Hypothesis
Treatment with systemically administered nivolumab when compared to placebo will result in 
greater efficacy as measured by recurrence-free survival (RFS) and overall survival (OS) in 
participants with completely resected Stage IIB/C melanoma with no evidence of disease (NED).
3.2
Background
Melanoma accounts for less than 5% of all skin cancers; however, it causes the greatest number of 
skin cancer–related deaths worldwide.0F1 Because earlier stage disease is prevalent, most deaths 
from melanoma occur in individuals who are initially diagnosed with low-thickness melanoma 
and not with advanced-stage disease, underscoring the importance of intervention in the early 
adjuvant (Stage I/II) setting.1F2 Despite patients with early stage disease contributing the largest 
population to melanoma-specific mortality under the current treatment guidelines, these patients 
represent a population less likely to be treated in the early adjuvant setting. 
In the United States, it is estimated that approximately 11,000 patients will be diagnosed with 
Stage II melanoma in 2019 half of whom will be diagnosed with Stage IIB/C melanoma. 
Worldwide (excluding the United States), approximately 44,000 patients will be diagnosed with 
Stage II disease in 2019, of which more than 50% are expected to be Stage IIB/C disease.2F3
Moreover, unlike other solid tumors, melanoma mostly affects young and middle-aged individuals 
(median age at diagnosis, 57 years).3F4 Between 1 to 4 percent of all melanomas occur in patients 
younger than 20 years of age.4F5,
5F6
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In contrast to patients who present with localized disease and primary tumors 1.0 mm or less, 
wherein a 5-year survival rate is achieved in more than 90% of patients, the 5-year survival rates 
for patients with localized melanomas more than 1.0 mm in thickness (T2-T4) range from 50% to 
90% depending on tumor thickness, ulceration, and mitotic rate. The likelihood of regional nodal 
involvement upon relapse, increases with tumor thickness as well as the presence of ulceration and 
high mitotic rate. 
Patients diagnosed with Stage IIB/C disease have thicker melanomas (> 2.0 mm). These patients 
have an unmet clinical need as there is no clear safe and effective systemic adjuvant therapy to 
prevent disease relapse once the primary tumor has been completely resected, which is the current 
standard of care for these patients. Approximately, 15% to 20% of patients diagnosed with 
Stage IIB and 30% of patients diagnosed with Stage IIC melanoma will have a relapse of their 
melanoma at 24 months.6F7 Within 5 years of surgical resection, approximately 25% of patients with 
Stage IIB disease and 40% of patients with Stage IIC disease will have a relapse of their disease.7F8
A SEER Registry review conducted by Landow et al. (2016) revealed that 7.4% (95% CI: 7.2-7.7) 
of patients diagnosed with invasive melanoma limited to the skin died within 10 years of 
diagnosis.8F9 Relapse of disease portends a poor prognosis. Long-term survival in patients, once 
distant metastatic melanoma develops, has been less than 10%9,
9F10 or around 22% at 5-years from 
diagnosis.8
A greater understanding of the role of tumor burden as a modulating factor in the efficacy of 
anti-melanoma therapy is important. It is apparent that treatments for melanoma have greater odds 
of efficacy in patients with a smaller, more-limited disease burden. This has been observed with 
regional therapies (talimogene laherparepvic, isolated limb infusion or perfusion), targeted 
therapies (dabrafenib + trametinib, vemurafenib) and with immunotherapies (pembrolizumab, 
ipilimumab, nivolumab). Specifically, for anti-PD-1 immunotherapy, it has been reported that the 
ratio of T-cell invigoration to tumor burden may be associated with anti–PD-1 response.10F11,
11F12
The introduction of therapies earlier in the course of the disease, when the tumor burden is much 
lower, to eradicate undetectable minimal residual disease prior to developing metastasis, therefore, 
has the potential for greatly increasing the chance of cure and substantially influencing melanoma-
specific mortality. To extend the potential benefit of immunotherapy in the adjuvant setting to 
pediatric patients, pediatric patients diagnosed with Stage IIB/C melanoma ≥12 year old will also 
be included in this trial.
3.2.1
Pediatric Melanoma
Pediatric melanoma, a rare cancer, is usually defined as melanoma occurring in patients younger 
than 20 years, representing approximately 1 to 4 percent of all melanomas.5,6 Melanoma is the 
second-most-common adult-type cancer in this age group (after thyroid cancer). Melanoma is rarer 
in younger children, with estimated annual incidence rates of one, two, three, and ten per million 
in the age groups 1 to 4, 5 to 9, 10 to 14, and 15 to 19, respectively.8 The number of Stage IIB/C 
melanoma cases (at least one case) estimated in 2019 in patients less than 20 years of age by 
country, is displayed in the table below (Table 3.2.1-1).12F13
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Table 3.2.1-1:
Estimated Number of Melanoma Cases in Patients Less than 20 
years of Age by Country
Country
Estimated number of melanoma cases (males and females) in 2019
Argentina
4
Australia
4
Belgium
1
Brazil
41
Canada
1
Chile
2
China - Rural
74
China - Urban
2
Colombia
7
Denmark
1
Egypt
1
France
4
Germany
7
Greece
1
India - Rural
1
Indonesia
1
Italy
7
Japan
2
Mexico
7
Netherlands
2
Nigeria
7
Portugal
2
Russia
9
South Africa
1
Spain
6
Sweden
1
Switzerland
1
Taiwan
2
Turkey
5
United Kingdom
4
United States
16
Venezuela
3
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Melanomas in children frequently are diagnosed as having thicker Breslow depths than in adults.13F14
Children less than 10 years old are more likely to present with a higher stage disease, which may 
in part be due to delayed diagnosis of children with melanoma.14F15 Similar to adult melanoma, tumor 
thickness, ulceration, lymph node status, and stage are found to be significant predictors of survival 
in patients with pediatric melanoma.15F16 Despite the increasing incidence of melanoma in children 
and adolescents, there remains a paucity of research on this population. Currently, the management 
of pediatric and adolescent melanoma is based primarily on well-established practice guidelines 
used for adult patients. Additional studies are needed to evaluate outcomes as they relate to 
treatment and disease presentation in preadolescents and adolescents.5
3.2.2
The Adjuvant Treatment of Patients with Stage IIB/C Melanoma with 
Nivolumab is a Promising Strategy
At present, wide surgical excision of the primary melanoma with an offer to perform a sentinel 
lymph node biopsy is standard of care for patients with clinical Stage II melanoma of all substages. 
Patients who have a positive sentinel lymph node are upstaged to Stage III and can undergo either 
surveillance of the nodal basin with ultrasound or complete lymph node dissection. Per current 
guidelines, patients with node positive disease may be offered adjuvant nivolumab, 
pembrolizumab, or dabrafenib/trametinib (BRAF V600 activating mutation) or observation. 
Current treatment recommendations for patients with a negative sentinel lymph node (such as the 
CA20976K study population) or for patients in whom a sentinel lymph node biopsy was not 
conducted for any reason, is observation with periodic surveillance to detect disease recurrence, 
or treatment with high-dose interferon. For melanomas measuring more than 2 mm in thickness, 
which would include patients diagnosed with Stage IIB and IIC, the evaluation of the sentinel 
lymph node for disease involvement and a wide excision of the primary melanoma with 2-cm 
margins is highly recommended.10,14
There is an unmet need for adjuvant therapy in patients with earlier stage melanoma, such as Stage 
IIB and IIC. These patients do not have evidence of macroscopic or clinically detectable metastases 
but are at high risk of recurrence, which speaks to the presence of clinically occult metastases. 
Given the toxicity and limited efficacy of currently available adjuvant therapies such as high-dose 
interferon-alfa for early stage melanoma, most guidelines recommend observation for patients with 
Stage IIB and IIC melanoma who have had a wide excision of their melanomas and a negative 
sentinel lymph node biopsy.
The goal of adjuvant therapy is to cure patients with the lowest burden of disease 
(ie, micrometastatic disease after complete surgical resection). The mechanistic rationale for 
adjuvant therapy is that invasive and motile tumor cells enter circulation before the tumor is 
diagnosed. The disseminated tumor cells are not eradicated by the surgical removal of the primary 
tumor or the regional lymph nodes and may survive for years in a dormant state or as subclinical 
micrometastases in distant organs. After months or years of dormancy, some tumor cells may 
resume proliferation and form clinically detectable macrometastases.16F17,
17F18 The proven efficacy of 
immunotherapies (anti-CTLA-4 and anti-PD-1 agents) in the treatment of unresectable/metastatic 
melanoma and in the adjuvant Stage III melanoma setting, make such agents a natural choice to 
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study in patients diagnosed with Stage IIB/C melanoma, where the burden of disease is relatively 
low. 
3.2.2.1
Harnessing the Success of Immunotherapy in Patients with Late Stage 
Melanoma to Patients with Stage IIB/C Melanoma
As discussed above, the efficacy and acceptable safety profile of checkpoint-inhibitors in patients 
with more advanced melanoma make these agents a suitable choice to study in the earlier stage 
melanoma setting. The data obtained with these agents in later stage melanoma, is presented below 
and support the study of immunotherapies in Stage IIB/C melanoma. The efficacy and safety of 
checkpoint inhibitors and the experience with other types of systemic therapies is also briefly 
described. As therapies in the treatment of melanoma were first introduced in more advanced 
disease settings prior to being studied in earlier stage disease, the data will be presented 
accordingly, starting with the data from trials in unresectable/metastatic melanoma, followed by 
data from the Stage III and Stage II adjuvant melanoma setting. When available, the efficacy of 
these systemic therapies in relation to the tumor burden is also described. Collectively, these data 
form the basis for studying nivolumab in the earlier stages of melanoma on the current trial.
Unresectable/Metastatic Melanoma
An examination of immunotherapy and other trials for unresectable or metastatic melanoma points 
to the potential value of treating patients with a lower tumor burden. Until the approval of 
ipilimumab as an effective immunotherapy in 2011 by the United States Food and Drug 
Administration (US FDA), dacarbazine, an alkylating agent, was the standard of care due to the 
ineffectiveness of other single agents or combination therapies in improving the OS of 
patients.10,
18F19 Dacarbazine was approved by the FDA in 1974 after clinical trials reported a 
complete response rate in < 5% and 5-year survival in 2% to 6% of patients. 
Since the earliest report in the 19th-century that cancer and the immune system were interlinked, 
based on the fact that tumors were frequently observed at sites of chronic inflammation, as well as 
the presence of immune cells in tumor tissues, efforts were made to harness immunotherapy as a 
promising treatment option for advanced melanoma. High-dose IL-2, a cytokine capable of 
expanding effector T-cells (Teffs) and regulatory T-cells (Tregs) was approved by the US FDA in 
1998 to treat metastatic melanoma in first-line and second-line settings. Although response rates 
are modest (< 20%) with this agent, patients with a complete response (< 10%) tend to have 
extremely durable responses and high rates of long-term survival (> 5 years).19F20,
20F21,
21F22 Although 
durable effects of immunotherapy were observed with IL-2 immunotherapy, high-dose IL-2 is 
associated with significant toxicities, and its use is restricted to institutions with medical staff 
experienced in the administration and management of these regimens. 
To further bolster the immune response, studies combining chemotherapy and immunotherapy 
(biochemotherapy) were conducted on the basis that cytotoxic chemotherapy could stimulate the 
immune response via release of tumor antigens through chemotherapy induced cell lysis. Although 
a higher response rate and an improvement in PFS was noted with biochemotherapy over CVD 
alone, an improvement in OS was not observed22F23 and biochemotherapy therapy was associated 
with severe toxicity.
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The search for more efficacious and safer immunotherapy approaches was revolutionized by the 
discovery of inhibitors of the inhibitory immune checkpoint receptor, cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4). CTLA-4 blocks T-cell activation and induces immune tolerance. 
Ipilimumab, an anti-CTLA-4 antibody, blocks the inhibitory effect, enhancing pro-inflammatory 
T-cell cytokine production, and increasing clonal T-cell expansion and infiltration in responding 
tumors. Ipilimumab was approved by the US FDA for the treatment of advanced melanoma in 
2011.23F24 Results from 2 Phase 3 pivotal trials in Stage III/IV unresectable/metastatic melanoma 
supported the use of ipilimumab in previously treated (CA184002) and previously untreated 
(CA184024) metastatic melanoma. CA184002 randomly assigned patients to ipilimumab, gp100 
peptide vaccine or ipilimumab plus gp100 peptide vaccine. CA184024 randomly assigned patients 
to dacarbazine plus ipilimumab or ipilimumab plus placebo. Results from these trials showed that 
ipilimumab was associated with improved response rates, response duration, PFS and OS, 24F25,
25F26
with long-term survival in approximately 20% of patients on the ipilimumab arm.26F27 High rates of 
Grade 3-4 AEs were observed in these trials, which utilized a higher dose of ipilimumab 
(10 mg/kg) and in combination with dacarbazine. Currently, ipilimumab is administered at 3 
mg/kg in the unresectable/metastatic melanoma setting, and not in combination with dacarbazine. 
The relationship of melanoma tumor burden to PFS and OS in an immunotherapy trial was 
demonstrated by Nishino et al (2014) in a Phase 1 trial of ipilimumab in combination with 
bevacizumab. The authors reported that patients with a median tumor diameter less than 38 mm 
had better median PFS and OS compared to patients with a median diameter of greater than 38 
mm. (PFS of 27.5 months vs. 4.1 months; OS: Not reached vs. 12.6 months). The risk of 
progression and death increased by 14% and 18%, respectively, with every 5 mm increase in 
baseline diameter. The study underscores the importance of treating the disease when the tumor 
burden is much lower, which may be the case in earlier state diagnosis.27F28
Following the approval of ipilimumab, nivolumab, an anti-PD-1 monoclonal antibody, was 
approved by the United States FDA in 2014 for the treatment of patients with metastatic melanoma. 
The PD-1 receptor binds to PD-L1 and PD-L2, and acts as a T-cell co-inhibitory molecule, 
suppressing T-cell activation. Two Phase 3 clinical trials (CA209066 and CA209067) 
demonstrated the efficacy of nivolumab in previously untreated unresectable Stage III or IV 
melanoma. CA209066 was a randomized double-blind trial of nivolumab versus dacarbazine, 
where nivolumab demonstrated a significantly higher response rate (40% vs 14%), PFS (5.1 vs 
2.2 months), and 1-year OS rate (73% vs. 42%).28F29 CA209067 was a randomized double-blind trial 
where patients were assigned to nivolumab plus ipilimumab, nivolumab or ipilimumab. Response 
rates of 57%, 44% and 19% were observed in the nivolumab plus ipilimumab arm, nivolumab arm, 
and ipilimumab arm respectively. Median PFS was 11·5 months (95% CI 8.7−19.3) in the 
nivolumab plus ipilimumab group, 6.9 months (5.1−10.2) in the nivolumab group, and 2.9 months 
(2.8−3.2) in the ipilimumab group. At a minimum follow-up of 48 months, median OS was not 
reached (95% CI: 38.2−not reached) in the nivolumab plus ipilimumab group, 36·9 months 
(28·3−not reached) in the nivolumab group, and 19·9 months (16.9−24.6) in the ipilimumab 
group.29F30,
30F31 The potential benefit of treating with immunotherapy at a point that there is a lower 
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tumor burden is suggested by subgroup analyses of this trial demonstrating increasingly higher 
3-year PFS as well as OS rates, with decreasing tumor burden (from > 97 mm to ≤31 mm), both 
in the nivolumab as well as nivolumab plus ipilimumab arms.30
Similarly, pembrolizumab monotherapy, another anti-PD-1 agent, has been shown to improve 
response and PFS compared to chemotherapy (KEYNOTE-002) or ipilimumab monotherapy 
(KEYNOTE-006) in unresectable Stage III or IV melanoma.31F32,
32F33 As noted with nivolumab, 
several authors have reported better efficacy outcomes with lower tumor burden with the use of 
pembrolizumab. Complete responses were noted in patients who had significantly smaller 
metastases (< 5 cm) or baseline sum of lesion diameters < 10.2 cm (median). Huang et al (2017)
reported that the anti-PD-1 response may be associated with the ratio of T-cell invigoration to 
tumor burden. 11 The authors studied pre- and post-peripheral blood samples from 29 patients with 
Stage IV melanoma receiving pembrolizumab. The researchers noted that the ratio of exhausted 
CD8+ T cell phenotype to tumor burden distinguished clinical outcomes and predicted response. 
Therefore, the authors concluded that having T-cell invigoration was not adequate by itself; rather, 
it was the relative balance between the tumor burden and T-cell invigoration that contributed to 
response. This finding again suggests that better outcomes with anti-PD-1 agents may be achieved 
early during the course of the disease when the tumor burden is low.11
The growing interest in immunotherapy as a modality to treat metastatic melanoma became evident 
when the oncolytic virus, talimogene laherparepvic (T-VEC), a genetically modified 
nonpathogenic herpes simplex virus type 1 was approved by the FDA in 2015, in patients with 
refractory Stage IV or unresectable Stage III melanomas.33F34 The virus after injection into a 
metastatic melanoma lesion, enters into both normal and malignant cells. The virus replicates in 
the melanoma cells, leading to tumor cell lysis and the release of tumor-specific antigens, which 
are recognized by antigen presenting cells, activating melanoma-specific T-cell responses.19 In this 
study, 40% of patients had a complete response following T-VEC treatment, and patients with 
tumor burden less than the median (14.5 cm2) had significantly improved durable and overall 
response rates, as well as improved OS.34F35
Other than immunotherapies, targeted therapies inhibiting either BRAF (intracellular signaling 
kinase in the MAPK pathway) or MEK (downstream target of BRAF) have been approved as 
monotherapies in unresectable/metastatic melanoma but will not be discussed in detail here. 
Interestingly, as seen above with the immunotherapies, disease burden was also seen to play an 
important role in predicting response to combination BRAF-MEK inhibition in advanced 
melanoma. A pooled analysis of Phase 3 dabrafenib plus trametinib trials conducted by 
Schadendorf et al. (2017) showed that lower tumor burden, as characterized by normal LDH levels, 
less than three metastatic organ sites, and a sum of lesion diameters less than 66 mm identified the 
best prognostic group of those receiving combination therapy, with a 3-year PFS rate of 42%.35F36
The durable responses seen with immunotherapies in the advanced melanoma setting led to the 
further investigation of these agents in the adjuvant melanoma setting. In addition, the observation 
of increased efficacy in subgroups with a lower tumor burden is particularly important in an 
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adjuvant setting, when tumor burden is at a microscopic level where immunotherapy may provide 
the greatest opportunity for cure.
Adjuvant melanoma (Stage III/IV resected)
A number of controlled trials with adjuvant cytotoxic chemotherapy in patients diagnosed with 
Stage II and III melanoma did not demonstrate any therapeutic advantage; therefore adjuvant 
systemic chemotherapy is not indicated in melanoma.14,
36F37 As a result, efforts have been focused 
on other adjuvant systemic treatment modalities such as immunotherapy with interferons (IFNs), 
targeted therapies, and checkpoint inhibitors, with most of the experience in the Stage III adjuvant 
setting. Systemic therapies that have had a notable influence in the Stage III adjuvant setting, and 
that could potentially be of value in earlier Stage IIB/C melanoma due to their established efficacy 
are briefly discussed below. 
The earliest investigations with immunotherapies in adjuvant melanoma started with IFNs, 
cytokines secreted by leukocytes that play an important role in the immunomodulatory, 
antiangiogenic, antiproliferative, and antitumor activities. High-dose IFN α-2b was approved by 
the US FDA and in Europe in 1996 as an adjuvant therapy for the treatment of resected Stage 
IIB/III melanoma based on results of the ECOG 1684, a trial that showed a benefit on RFS and 
OS.37F38 Although the hazard ratio for RFS was maintained at a median follow-up of 12.6 years, the 
continued benefit with OS was not maintained.38F39 Adjuvant PEG-IFN was approved by the US 
FDA in 2011 for the treatment of patients with resected Stage III melanoma (EORTC 18991) based 
on a favorable RFS (HR = 0.82, P = 0.01) seen at a median follow-up of 3.8 years.39F40 The toxicity 
profile of high-dose IFN spurred the study of low to intermediate dose IFNs. While improvement 
in relapse-free survival was noted in a few prospective randomized trials, no improvement in OS 
was demonstrated. As such, high-dose IFN with a planned duration of up to a year or pegylated-
interferon with a planned duration of up to 5 years, is an option for patients with completely 
resected Stage III disease. As very few patients with completely resected in-transit disease were 
included in these IFN trials, guidelines do allow for the use of IFN in this patient population, but 
with a weaker recommendation. 40F41
Similar to research in the unresectable and metastatic melanoma setting, an attempt was made to 
improve upon the efficacy of immunotherapy by combining with chemotherapy in the adjuvant 
melanoma setting. The SWOG S0008 trial established the role of biochemotherapy in completely 
resected Stage III melanoma except for Stage IIIA-N1a (non-ulcerated primary tumor with 
micrometastases in one sentinel lymph node).
41F42 An improved median RFS of 4.0 years was noted 
in the biochemotherapy arm (cisplatin, vinblastine and dacarbazine, plus interleukin-2 and 
interferon) versus 1.9 years in the high-dose interferon-alfa-2b arm after a median follow-up of 
7.2 years. There was no significant difference in the median OS as well as the 5-year OS rate 
between the 2 groups. 
Based on the efficacy of ipilimumab in metastatic melanoma, a Phase 3 double-blind randomized 
multicenter trial, EORTC 18071 (CA209029) was designed. The trial compared adjuvant high-
dose ipilimumab (10 mg/kg) to placebo in patients with completely resected Stage III melanoma 
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(Stage IIIA disease [if N1a, at least one metastases > 1 mm] or with Stage IIIB-C disease but no 
in-transit metastases). The ipilimumab arm demonstrated an improvement in RFS (HR = 0.75, 
P = 0.013) versus placebo at a median follow-up of 2.74 years, resulting in approval by the US 
FDA in 2015.
42F43 The benefit in RFS was maintained at a median follow-up of 5.3 years (HR = 0.76, 
P < 0.001). In addition, a benefit in OS was also observed (HR = 0.72, P = 0.001).43F44 As a result, 
ipilimumab became a standard therapy in Stage III adjuvant melanoma.
Following the success of nivolumab in metastatic melanoma, and on the basis of a more favorable 
safety profile than ipilimumab, nivolumab 3 mg/kg every 2 weeks for 1 year was studied in a 
Phase 3 randomized, double-blind, multicenter international trial (CA209238) in completely 
resected Stage IIIB/C and Stage IV participants. Ipilimumab, the active comparator was dosed at 
10 mg/kg every 3 weeks for four doses, followed by dosing every 12 weeks, for a maximum of 
one year. With a minimum follow-up of 18 months, nivolumab demonstrated a statistically 
significant and clinically meaningful improvement in RFS (HR = 0.65, P < 0.001) and distant 
metastases-free survival (DMFS) (HR = 0.73) versus ipilimumab; the observed separation of the 
RFS and DMFS curves was maintained over 24 months.44F45,
45F46 Notably, the activity of nivolumab 
was observed regardless of BRAF mutation status. Nivolumab received US FDA and European 
Medicines Agency approval in December 2017 and July 2018, respectively, for resected Stage III 
and IV melanoma. Similarly, a Phase 3 trial (KEYNOTE -054) in Stage III resected patients was 
conducted with pembrolizumab 200 mg every 3 weeks for a maximum of one year versus placebo. 
The active therapy arm was associated with significantly longer RFS. 46F47 As with nivolumab, the 
benefit of treatment with pembrolizumab was observed regardless of BRAF mutation status. The 
safety profile of the anti-PD-1 agents was generally consistent with the safety profile observed 
with these agents in the metastatic setting. Due to the superior efficacy and favorable adverse event 
profile of nivolumab and pembrolizumab, these agents have become the preferred immunotherapy 
in Stage III completely resected patients.41
In addition to immunotherapies, modern combination targeted therapies such as BRAF-MEK 
inhibitors have also been evaluated as adjuvant treatments in Stage III melanoma on the basis of 
their efficacy in the advanced melanoma setting. The combination of dabrafenib plus trametinib 
was approved by the US FDA and the European Commission as adjuvant therapy for patients with 
completely resected BRAF V600E/K–mutant Stage III melanoma based on the RFS benefit to this 
combination seen in the Phase 3 COMBI-AD trial. Subgroup analysis of RFS demonstrated similar 
treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, 
and ulceration.47F48
From the above discussion, the concept of moving immunotherapies from a more advanced setting 
where their efficacy has been well established, into a setting of occult or microscopic residual 
disease is well supported by the documented safety and efficacy data of these agents in the adjuvant 
setting. The efficacy of anti-PD-1 agents in the adjuvant setting was demonstrated independent of 
BRAF mutation status. These data support the study of checkpoint inhibitors in Stage IIB/C 
melanomas, where there exists compelling unmet clinical need. 
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Adjuvant Melanoma (Stage II)
As discussed earlier, for patients presenting with Stage IIB/C melanoma, the general 
recommendation, globally, is to perform a wide local excision with a 2 cm margin and offer a 
sentinel lymph node biopsy to detect regional lymph node involvement, followed by observation 
for recurrence of melanoma. Adjuvant therapies were generally not recommended for these 
participants, other than immunotherapies with interferons. Stage IIB/C melanomas are considered 
high-risk melanomas due to their relatively higher tumor thicknesses (2 mm to > 4 mm), and the 
presence of ulceration, all recognized high-risk features. Systemic therapies studied in the adjuvant 
Stage II setting will be briefly described below.
In recognition of the risk of recurrence, the NCCN 2018 guidelines (but not the 2019 guidelines) 
included the option of offering high-dose interferon-alfa (IFN-α), a category 2B recommendation, 
to patients diagnosed with Stage IIB/C melanoma.10 In addition, adjuvant IFN is offered in some 
European countries for high-risk resected Stage II or III melanoma on the basis of reduction in 
RFS, but has not been universally adopted because of the small OS benefit and the significant 
toxicity.14 A RFS benefit to INF-α was seen in ECOG 1690, a trial that compared high and 
low-dose adjuvant INF-α in patients diagnosed with Stage IIB/III melanoma.48F49 The RFS benefit 
[hazard ratio (HR) = 0.75, P = 0.035] and a trend towards improved OS (HR = 0.72, P = 0.059) 
seen in a French trial conducted in patients with Stage II melanomas thicker than 1.5 mm, and 
clinically undetectable node metastases, formed the basis for approval of low-dose INF-α in 
Europe.49F50 Although efficacy in RFS, and in some cases OS, has been observed with INF-α, the 
toxicity profile is substantial, especially, at high doses, greatly limiting its use in this early stage 
patient population.42,47,
50F51,
51F52
Based on the success of BRAF-targeted therapy in more advanced settings, BRAF-targeted therapy 
has been studied in fully resected Stage IIC BRAF-mutated melanoma. The BRIM-8 trial was a 
Phase 3, double-blind, randomized, placebo controlled study that compared adjuvant vemurafenib 
monotherapy versus placebo in resected Stage IIC patients, pooled with patients with resected 
Stage III disease, designated as cohort 1.52F53 A separate cohort of Stage IIIC patients, designated as 
cohort 2 was also enrolled. In cohort 1 (patients with Stage IIC–IIIA–IIIB disease), after a median 
follow-up of 30.8 months, median disease-free survival was not reached (95% CI not estimable) 
in the vemurafenib group versus 36·9 months (21.4–not estimable) in the placebo group (HR 0.54 
[95% CI 0.37–0.78]; log-rank P = 0·0010); however, the result was not significant because of the 
pre-specified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to 
show a significant disease-free survival benefit. 
In addition to the clinical benefits gained by curing localized melanoma, curing patients early of 
melanoma may also be very desirable to decrease direct melanoma-related costs, which tend to be 
higher as the disease advances. Buja et al (2018) built a highly detailed decision-making model to 
estimate the direct melanoma-related costs by disease stage and by phase of diagnosis and 
treatment according to clinical guidelines. The mean per-patient cost of the whole melanoma 
pathway (including one year of follow-up) ranged from €149 for stage 0 disease to €66,950 for 
Stage IV disease. The cost for Stage IIB and IIC participants was estimated to be €5,009 and 
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€5,989 respectively. This cost doubles to €10,210 once a patient develops Stage III disease, and 
increases almost 12 times to €66,950 for a patient who develops Stage IV disease.53F54 Given the fact 
that durable responses have been observed in more advanced settings with anti-CTLA-4 and anti-
PD-1 immunotherapies, successful treatment of patients in Stage IIB/C melanoma may also 
translate to a positive socioeconomic impact. 
Due to the success of checkpoint-inhibitors in metastatic melanomas as well as in Stage III 
adjuvant melanomas, these agents are now being evaluated in the treatment of patients with 
completely resected Stage IIB/C melanoma. Pembrolizumab, 200 mg every 3 weeks, for a 
maximum of 1 year of therapy is being evaluated in patients with completely resected Stage IIB/C 
melanoma who have a negative sentinel lymph node biopsy, in a double-blind, randomized, 
international trial (KEYNOTE -716, NCT03553836). As observation is the generally accepted 
standard of care in this setting, the comparator arm is a placebo, and patients are randomized in a 
1:1 ratio. A single arm Phase 2 trial in the same study population, using nivolumab, is also currently 
enrolling (NCT03405155). Other clinical trials with immunotherapies such as peptide vaccines 
(NCT03617328) are also being conducted in earlier phases that include resected Stage II 
participants, underscoring the belief that immunotherapies could be more effective when 
introduced earlier in the course of the disease.
In conclusion, there is an unmet need for effective adjuvant therapies in adult and pediatric patients 
with Stage IIB/C melanoma. The robust clinical activity of adjuvant nivolumab in participants 
with more advanced melanoma and the potential for increased benefit in patients with lower burden 
of disease warrant the further investigation of nivolumab in this population. We hypothesize that 
adjuvant treatment with nivolumab has the potential to significantly impact clinical outcomes such 
as RFS, DMFS, and OS in patients diagnosed with Stage IIB/C melanoma.
3.2.3
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend on acquisition of traits that allow cancer cells to evade 
immunosurveillance and escape effective innate and adaptive immune responses.45,46,
54F55 Current 
immunotherapy efforts attempt to break the apparent tolerance of the immune system to tumor 
cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).55F56 Collectively, these signals govern 
the balance between T-cell activation and tolerance.
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, ICOS, and BTLA.56F57 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T-cell activation, and expansion of previously activated cells. Evidence for a 
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negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.57F58 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the binding 
of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds specifically to PD-1 
and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a cytomegalovirus 
(CMV) re stimulation assay with human peripheral blood mononuclear cells (PBMC), the effect 
of nivolumab on antigen specific recall response indicates that nivolumab augmented IFN-γ 
secretion from CMV specific memory T-cells in a dose-dependent manner versus isotype-matched 
control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor 
immune response and results in tumor rejection in several immunocompetent mouse tumor models 
(MC38, SA1/N, and PAN02).58F59
3.3
Benefit/Risk Assessment
Stage IIB/C, localized, resected melanoma represents a population of high unmet need due to the 
potential for locoregional, nodal or systemic relapse, which dramatically impacts post-recurrence 
survival, especially in the case of systemic relapses. The 5-year survival of patients dramatically 
drops from 98.4% for localized disease to 63.6% for disease that has spread regionally, and to 
22.5% for distant metastatic disease.8 The current recommended standard of care for patients 
diagnosed with Stage IIB/C melanoma is observation. Even though interferon-alfa, which has been 
shown to improve disease-free survival and OS in a small subset of patients, and could be used as 
an adjuvant treatment in Stage IIC patients, the toxicity profile precludes most physicians from 
using the agent as adjuvant treatment in this patient population. In fact, the most recent version of 
the NCCN guidelines (Jan 2019) does not recommend interferon-alfa in resected Stage IIB and IIC 
patients. 41
Anti-PD1 antibodies such as nivolumab and pembrolizumab have demonstrated activity in the 
metastatic setting, as well as in resected Stage III/IV (nivolumab) and Stage III (pembrolizumab) 
melanoma. Nivolumab has been shown to have an acceptable safety profile, described in detail in 
the current Investigator Brochure (IB) for nivolumab. A pattern of immune-related AEs has been 
defined, for which management algorithms have been developed; these are provided in Appendix 
5. Most high-grade events were manageable with the use of corticosteroids or hormone 
replacement therapy (endocrinopathies) as instructed in these algorithms. Additional details on the 
safety profile of nivolumab, including results from other clinical studies, are also available in the 
nivolumab Investigator Brochure (IB).
This study to investigate adjuvant treatment after a complete surgical resection of Stage IIB and 
IIC melanoma allows the enrollment of minors who are 12 years and older. There is no predicted 
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higher risk for toxicity for these pediatric patients, who are often seen by medical oncologists for 
cancer care versus pediatric oncologists given divergent expertise amongst these specialties. 
The robust clinical activity demonstrated by nivolumab in participants with advanced melanoma, 
the manageable safety profile, and the lack of standard of care for participants who are at high risk 
for recurrence after a complete surgical resection of Stage IIB and IIC melanoma supports the 
further development of nivolumab in this population of participants.
It is the hypothesis of the trial that there will be improvements in RFS and OS in patients who have 
complete resections but are at high risk for recurrence of their melanoma. Since the median age of 
patients diagnosed with melanoma with localized disease is younger than that of other cancer 
patients, an improvement in RFS and OS is certainly meaningful, with the potential for years of 
improved quality of life and productivity, which on balance outweighs the risks of nivolumab 
treatment.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpointsa
Objectives
Endpoints
Primary
To compare the efficacy, as measured by recurrence-
free survival (RFS), provided by nivolumab 
monotherapy versus placebo in participants with 
completely resected Stage IIB/C melanoma with no 
evidence of disease who are at high risk for 
recurrence.
RFS
Secondary
To compare the overall survival (OS) provided by 
nivolumab monotherapy versus placebo in 
participants with completely resected Stage IIB/C 
melanoma with no evidence of disease, who are at 
high risk for recurrence.
OS
To assess safety and toxicity of nivolumab 
monotherapy in participants with completely resected 
Stage IIB/C melanoma with no evidence of disease.
Occurrence and severity of AEs as defined by NCI 
CTCAE v5.
To evaluate distant metastases-free survival (DMFS)
DMFS
To evaluate investigator-assessed outcomes on next-
line therapies.
•
Objective response rates (if applicable)
•
Duration of treatment on next-line therapies
•
Progression-free survival through next-line therapy
(PFS2) is defined as the time from randomization to  
recurrence/objective disease progression after the 
start of the next-line of systemic anti-cancer therapy, 
or to the start of a second next-line systemic therapy,
or to 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 
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Table 4-1:
Objectives and Endpointsa
Objectives
Endpoints
treatment, second objective disease progression, or 
death from any cause, whichever occurs first.
Exploratory
To characterize the pharmacokinetics (PK) and 
explore exposure-response relationships with respect 
to safety and efficacy.
PK parameters and exposure metrics calculated from 
serum concentration-time data and characterization of 
exposure-response relationships
To characterize the immunogenicity of nivolumab.
Detection of anti-nivolumab antibodies
Abbreviations: AE, adverse events;
 
 
 
 
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 NCI CTCAE, National Cancer Institute Common Terminology for Adverse Events; OS, overall survival; 
 PFS2, progression-free survival through next-line therapy; PK, 
pharmacokinetics; 
 
a Objectives and endpoints for participants entering the optional open-label nivolumab are very similar to blinded 
nivolumab/placebo participants with some subtle differences in endpoints to account for the open-label non-
randomized nature of treatment and for participants presenting with recurrent unresectable/metastatic disease in the 
event of recurrence. 
 
5
STUDY DESIGN
5.1
Overall Design
Please refer to the Study Rationale Section (Section 3.1.1) for an overview of the study design. 
The study design schematic is presented in Figure 5.1-1:
Figure 5.1-1:
Study Design Schematic (Applicable to Adult and Pediatric 
Participants ≥ 12 years old)
Abbreviations: IV, intravenous; Nivo, nivolumab; Q4W, every 4 weeks; SLN, sentinel lymph node; WLE, wide local 
excision.
a Pediatric dosing weight-based under 40 kg and for sites preferring weight-based dosing in pediatrics
b Tumor material obtained from surgery or biopsy
c Recurrence > 6 months after completion of 1 year of nivolumab treatment
d After recurrence, participant assigned to placebo arm will be offered to cross-over to nivolumab
e Resectable disease (Arm 1): Nivo 480 mg IV Q4W for 12 months
Unresectable disease (Arm 2): Nivo 480 mg IV Q4W for 24 months
5.1.1
Nivolumab or Placebo Blinded Treatment 
The Nivolumab or Placebo Blinded portion will consist of: screening, treatment, and follow-up, 
outlined below. For a complete list of study required procedures, please refer to Section 2
(Schedule of Activities) and Section 9 (Study Assessment and Procedures).
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Screening:
•
Establish participant’s initial (pre-screen) eligibility, sign informed consent form (ICF). 
Record any hereditary risk factors for melanoma, if available, in the participant’s medical 
history. Pay special attention to the skin and nodal examination.
•
Register participant for screening using the IRT.
•
Assess for complete study eligibility within the required timeframe found in Table 2-1.
•
Ship tumor tissue as specified in Section 6.1 (Inclusion Criteria) and Section 9.8.2 (Tissue 
Specimens) to the central laboratory prior to randomization. Confirmation from central 
laboratory on receipt of Screening tumor tissue is not required for randomization in the IRT. 
•
WOCBP: Document negative pregnancy test within 24 hours prior to first study treatment.
•
Submit screening/baseline imaging to the radiology vendor. Participant management/study 
enrollment is based on the investigator’s assessment of disease-free status.
•
Laboratory and other tests may be repeated as needed. Eligibility is assessed by most current 
result prior to randomization (see Section 6.1).
Treatment:
•
Following eligibility confirmation, participant will be randomly assigned (2:1), within IRT, to 
either nivolumab (Arm A) or placebo (Arm B).
•
On-study laboratory assessments: Draw within 72 hours prior to dosing. WOCBP: Pregnancy 
test every cycle prior to dosing.
•
Physical examination: Within 72 hours prior to dosing. Pay special attention to skin and nodal 
examination.
•
Within 3 calendar days (72 hours) from randomization, participant must receive the first dose 
of study medication. 
•
•
Adverse event assessments: Document at each clinic visit.
•
PK, immunogenicity, 
 
Collect per Table 9.5-1,
•
Tumor surveillance assessments: Every 26 weeks (± 14 days), starting from the first dose of 
study treatment, throughout the 12 months of treatment. No central imaging assessments are 
planned; submit scans to a central imaging vendor for holding.
Treatment Arms and Treatment Duration Details
All participants on nivolumab or placebo will be treated until recurrence, unacceptable toxicity, 
participant withdrawal of consent, or a maximum of 12 months from first dose of study treatment, 
whichever occurs first. Dosing details for the randomized blinded treatment are provided below.
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•
Arm A (Nivolumab):
−
Adult Dosing:
♦Nivolumab 480 mg IV flat dose over approximately 30 minutes every 4 weeks (Q4W).
−
Pediatric Dosing:
♦12-17 years of age and weighing ≥40 kgs: Nivolumab 480 mg IV Q4W.
♦12-17 years of age and weighing < 40 kgs: 6 mg/kg Q4W up to a maximum of 240 mg.
♦For centers that do not prefer to use flat dosing: 6 mg/kg Q4W (maximum of 240 mg
for weight < 40 kgs; maximum of 480 mg for weight ≥40 kgs).
♦All nivolumab infusions to be administered over approximately 30 minutes.
•
Arm B: Adults and Pediatrics: Nivolumab matched placebo (0.9% Sodium Chloride for
Injection/5% Dextrose for Injection) IV over approximately 30 minutes Q4W.
Follow-Up:
•
Begins after 12 months of treatment or when the decision is made to discontinue a participant
from study therapy.
Safety Assessments
•
Two in-person follow-up safety assessment visits, 30 days (FU1) and 100 days (FU2) after the
last dose of study treatment.
•
Following Visits 1 and 2, conduct additional in-person safety assessments approximately every
12 weeks for 12 months (1 year). These assessments can be conducted along with the additional
physical examinations described below in the section “Monitoring for Disease Recurrence”.
Please refer to the Schedule of Activities, Table 2-3 for additional details regarding safety
follow-up after discontinuation of study treatment.
Monitoring for Disease Recurrence
•
After Follow-up visit 2: Participants will visit the clinic for a physical examination
approximately every 12 weeks for 12 months (1 year), with special attention to skin and nodal
examination. For participants initiating subsequent systemic anti-cancer therapy for a
melanoma recurrence, other than receiving optional open-label nivolumab in this study, or for
a new non-melanoma cancer, follow-up assessments can be done per local standard of care.
•
Tumor surveillance assessments: Every 26 weeks ± 14 days during the first, second and third
year; every 52 weeks ± 28 days from 36 months to 60 months (all timepoints relative to first
dose). Participants who develop a loco-regional recurrence only, must be followed by
surveillance imaging until the development of distant metastases. Note: If a participant starts
systemic therapy for melanoma recurrence after study drug discontinuation, other than optional
open-label nivolumab, or for a new non-melanoma cancer, follow-up scans can be done as per
standard of care.
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 PK, 
•
PK/immunogenicity samples: See Table 9.5-1.
Survival Status Follow-Up (in-person or by telephone)
•
Every 12 weeks (± 14 days) following the second follow-up visit, calculated from first dose of 
study treatment until the OS final analysis. 
In the event of disease recurrence
•
Treatment unblinding will occur if knowledge of the treatment assignment is necessary to 
determine subsequent systemic anti-cancer therapy (including participation in the optional 
open-label nivolumab treatment). Please refer to Section 7.3.1 (Unblinding: emergency, 
Accidental, and In the Event of Disease Recurrence) for details regarding unblinding.
•
Participants agreeing to optional open-label nivolumab treatment: Follow assessments 
described in detail in Section 2 (Schedule of Activities). 
•
Participants opting to not participate in open-label nivolumab treatment: Treat per 
investigator’s choice; continue to follow the Schedule of Activities (Table 2-3).
•
Submit biopsy tissue at recurrence and de-identified pathology reports of biopsies confirming 
recurrence to the central vendor.
5.1.2
Optional On-Protocol Open-Label Nivolumab Treatment After First 
Recurrence
In the event of disease recurrence, participants on the blinded nivolumab or placebo portion will 
be offered the option to receive open-label on-protocol nivolumab treatment. The primary 
objective of the overall study is to compare the RFS of nivolumab versus placebo. The inclusion 
of open-label nivolumab provides an opportunity for patients entering the randomized blinded 
study to gain access to nivolumab, if clinically indicated, in the event of recurrence. 
The optional nivolumab treatment portion of the study will consist of screening, treatment, and 
follow-up. Key study elements are outlined briefly below. For a comprehensive list of study 
required procedures, please refer to Section 2 (Schedule of Activities) and Section 9.1 (Study 
Assessment and Procedures).
Screening:
•
Participants sign a separate optional informed consent form (ICF). For all other screening 
requirements, please refer to the Schedule of Activities table (Table 2-1) and eligibility criteria 
(Section 6).
•
Submit images to central imaging vendor. Participant management/study enrollment is based 
on the investigator’s assessment of disease status.
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•
After meeting all eligibility criteria, participant is assigned to the appropriate arm for open-
label nivolumab using the IRT.
Treatment:
For safety, efficacy, 
 PK, immunogenicity 
 assessments required 
during treatment, please refer to the Schedule of Activities table (Table 2-2).
•
Submit images to central imaging vendor. Participant management during treatment is based 
on the investigator’s assessment of disease recurrence/progression.
•
Within 3 calendar days (72 hours) of assignment to open-label treatment with nivolumab, the 
participant must receive the first dose of study medication (Day 1 of Cycle 1). 
Treatment Arms and Duration:
•
Participants will be treated until recurrence/progression, unacceptable toxicity, participant 
withdrawal of consent, or for a maximum of 12 months (Arm 1: resectable disease) or 24 
months (Arm 2: unresectable/metastatic disease) from the first dose of open-label study 
treatment, whichever occurs first. Dosing details for nivolumab are as described in Section 5.1
under “Treatment”.
Follow-Up of Participants Receiving Open-Label Nivolumab 
•
Begins after 1 year (12 months) of treatment for Arm 1 participants and after 2 years (24 
months) of treatment or when the decision is made to discontinue a participant from study 
therapy.
Monitoring for Disease Recurrence/Progression
•
Submit scans to central imaging vendor. Tumor surveillance assessments per Schedule of 
Activities (Table 2-3).
•
Submit de-identified pathology reports of biopsies confirming recurrence/progression to the 
central vendor. 
Safety Assessments, 
 PK, Immunogenicity, 
 and 
Survival Status Follow-Up
•
Please refer to Schedule of Activities (Table 2-3). 
5.1.3
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 CA20976K. Additionally, the DMC will provide advice to the 
sponsor regarding actions the committee deems necessary for the continuing protection of 
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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 both blinded treatment, and in the optional 
open-label nivolumab treatment after first recurrence portion of the trial. 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.
A Study Steering Committee (SSC), consisting of Investigators and personnel members 
representing the Sponsor of the study, will be established to obtain scientific guidance and advice 
for the protocol and conduct of the study. Details of the SSC responsibilities and procedures will 
be specified in the SSC charter.
5.2
Number of Participants
Approximately 
 participants diagnosed with Stage IIB/C melanoma that has been completely 
resected and who have no evidence of disease will be randomized (2:1) to nivolumab monotherapy 
or placebo.
5.3
End of Study Definition
The start of the trial is defined as first patient first visit. End of trial/study is defined as the 
completion of the the last visit or scheduled procedure shown in the SCHEDULE OF ACTIVITIES
for the last participant, or the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same. Additional information regarding post-study treatment 
follow-up can be found in Section 8.1.1.
5.4
Scientific Rationale for Study Design
CA20976K (CA20976K: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 76K) is 
a Phase 3 randomized, double blind study of nivolumab monotherapy versus placebo in 
participants with completely resected Stage IIB and IIC melanoma with no evidence of disease. 
The current standard of care for patients presenting with Stage IIB/C is a wide local excision 
followed by a sentinel lymph node biopsy. Following surgery, observation is the current gold 
standard. Interferon-alfa is the only adjuvant therapy that is offered as a possible treatment option 
in this patient population due to benefit seen in relapse/disease-free survival, with an unclear 
benefit in OS. Given the unexceptional benefit and high toxicity profile in a patient population that 
is free of disease, it is controversial whether interferon can be considered standard of care for Stage 
IIB/C melanoma. As a result, most patients are generally observed until recurrence of disease, at 
which point subsequent treatment is initiated depending on the site and extent of the recurrence. A 
placebo infusion was therefore chosen as the comparator arm on this trial.
Nivolumab (OPDIVO®) as a single agent was chosen as the active arm as it has demonstrated 
clinical benefit in participants with unresectable or metastatic melanoma, as well as in Stage III 
and IV resected melanoma. It has been approved for use in multiple countries, including the US 
and EU, and has been approved for several other indications (eg, metastatic NSCLC, advanced 
RCC, cHL). There is a reasonable expectation that nivolumab may be effective in resected Stage 
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IIB/C melanoma based on the demonstrated effectiveness of nivolumab first proven in 
unresectable/metastatic melanoma and subsequently as an adjuvant therapy in Stage III/IV 
completely resected melanoma.
Based on nivolumab’s efficacy in more advanced melanoma settings (Stage III/IV adjuvant and 
Stage III/IV unresectable/metastatic), the 2:1 randomization provides an opportunity to offer this 
therapy to more Stage IIB/C patients who have a prognosis similar to Stage IIIB patients (per 
American Joint Committee on Cancer [AJCC] 8th edition). Direct evidence of nivolumab’s benefit 
in this setting, while previously limited, is evolving,59F60 and we hypothesize that participants 
assigned to the nivolumab arm may derive greater benefit versus participants in the placebo arm. 
The 2:1 randomization facilitates gaining additional experience, including additional safety data 
on nivolumab, to characterize and better inform the risk-benefit profile in this earlier Stage IIB/C 
melanoma study population, in which observation following wide local excision and negative 
sentinel lymph node involvement for melanoma is the generally accepted current standard of care.
 
5.4.1
Rationale for Treatment with Blinded Nivolumab
There is currently an unmet medical need for effective adjuvant therapies for patients diagnosed 
with Stage IIB and IIC cutaneous melanoma. Results from this study will help to define the role 
of nivolumab as an adjuvant immunotherapy in patients with Stage IIB and IIC cutaneous 
melanoma. 
Cutaneous malignant melanomas are staged according to the AJCC (see Appendix 1 for List of 
Abbreviations) tumor/node/metastasis (TNM) classification and staging system. The AJCC 8th 
edition tumor staging for patients presenting with Stage II cutaneous malignant melanomas is 
shown below.60F61
When T is…
And N is…
And M is….
The pathological Stage 
is….
T2b/T3a
N0
M0
IIA
T3b/T4a
N0
M0
IIB
T4b
N0
M0
IIC
T2: >1.0–2.0 mm; T3: >2.0–4.0 mm; T4: >4.0 mm; a: without ulceration; b: with ulceration; N0: No regional 
metastases detected; M0: No evidence of distant metastasis
Stage IIB (T3b/T4a, N0, M0) and IIC (T4b, N0, M0) melanomas are classified as localized 
melanomas without nodal involvement but are a higher risk category compared to Stage I and IIA 
melanomas due to a relatively worse prognosis. Patients diagnosed with Stage IIB and IIC 
melanoma have 5-year melanoma-specific survival (MSS) reported as 87% and 82%, respectively. 
The corresponding 10-year survival rates have been reported as 82% and 75%, respectively. Initial 
relapses are reported most frequently as local/in-transit after resection of Stage IIB melanoma 
(47%), while systemic relapses are more frequent after resection of Stage IIC melanoma (52%).61
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Lung is the most frequent site of systemic relapse reported for both subtypes, with the second most 
frequent site being the liver for patients diagnosed with Stage IIB and brain for patients diagnosed 
with Stage IIC melanoma.61F62 Once disease recurs, the site of initial relapse is the primary 
determinant of post-recurrence survival. Patients with systemic relapses have historically had a 5-
year survival rate of 7% followed by 22, 33 and 57% for nodal, in-transit and local relapses 
respectively.
62F63 These poor prognoses in patients with both systemic and local relapse highlight 
the importance of controlling localized disease to prevent melanoma metastases.62
The rationale for adjuvant treatment for patients diagnosed with localized melanoma stems from 
the fact that most deaths from melanoma will occur in patients initially diagnosed with localized 
early stage disease without lymph node involvement.63F64 The relatively similar prognosis of patients 
with Stage IIB/C melanoma and patients with Stage IIIB melanoma (5-year MSS for Stage IIIB = 
83%), the poorer prognosis for these patients after relapse, underscore the need to prevent local or 
systemic relapses and provide support for the study of new systemic interventions to prevent 
metastases in the Stage IIB/C adjuvant melanoma setting.
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype monoclonal antibody (mAb) 
that binds programmed death-1 (PD-1) on activated immune cells and disrupts engagement of the 
receptor with its ligands programmed death-ligand 1 (PD-L1) (B7 H1/CD274) and programmed 
death-ligand 2 (PD-L2) (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting 
the host antitumor response. In clinical trials, nivolumab has demonstrated activity in several tumor 
types, including melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC).
Nivolumab, with or without ipilimumab, is approved in the United States (US), European Union, 
and other countries for multiple indications. Nivolumab, as a monotherapy, and in combination 
with ipilimumab, is approved in Stage III/IV unresectable/metastatic melanoma.64F65 Recently, 
nivolumab monotherapy has been approved as an adjuvant therapy in patients with completely 
resected Stage III and IV melanoma. The established safety and efficacy of nivolumab in patients 
with unresectable and metastatic melanoma, as well as in patients with resected Stage III 
melanoma, makes nivolumab an ideal candidate to study in patients with earlier Stage IIB/C 
melanoma, characterized by a lower disease burden, where immunotherapy may be more effective. 
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5.4.5
Rationale for Blinding (Nivolumab Versus Placebo)
The study will be double-blinded in order to minimize bias arising from differences in thresholds 
for classification of recurrence between the arms, which could subsequently affect treatment 
duration between the arms and have an impact on the primary endpoint of RFS. In addition, 
blinding will reduce bias in reporting, classification, and management of adverse events. 
Participants with recurrence who discontinue treatment may require knowledge of which treatment 
arm they were assigned to in order to appropriately select any post-recurrence subsequent therapy 
(including treatment of participants in the optional open-label nivolumab portion of the trial). 
Therefore, in the event of recurrence of disease and treatment discontinuation of each participant, 
the participant̓s treatment assignment will be unblinded via the Interactive Response 
Technology (IRT) to inform the appropriate subsequent treatment. 
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5.5
Justification for Dose
5.5.1
Rationale for 480 mg Flat Dose Every 4 Weeks
A nivolumab dose of 480 mg given every 4 weeks (Q4W) was selected for this study based on 
available PK, safety, and efficacy data. 
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Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, cHL, SCCHN, CRC, and urothelial carcinoma and has been safely administered at 
doses up to 10 mg/kg Q2W. Nivolumab monotherapy was originally approved as a body-weight 
based dose of 3 mg/kg Q2W, and was recently updated to 240 mg Q2W or 480 mg Q4W in multiple 
indications.100F101 Less frequent 480 mg Q4W dosing regimens can reduce the burden to patients of 
frequent, lengthy IV treatments and allow combination of nivolumab with other agents using 
alternative dosing regimens. 
The benefit-risk profiles of nivolumab 240 mg Q2W and 480 mg Q4W are predicted to be 
comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive characterization of 
nivolumab PK, safety, efficacy, and exposure-response relationships across indications. 
Population PK (PPK) analyses have shown that the PK of nivolumab is linear with proportional 
exposures over a dose range of 0.1 to 10 mg/kg; no clinically meaningful differences in PK across 
ethnicities and tumor types were observed. Using the PPK model, the exposures following 
administration of several dosing regimens of nivolumab administered as a flat dose were 
simulated, including 240 mg Q2W and 480 mg Q4W. The simulated average serum concentration
at steady state [Cavgss] following administration of nivolumab 480 mg Q4W are predicted to be 
similar to those following administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W 
administered to participants over a wide body weight range (34-180 kg) across tumor types. 
Extensive exposure-response (E-R) analyses of multiple PK measures (maximum serum 
concentration at Day 1[Cmax1], average serum concentration at Day 28 [Cavg28], and trough 
serum concentration at Day 28 [Cmin28]) and efficacy and safety endpoints indicated that the 
efficacy of the flat-dose 480 mg IV regimen are similar to that of 3 mg/kg Q2W IV regimen. In 
E-R efficacy analyses for OS and ORR conducted in melanoma, RCC, and NSCLC using Cavg28 
as the exposure measure, probabilities of achieving a response and survival probabilities at 1 year 
and 2 years for IV 480 mg Q4W were similar to that of IV 3 mg/kg Q2W. In E-R safety analyses, 
it was demonstrated that the exposure margins for safety are maintained following nivolumab 480 
mg Q4W, and the predicted risks of discontinuations due to AEs or death, AE Grade 3+, and 
immune-mediated AEs (IMAEs) Grade 2+ are similar following nivolumab 480 mg Q4W relative 
to nivolumab 3 mg/kg Q2W across tumor types. In addition, nivolumab exposures with 240 mg 
Q2W and 480 mg Q4W flat-dose IV regimens across tumor types are maintained well below the 
corresponding exposures observed with the well-tolerated 10 mg/kg IV nivolumab Q2W dose 
regimen.
Additional details on nivolumab safety and risk-benefit can be found in the investigator brochure.
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5.5.3
Rationale for Nivolumab 30-Minute Infusion Duration
Nivolumab is currently approved using a 30-minute infusion as a monotherapy.64
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
6.1.1
Inclusion Criteria - Blinded Nivolumab or Placebo Treatment
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.
i)
For participants unable to give their written consent, in accordance with local 
regulations, one or both parents, a guardian, or a legally acceptable representative must 
be informed of the study procedures and must document permission by signing the ICF 
approved for the study prior to clinical study participation.
ii) For minors: Each participant must be informed about the nature of the study to the 
extent compatible with his or her understanding. Should a participant become capable 
or reach the age of majority, his or her consent should be obtained as soon as possible. 
The explicit wish of a participant who is a minor or is unable to provide his or her 
written consent but who is capable of forming an opinion and assessing information to 
refuse participation in or to be withdrawn from the clinical study at any time should be 
considered by the investigator.
iii) Minors who are judged to be of an age of reason as determined by local requirements 
should also give their assent. The assent should be documented based on local 
requirements. Continued assent should be documented when important new 
information becomes available that is relevant to the participant’s assent. 
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Participants must have been diagnosed with Stage IIB/C cutaneous melanoma (AJCC 
Staging, 8th edition; see Appendix 8) and have histologically confirmed melanoma that is 
completely surgically resected, with documented negative margins (per local standard) for 
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disease on resected specimens. All melanomas, except ocular/uveal and mucosal 
melanoma, regardless of primary site of disease will be allowed. Participants with Stage 
IIB/C melanoma who present with synchronous or metachronous Stage < 2 melanomas 
that have been completely resected will be allowed.
NOTE: A copy of the de-identified pathology report(s) confirming Stage IIB or IIC 
disease and negative margins on the resected specimen must be sent to the Central 
Laboratory vendor prior to randomization.
a) Complete resection with documented negative margins (per local standard) and sentinel 
lymph node assessment for presence/absence of disease, must be performed within 12 
weeks prior to randomization. Note: In case of delays exceeding 12 weeks due to 
unforeseen circumstances, the eligibility should be discussed with the Medical Monitor or 
designee.
b) Participants must have a negative sentinel lymph node biopsy. Participants in whom a 
sentinel lymph node biopsy procedure could not be done or a sentinel lymph node was not 
detected are not eligible. 
NOTE: A copy of the de-identified pathology report confirming sentinel lymph node 
negativity must be sent to the Central Laboratory vendor prior to randomization.
c) The pathology report for Stage IIB, IIC, and sentinel lymph node biopsy must be reviewed, 
and review documented by the investigator.
d) Participants must have disease-free status documented by a complete physical examination 
(within 14 days) and imaging studies within 4 weeks (28 days) prior to randomization. 
Imaging studies must include CT scans of the chest/abdomen/pelvis or CT scan of the chest 
and MRI scans of the abdomen and pelvis, and all known sites of resected disease (imaging 
of extremities for resected melanomas located in the extremities is not a requirement and 
may be conducted per local standard of care). Participants with signs and symptoms 
consistent with brain metastases should have imaging studies done to rule out the presence 
of brain metastases. 
i)
Participants with equivocal lymph nodes on imaging (≥ 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 (as listed 
above) should be available and showing no progressive and measurable (lymph nodes 
≥ 15 mm in short axis) disease or PET/CT demonstrating no FDG uptake. The second 
scan should occur at least 4 weeks after the initial scan. Participants with incidental 
findings (eg, indeterminate nodules noted on imaging) reported during screening may 
be eligible if confirmation of disease-free status can be documented by 
histology/cytology, imaging studies, or in certain situations by discussing with the 
Medical Monitor or designee. Note: Participants who have had a history of metastatic 
melanoma and have had their metastatic melanoma resected are not eligible. 
e) The complete set of baseline images must be available before randomization.
f)
Participant has not been previously treated for melanoma beyond complete surgical 
resection of the melanoma lesion.
g) Participant has recovered adequately from toxicity and/or complications from surgery prior 
to study start.
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h) ECOG performance status of 0 or 1 at the time of enrollment (Appendix 6)
i)
Tumor tissue from the primary diagnostic biopsy (minimum of 15 unstained slides, 
preferably freshly cut, or 1 FFPE block to contain sufficient tissue for at least 15 sections) 
must be shipped to the central laboratory prior to randomization (see Section 9.8.2 for 
details). If the required tumor tissue content cannot be provided, the eligibility should be 
discussed with the Medical Monitor or designee. 
j)
Participants must be able and willing to comply with the study visit schedule and study 
procedures.
3) Age and Reproductive Status
a) Males and Females, ≥12 years of age
i)
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
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment. An extension up to 72 hours prior to the start of study 
treatment is permissible in situations where results cannot be obtained within the standard 
24-hour window.
c) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) plus 5 half-
lives of study treatment plus 30 days (duration of ovulatory cycle) for a total of 5 months 
after the last dose of study treatment. 
4) NOTE: As per Protocol Amendment 02, nivolumab IB v19, male study participants will not 
be required to use contraceptive measures and/or a latex or other synthetic condom during 
sexual activity with a WOCBP partner. WOCBP who are continuously not heterosexually 
active are also exempt from contraceptive requirements, and still must undergo pregnancy 
testing as described in this section.
a) Not applicable as per Protocol Amendment 02. Males who are sexually active with 
WOCBP must agree to follow instructions for method(s) of contraception for a total of 7 
months post-treatment completion [ie, 90 days (duration of sperm turnover) plus the time 
required for study drug to undergo approximately five half-lives]. In addition, male 
participants must be willing to refrain from sperm donation during this time.
b) Not applicable as per Protocol Amendment 02. Azoospermic males are exempt from 
contraceptive requirements unless the potential exists for fetal toxicity due to study drug 
being present in seminal fluid, even if the participant has undergone a successful vasectomy 
or if the partner is pregnant. 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 on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy and when applicable, the potential of fetal toxicity 
occurring due to transmission of study drug to a developing fetus. Investigators shall advise on the 
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use of highly effective methods of contraception (Appendix 4), which have a failure rate of < 1% 
when used consistently and correctly.
6.1.2
Inclusion Criteria for Participants Receiving Treatment after Recurrence 
1) Signed Written Informed Consent
a) Participants must have signed and dated a separate IRB/IEC approved written informed 
consent form for open-label treatment with nivolumab monotherapy in accordance with 
regulatory and institutional guidelines. All other informed consent related details discussed 
in Section 6.1.1 for participants receiving blinded treatment apply to participants receiving 
treatment after recurrence. 
2) Type of Participant and Target Disease Characteristics
a) Participant must have been randomized, treated and have documented recurrence (per 
Section 9.1.2.1) of melanoma on blinded nivolumab or placebo treatment 
b) Recurrent disease must have been diagnosed within 3 years of last dose of blinded study. 
Participants assigned to blinded nivolumab treatment must have completed 1 year of 
therapy and have experienced disease recurrence more than 6 months following the last 
dose.
c) Participant must not have received any other systemic anticancer therapy (including 
investigational anticancer therapy) or loco-regional anticancer therapy (other than surgery 
for complete resection of the recurrence and radiation therapy administered with a 
palliative intent) between the last dose of blinded study treatment and the first dose of open-
label study treatment. 
NOTE: Prior adjuvant radiation therapy (RT) after neurosurgical resection for central 
nervous system (CNS) lesions or prior RT to CNS metastases is allowed.
d) Palliative/definitive radiotherapy, if administered, must have been completed at least 2 
weeks prior to study drug administration 
e) Arm 1 (resectable disease only): Complete documented resection of recurrent disease 
(preferably within 12 weeks prior to assignment to open-label treatment) with margins 
negative (per local standard) for disease. For CNS lesion(s), documentation indicating that 
there has been complete resection of CNS lesion(s) will suffice as confirmation of negative 
margins.
NOTE: A copy of the de-identified pathology report(s) confirming negative margins on 
the resected specimen must be sent to the Central Laboratory vendor prior to assignment 
to open-label treatment.
f)
Arm 1 (resectable disease only): Participants must have disease-free status documented by 
a complete physical examination and imaging studies within 4 weeks (28 days) prior to 
assignment to open-label treatment. See Table 2-1 (Screening Schedule of Activities) for 
imaging related details. 
g) Arm 2: (unresectable/metastatic disease only): Participants with brain metastases are 
eligible if brain metastases have been treated and there is no MRI evidence - except where 
contraindicated in which CT scan is acceptable of progression for at least 8 weeks after 
treatment is complete and within 28 days prior to first dose of open-label study drug 
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administration. Cases should be discussed with the Medical Monitor or designee. There 
must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 
10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
h) Participant has recovered adequately from toxicity and/or complications from prior blinded 
study treatment and surgery or palliative radiotherapy prior to assignment.
i)
ECOG performance status of 0 or 1 at the time of enrollment (Refer to Appendix 6)
j)
Tumor tissue from the recurrent site of disease per Section 9.8.2.
3) Age and Reproductive Status (All age and reproductive status related details discussed in 
Section 6.1.1 for participants receiving blinded therapy apply to participants opting to receive 
open-label nivolumab)
6.2
Exclusion Criteria 
6.2.1
Exclusion Criteria - Blinded Nivolumab or Placebo Treatment
1) Medical Conditions
a) History of ocular or mucosal melanoma.
b) 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.
c) 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.
d) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
e) Women who are pregnant or breastfeeding.
f)
Participants with serious or uncontrolled medical disorders. Additionally, in the case of 
prior SARS-CoV-2 infection, symptoms must have completely resolved and based on 
investigator assessment in consultation with the BMS Medical Monitor or designee, there 
are no sequelae that would place the participant at a higher risk of receiving investigational 
treatment.
2) Prior/Concomitant Therapy
a) Use of an investigational agent or an investigational device within 28 days before 
administration of first dose of study drug.
b) Treatment directed against the resected melanoma (eg, chemotherapy, radiation therapy, 
targeted agents, biotherapy, or limb perfusion) that is administered after the complete 
resection.
c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 
antibody, or agents that target IL-2 pathway any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways. Exception: Prior adjuvant 
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treatment with interferon (for melanoma other than study entry melanoma) is allowed if 
completed ≥ 6 months prior to randomization.
d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) 
to 
treat 
the 
disease 
under 
study 
within 
2 weeks 
prior 
to 
randomization/treatment. Such medications are permitted if they are used as supportive 
care. Refer to Section 7.7.1 for prohibited therapies.
e) Participants who have received a live / attenuated vaccine within 30 days of first treatment.
f)
The concomitant use of topical Toll-like receptor 7 (TLR7) agonists (eg, imiquimod), 
calcineurin inhibitors (eg, tacrolimus), or topical immunotherapy/contact sensitizer 
preparations, eg, but not limited to 2,4-dinitrochlorobenzene (DNCB), squaric acid 
dibutylester (SADBE), and diphencyprone (DPCP) at or near the primary tumor site, are
not specifically excluded, but consultation with the Medical Monitor or designee is highly 
recommended prior to enrolling participants using these agents.
g) Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol-specific 
washout period is achieved. If a study participant has received an investigational 
COVID-19 vaccine prior to Screening, enrollment must be delayed until the full dosing 
schedule of the vaccine has been completed and the biologic impact of the vaccine is 
stabilized, unless a delay would compromise the participant’s health or suitability for 
enrollment, as determined by discussion between the Investigator and the BMS Medical 
Monitor or designee.
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100×103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine > 1.5 x ULN, unless creatinine clearance ≥40 mL/min (measured or 
calculated using the Cockroft-Gault formula)
Female CrCl = [(140 - age in years) x weight in kg x 0.85] ÷ [72 x serum creatinine in
mg/dL]
Male CrCl = [(140 - age in years) x weight in kg x 1.00] ÷ [72 x serum creatinine in mg/dL]
f)
AST/ALT: > 3.0 x ULN 
g) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x 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) Known history of allergy or hypersensitivity to study drug components.
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b) Known history of severe hypersensitivity reaction (Grade ≥3) to any monoclonal antibody.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
6.2.2
Exclusion Criteria for Participants Receiving Treatment After 
Recurrence
1) Medical Conditions
a) Recurrent disease diagnosed greater than (>) 3 years after last dose of blinded study 
treatment.
b) Participants who experience a second recurrence or progression before enrollment into the 
open-label treatment portion of the trial.
NOTE: All other exclusion criteria described in Section 6.2.1 for participants receiving 
blinded study treatment apply to participants opting to receive open-label treatment after 
first recurrence. To address exclusion 2c, prior treatment with nivolumab, an anti-PD-1 
agent, due to participation in the blinded-treatment on this trial, is permitted. Prior adjuvant 
radiation therapy (RT) after neurosurgical resection for central nervous system (CNS) 
lesions or prior RT to CNS metastases is allowed.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized (blinded-treatment participants) or enrolled (open-label 
nivolumab treatment after first recurrence) in the study/included in the analysis population. 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, as applicable, and to respond to queries from regulatory authorities. 
Minimal information includes date of consent, demography, screen failure details, eligibility 
criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has not 
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been treated). If re-enrolled, the participant must be re-consented and assigned a new participant 
number from IRT.
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.
Laboratory parameters and/or assessments that are included in Section 2, 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.
Testing for asymptomatic COVID-19, for example, by reverse transcription polymerase chain 
reaction (RT-PCR) or viral antigen is not required. However, some participants may develop 
suspected or confirmed symptomatic COVID-19 infection or be discovered to have asymptomatic 
COVID-19 infection during the Screening period.103F104 In such cases, participants may be considered 
eligible for the study after meeting all inclusion/exclusion criteria related to serious or uncontrolled 
medical disorders, and after meeting the following criteria:
•
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result, and
•
At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and
•
Symptoms (eg, cough, shortness of breath) have resolved, and
•
In the opinion of the Investigator, there are no COVID-19 sequelae that may place the 
participant at a higher risk of receiving investigational treatment, and
•
Negative follow-up RT-PCR or viral antigen test for COVID-19 based on institutional, local, 
or regional guidelines
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 as 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.
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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.
The investigational products are nivolumab and 0.9% Sodium Chloride for Injection/5% Dextrose 
for Injection (Table 7-1). Solutions used as placebo (ie, 0.9% Sodium Chloride Injection or 5% 
Dextrose Injection) should also be sourced by investigative sites if available and permitted by local 
regulations.
Premedications or medications used to treat infusion-related reactions should be sourced by the 
investigative sites if available and permitted by local regulations. 
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Table 7-1:
Study Treatments for CA20976K
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IP
Blinded- or Open-
Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558 
(Nivolumab) Solution 
for Injection
10 mg/mL
IP
Open-labela
Vials
Refer to the label on 
container and/or 
Pharmacy Manual
0.9% Sodium Chloride 
for Injection
N/A
IP
Open-labela
Various (local 
commercial product)
As per package insert
5% Dextrose for 
Injection
N/A
IP
Open-labela
Various (local 
commercial product)
As per package insert
Abbreviations: IP, Investigational Product; Non-IP, Non-Investigational Product.
a The term “open-label” refers to the medication as it is upon receipt at the pharmacy. The blinded-treatment will be conducted in a double-blinded fashion.
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7.1
Treatments Administered
7.1.1
Treatment with Nivolumab or Placebo
Blinded Nivolumab/Placebo Treated Participants
Adult participants should receive nivolumab (or matching placebo) at a dose of 480 mg as an 
approximately 30-minute infusion on Day 1 of each treatment cycle until unacceptable toxicity, 
withdrawal of consent, completion of 12 months of treatment (from first dose of study treatment), 
disease recurrence, or the study ends, whichever occurs first. Participants should begin study 
treatment (Cycle 1) within 3 calendar days of randomization. Subsequent cycles could be initiated 
within ± 3 days of the target visit date. When the initiation of a subsequent cycle is delayed (eg, 
due to an AE in the preceding cycle), the target visit date of all future cycles should be calculated 
from the day the participant was actually administered the study treatment in the delayed 
subsequent cycle.
Pediatric participants (≥12 years old) who weigh ≥40 kg should receive nivolumab (or matching 
placebo) at a dose of 480 mg as an approximately 30-minute infusion on Day 1 of each treatment 
cycle every 4 weeks, until unacceptable toxicity, withdrawal of consent, completion of 12 months 
of treatment (from first dose of study treatment), disease recurrence, or the study ends, whichever 
occurs first. Participants should begin study treatment within 3 calendar days of randomization. 
The timing of initiation of subsequent cycles is the same as in adults.
For pediatric participants who weigh < 40 kg, nivolumab (or matching placebo) should be dosed 
at 6 mg/kg (maximum 240 mg, Q4W) as an approximately 30-minute infusion. 
Weight based dosing (6 mg/kg up to a maximum of 240 mg for participants weighing < 40 kgs 
and a maximum of 480 mg for participants weighing ≥40 kgs) can be used for centers that do not
prefer to dose nivolumab as a flat dose. 
Pediatric 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.
Open-Label Nivolumab Treatment 
Treatment details for adults and adolescent are as in Section 7.1.1 for blinded study treatment, 
except that the use of a matching placebo is not applicable to the open-label nivolumab portion of 
the trial. In addition, nivolumab 480 mg will be administered Day 1 of each treatment cycle until 
unacceptable toxicity, withdrawal of consent, completion of 12 months (Arm 1: resectable disease) 
or 24 months (Arm 2: unresectable/metastatic disease) of treatment (from first dose of open-label 
nivolumab), disease progression, or the study ends, whichever occurs first.
7.1.2
General Treatment Administration Considerations 
There will be no dose escalations or reductions of nivolumab allowed. Doses of nivolumab may 
be interrupted, delayed, or discontinued depending on how well the participant tolerates the 
treatment. Dosing visits are not skipped, only delayed. 
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For Q4W dosing cycles, participants may be dosed within a ± 3 day window. Premedications are 
not recommended for the first dose of nivolumab. Participants should be carefully monitored for 
infusion reactions during nivolumab administration. If an acute infusion reaction is noted, 
participants should be managed according to Section 7.4.2. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Please see the nivolumab IB and pharmacy manual for specific infusion preparation, and infusion 
set/infusion bag compatibility recommendations.
7.2
Method of Treatment Assignment
The exact procedures for using the IRT will be detailed in the IRT manual.
7.2.1
Blinded Nivolumab or Placebo Treatment
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study through IRT website to obtain the participant number. 
Every participant who signs the informed consent form must be assigned a participant number in 
IRT. Specific instructions for using IRT will be provided to the investigational site in a separate 
document. The investigator or designee will register the 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 (Year of birth, if local regulations do not allow use of entire date of birth)
•
Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through the IRT. The sponsor, participants, investigator, and site staff will be blinded 
to the study drug administered during the study. Each investigative site must assign an unblinded 
pharmacist/designee, and an unblinded site monitor will be assigned by sponsor to provide 
oversight of drug supply and other unblinded study documentation. The randomization call may 
be performed by the blinded study coordinator or another suitable individual designated by the 
investigator; a notification of the actual treatment assignment will be sent by the IRT to the 
unblinded pharmacy site staff. The following information is required for participant 
randomization:
•
Participant number
•
Date of birth (Year of birth, if local regulations do not allow use of entire date of birth)
•
Participants will be stratified by:
−AJCC T-Stage, 8th edition (T3b vs. T4a vs. T4b)
•
Participants will be treated with one of the following:
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−Arm A: nivolumab 480 mg IV Q4W (for a maximum of 12 months from first dose of study 
treatment)
♦Pediatric dosing as per Section 7.1.1
−Arm B: nivolumab matched placebo IV Q4W (for a maximum of 12 months from first dose 
of study treatment)
7.2.2
Optional Open-Label Nivolumab Treatment After First Recurrence
In the event of recurrence on blinded study treatment, participants may be eligible to receive 
open-label nivolumab monotherapy. The open-label nivolumab portion of the trial is comprised of 
two arms, without stratification or randomization. If participants agree to participate in the open-
label nivolumab portion of this trial, the participant’s treatment assignment in the randomized 
portion of the trial will be unblinded. Depending on the resectability of the recurrence (resectable 
versus not), as determined by the investigator/treating physician, participants will be assigned to 
either Arm 1 (resectable disease) or Arm 2 (unresectable/metastatic disease). The same participant 
ID assigned in the randomized, blinded portion of the trial will be carried forward in open-label 
nivolumab treatment phase.
Participants on Arm 1 and Arm 2 will be treated on a nivolumab regimen (480 mg IV Q4W) for a 
maximum of 12 and 24 months respectively. 
Please see Section 7.1.1 further treatment details, including dosing flexibility in pediatrics.
Participants who have received blinded study treatment, experiencing recurrence, but who do not 
wish to participate in the open-label nivolumab portion of the trial, can be treated per standard of 
care by the investigator/treating physician and will continue to be followed per follow-up 
procedures outlined in the Schedule of Activities (Section 2).
For participants receiving open-label nivolumab monotherapy after recurrence, the information 
collected by the IRT will be similar to that collected prior to randomization, minus the stratification 
information. 
7.3
Blinding 
This is a randomized double-blind trial. For the optional open-label nivolumab portion, each 
participant will be assigned to the specific arm (Arm 1 or Arm 2) using an Interactive Response 
Technology (IRT). Access to treatment codes will be restricted from all participants, and site and 
BMS personnel prior to database lock, with exception as specified below.
Designated staff of Bristol-Myers Squibb Research & Development may be unblinded (obtain the 
randomization codes) prior to database lock to facilitate the bioanalytical analysis of 
pharmacokinetic samples and immunogenicity. A bioanalytical scientist in the Bioanalytical 
Sciences department of Bristol-Myers Squibb Research & Development (or a designee in the 
external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples.
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7.3.1
Unblinding: Emergency, Accidental, and in the Event of Disease 
Recurrence
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 or designee, 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 or appointed designee should only call 
in for emergency unblinding AFTER the decision to unblind the participant has been documented.
For this study, the method of unblinding for emergency purposes is IRT.
In cases of accidental unblinding, contact the unblinded Clinical Trial Monitor and ensure every 
attempt is made to preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor or designee.
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Response Technology (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 or designee.
7.3.2
Unblinding in the Event of Disease Recurrence 
Unblinding participants in the event of disease recurrence is necessary for participants who opt to 
participate in the optional open-label nivolumab component. Unblinding may be requested for 
election of subsequent systemic therapy (other than participation in optional open-label 
nivolumab), if the investigator feels that the selection of subsequent systemic therapy may be 
influenced by knowledge of the treatment assignment.
At the time of recurrence, if the participant’s treatment assignment is required to assign the 
next-line systemic therapy, an unblinding request should be made by the site investigator/staff to 
the BMS site monitor or a member of the BMS study trial management team, who will gain 
approval from the Medical Monitor or designee to proceed with unblinding of the treatment arm. 
The BMS site monitor or a member of the BMS study trial management team will work with the 
site to unblind the treatment arm through the IRT. 
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7.4
Dosage 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
Criteria to Delay, Resume, or Discontinue Nivolumab or Nivolumab-
Placebo
Dose delay criteria apply for all study drug-related adverse events (AEs) regardless of whether or 
not the event is attributed to nivolumab or placebo given the blinded nature of this study. All study 
drugs must be delayed until treatment can resume. AEs will be reported and managed per National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE, 
v5). Please refer to Table 7.4.1-1 below for AE criteria to delay, resume, or discontinue nivolumab 
or nivolumab-placebo. For additional criteria not covered in Table 7.4.1-1, please refer to the 
following sections for additional details: Section 7.4.1.1 for dose delay, Section 7.4.1.2 for dose 
resumption, and Section 7.4.1.3 for discontinuation from study treatment.
Table 7.4.1-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Study 
Treatment
Drug-Related Adverse 
Event (AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
Gastrointestinal
Colitis or Diarrhea
Grade 2 or 3 
Delay dose
Dosing may resume when AE 
resolves to baseline 
Grade 4 
Permanently 
discontinue
Renal
Serum Creatinine Increased
Grade 2 or 3 
Delay dose
Dosing may resume when AE 
resolves to Grade ≤ 1 or baseline 
value
Grade 4 
Permanently 
discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after 
pneumonitis has resolved to Grade 
≤ 1.
Grade 3 or 4 
Permanently 
discontinue
Hepatic
Aspartate aminotransferase 
(AST), alanine 
aminotransferase (ALT), or 
total bilirubin (T.bili) 
increased
AST or ALT > 
3x and ≤ 5x 
upper limit of 
normal (ULN) 
or T.bili > 1.5x 
and ≤3x ULN, 
Delay dose
Dosing may resume when 
laboratory values return to baseline.
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Table 7.4.1-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Study 
Treatment
Drug-Related Adverse 
Event (AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
regardless of 
baseline value
AST or ALT > 
5x ULN or 
T.bili > 3x 
ULN, 
regardless of 
baseline value
Delay dose or 
permanently 
discontinue 
In most cases of AST or ALT > 5x 
ULN, study treatment will be 
permanently discontinued. If the 
investigator determines a possible 
favorable benefit/risk ratio that 
warrants continuation of study 
treatment, a discussion between the 
investigator and the Medical 
Monitor/ designee must occur and 
approval from Medical Monitor 
prior to resuming therapy.
Concurrent 
AST or ALT > 
3x ULN and 
T.bili > 2x 
ULN, 
regardless of 
baseline value
Permanently 
discontinue 
Endocrinopathy
Adrenal Insufficiency
Grade 2 
adrenal 
insufficiency
Delay dose
Dosing may resume after 
adequately controlled with hormone 
replacement.
Grade 3 or 4 
adrenal 
insufficiency or 
adrenal crisis
Delay dose or 
permanently 
discontinue
Mandatory discussion with and 
approval from the Medical Monitor 
needed prior to resuming therapy. If 
adrenal insufficiency resolves or is 
adequately controlled with 
physiologic hormone replacement, 
participant may not require 
discontinuation of study drug.
Hyperglycemia
Hyperglycemia 
requiring 
initiation or 
change in daily 
management 
(Grade 2 or 3)
Delay dose
Dosing may resume if 
hyperglycemia resolves to Grade ≤ 
1 or baseline value, or is adequately 
controlled with glucose-controlling 
agents.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and 
approval from the Medical Monitor 
needed prior to resuming therapy. If 
hyperglycemia resolves, or is 
adequately controlled with glucose-
controlling agents, participant may 
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Table 7.4.1-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Study 
Treatment
Drug-Related Adverse 
Event (AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
not require discontinuation of study 
drug.
Hypophysitis/Hypopituitarism 
Symptomatic 
Grade 1-3 that 
is also 
associated with 
corresponding 
abnormal lab 
and/or pituitary 
scan
Delay dose 
Dosing may resume if 
endocrinopathy resolves to be 
asymptomatic, or is adequately 
controlled with only physiologic 
hormone replacement.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and 
approval from the Medical Monitor 
needed prior to resuming therapy. If 
endocrinopathy resolves or is 
adequately controlled with 
physiologic hormone replacement, 
participant may not require 
discontinuation of study drug.
Hyperthyroidism or 
Hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if 
endocrinopathy resolves to be 
asymptomatic, or is adequately 
controlled with only physiologic 
hormone replacement or other 
medical management.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and 
approval from the Medical Monitor 
needed prior to resuming therapy. If 
endocrinopathy resolves or is 
adequately controlled with 
physiologic hormone replacement 
or other medical management, 
participant may not require 
discontinuation of study drug.
Skin
Rash
Grade 2 rash 
covering > 
30% body 
surface area or 
Grade 3 rash 
Delay dose 
Dosing may resume when rash 
reduces to ≤ 10% body surface area.
Suspected 
Stevens-
Johnson 
syndrome 
(SJS), toxic 
epidermal
necrolysis 
Delay dose
Dosing may resume if SJS, TEN, or 
DRESS is ruled out and rash 
reduces to ≤ 10% body surface area.
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Table 7.4.1-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Study 
Treatment
Drug-Related Adverse 
Event (AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
(TEN) or drug 
reaction with 
eosinophilia 
and systemic 
symptoms 
(DRESS)
Grade 4 rash or 
confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
Neurological
Guillain-Barre Syndrome 
(GBS)
Any Grade
Permanently 
discontinue
Myasthenia Gravis (MG)
Any Grade
Permanently 
discontinue
Encephalitis
Any Grade 
encephalitis
Delay dose 
After workup for differential 
diagnosis, (ie, infection, tumor-
related), if encephalitis is not drug 
related, then dosing may resume 
when AE resolves. 
Any Grade 
drug-related 
encephalitis 
Permanently 
discontinue
Myelitis
Any Grade 
myelitis
Delay dose
After workup for differential 
diagnosis, (ie, infection, tumor-
related), if myelitis is not drug 
related, then dosing may resume 
when AE resolves.
Any Grade 
drug-related 
myelitis
Permanently 
discontinue
Neurological (other than 
GBS, MG, encephalitis, or 
myelitis)
Grade 2
Delay dose
Dosing may resume when AE 
resolves to baseline.
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Myocarditis
Symptoms 
induced from 
mild to 
moderate 
activity or 
exertion
Delay dose
Dosing may resume after 
myocarditis has resolved.
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Table 7.4.1-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Study 
Treatment
Drug-Related Adverse 
Event (AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
Severe or life 
threatening, 
with symptoms 
at rest or with 
minimal 
activity or 
exertion, and/or 
where 
intervention 
indicated
Permanently 
discontinue
Other Clinical AE
Pancreatitis: 
Amylase or Lipase Increased
Grade 3 with 
symptoms
Delay dose
Note: Grade 3 increased amylase or 
lipase without signs or symptoms of 
pancreatitis does not require dose 
delay. 
Dosing may resume when patient 
becomes asymptomatic.
Grade 4
Permanently 
discontinue
Uveitis 
Grade 2 uveitis
Delay dose
Dosing may resume if uveitis 
responds to topical therapy (eye 
drops) and after uveitis resolves to 
Grade ≤ 1 or baseline. If patient 
requires oral steroids for uveitis, 
then permanently discontinue study 
drug. 
Grade 3 or 4 
uveitis
Permanently 
discontinue
Other Drug-Related AE (not 
listed above)
Grade 2 non-
skin AE, 
except fatigue
Delay dose
Dosing may resume when AE 
resolves to Grade ≤ 1 or baseline 
value.
Grade 3 AE -
First 
occurrence 
lasting ≤ 7 days
Delay dose
Dosing may resume when AE 
resolves to Grade ≤ 1 or baseline 
value.
Grade 3 AE -
First 
occurrence 
lasting > 7 days
Permanently 
discontinue
Recurrence of 
Grade 3 AE of 
any duration
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Study 
Treatment
Drug-Related Adverse 
Event (AE) per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
Grade 4 or life-
threatening 
adverse 
reaction
Permanently 
discontinue
Other Lab abnormalities 
Other Drug-Related lab 
abnormality (not listed above)
Grade 3
Delay dose
Exceptions:
No delay required for: Grade 3 
lymphopenia. 
Permanent discontinuation for: 
Grade 3 thrombocytopenia > 7 days 
or associated with bleeding. 
Grade 4
Permanently 
discontinue
Exceptions: The following events 
do not require discontinuation of 
study drug: 
•
Grade 4 neutropenia ≤ 7 days.
•
Grade 
4 
lymphopenia 
or 
leukopenia.
•
Grade 4 isolated electrolyte 
imbalances/abnormalities that 
are not associated with clinical 
sequelae and are responding to 
supplementation/appropriate 
management within 72 hours of 
their onset.
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions.)
Hypersensitivity Reaction or 
Infusion Reaction
Grade 3 or 4
Permanently 
discontinue
Refer to Section 7.4.2 on Treatment 
of Related Infusion Reactions. 
7.4.1.1
Additional Dose Delay Criteria/Details
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, warrants delaying the dose of study medication.
•
SARS-CoV-2 infection either confirmed or suspected.
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.
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7.4.1.2
Additional Dose Resumption Criteria/Details
•
Participants may resume treatment with study drug if they have completed AE management 
(ie, corticosteroid taper) or are on ≤ 10 mg prednisone or equivalent, and meet the requirements 
per Table 7.4.1-1. 
•
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume 
treatment after all of the following criteria are met:
•
Symptomatic Participants: At least 10 days (20 days for severe/critical illness) have passed 
since symptoms first appeared. Asymptomatic participants: At least 10 days have passed since 
positive test result (eg, RT-PCR or viral antigen).
•
Resolution of symptoms (including at least 24 hours has passed since last fever without fever-
reducing medications).
•
Evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment.
•
Consultation by the BMS Medical Monitor or designee. For suspected cases, treatment may 
also resume if SARS-CoV-2 infection is ruled-out and other criteria to resume treatment are 
met.
•
Prior to re-initiating on-study treatment in a participant with a dosing delay lasting > 8 weeks 
due to COVID-19, the BMS Medical Monitor or designee must be consulted (see Section 8.1).
•
If treatment is withheld > 8 weeks from the last dose, the participant must be permanently 
discontinued from study therapy, except as specified in Section 7.4.1.3.
7.4.1.3
Additional Dose Discontinuation Criteria/Details
•
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. 
−
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons (including due to COVID-19) may be allowed if approved by the BMS Medical 
Monitor or designee.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing, may require discontinuation.
•
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 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.
•
Study treatment should be discontinued for disease recurrence (local, regional, or distant). 
Please 
refer 
to 
Section 
7.8.1
for 
continuation 
of 
treatment 
beyond 
disease 
recurrence/progression exceptions.
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Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor or designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary, for participant safety). Refer to Section 9.2.5, Pregnancy. 
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.
Please refer to Section 8.1 for full details of dose discontinuation criteria not covered here.
7.4.2
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours as an SAE if criteria are met.
Treatment recommendations are provided below based on CTCAE v5 grading definitions and may 
be modified based on local treatment standards and guidelines, as appropriate: 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction; Therapy or infusion interruption indicated 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 infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
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symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. (Note: If the infusion rate cannot be safely 
increased to the original infusion rate, the reduced infusion rate of 50% of the original infusion 
rate, or a reduced rate as determined per local standard, can be adopted for future infusions). 
Monitor participant closely. If symptoms recur, then no further nivolumab 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 CRF.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab. If necessary, corticosteroids (up 
to 25 mg of IV hydrocortisone [SoluCortef] or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]. Grade 4: Life-threatening consequences; urgent intervention indicated).
•
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
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 the unblinded BMS Clinical Trial Monitor should be contacted 
immediately.
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Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
Please refer to the current version of the Investigator Brochure and/or pharmacy manual for 
complete preparation, storage, and handling information for nivolumab.
7.5.1
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability
Not applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability as well as the 
participant’s medical record and CRF. Study drug will be administered in the clinic by trained 
personnel. 
7.7
Concomitant Therapy
Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of non-live vaccines (including non-live COVID-19 vaccines) in 
participants receiving nivolumab is unknown.
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids > 10 mg daily prednisone equivalent 
(except as stated in Section 6.2- Exclusion Criteria) only until treatment discontinuation. See 
Section 7.7.4 for permitted corticosteroid therapy.
•
Any additional, concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive non-palliative radiation therapy, or standard or investigational 
agents for treatment of melanoma) outside of study treatment. Participants who develop a new 
non-melanoma fully resectable malignancy (examples include but are not limited to: in situ 
bladder cancer, in situ gastric cancer, or in situ colon cancers; in situ cervical cancers/dysplasia; 
or breast carcinoma in situ; or prostate carcinoma) during the study may continue receiving 
study drugs if the only therapy required is hormonal therapy, surgery and/or radiation (and the 
surgery or radiation site does not overlap with a previous primary melanoma or melanoma 
metastasis location). Consultation with the Medical Monitor or designee is required once a new 
malignancy is detected.
•
Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as 
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supportive care. Use of marijuana and its derivatives for treatment of symptoms related to 
cancer or cancer treatment are permitted if obtained by medical prescription or if its use (even 
without a medical prescription) has been legalized locally.
•
Consultation with the Medical Monitor or designee is required prior to the use of topical Toll-
like receptor 7 (TLR7) agonists (eg, imiquimod), calcineurin inhibitors (eg, tacrolimus), or 
topical immunotherapy/contact sensitizer preparations, eg, but not limited to 2,4-
dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphencyprone 
(DPCP) at or near the primary tumor site.
•
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
•
Participants may receive other medications that the investigator deems to be medically 
necessary.
•
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.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
greater than 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.
7.7.3
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen per imaging study. Imaging contraindications and contrast risks are to be considered in 
this assessment. Participants with renal insufficiency are to be assessed as to whether or not they 
should receive contrast and if so, which contrast agent and dose is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis, therefore MRI 
contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. This will be outlined in the image acquisition manual.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist,
the investigator, and standards set by the local Ethics Committee.
7.7.4
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted.
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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. 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.
7.8.1
Treatment Beyond Disease Progression
7.8.1.1
Participants Receiving Optional Open-Label Nivolumab with 
Unresectable/Metastatic Disease (Arm 2) 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of Progressive Disease (PD). Participants will be 
permitted to continue treatment beyond initial RECIST 1.1 defined PD (Appendix 7), up to a 
maximum of 2 years treatment, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit
•
Participant is tolerating study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional study medication. 
All other elements of the main informed consent including the description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
A radiographic assessment/scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities in Section 2.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum of 5 mm absolute increase from 
time of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or 
the diameters of new measurable lesions compared to the time of initial PD. Treatment with study 
medication should be discontinued permanently upon documentation of further progression.
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New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Please refer to Table 7.4.1-1 for details regarding discontinuation of nivolumab or nivolumab-
placebo.
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Disease recurrence (local, regional, or distant). Please refer to Section 7.7.1 for continuation 
of treatment beyond disease recurrence/progression exceptions.
•
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, and only in countries where local regulations permit, 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). 
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If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page. 
8.1.1
Post Study Treatment Study Follow-up
In this study, RFS 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 (in this study or a 
rollover study) for collection of tumor surveillance assessments and survival follow-up data as 
required and in line with Section 2 and Section 5 until the OS final analysis.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol-defined window (see Schedule of Activities - Section 2). At the time of this request, 
each participant will be contacted to determine their survival status unless the participant has 
withdrawn consent for all contacts or is lost to follow-up.
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
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.
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•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities (Section 2).
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before 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, 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 CRF. 
They are intended to be used as safety monitoring by the treating physician. Additional testing 
or assessments may be performed as clinically necessary or where required by institutional or 
local regulations.
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9.1
Efficacy Assessments
9.1.1
Imaging Assessment for the Study
Images will be submitted to a central imaging vendor and may undergo blinded independent 
central review (BICR) at any time during the study. Prior to scanning first participant, sites should 
be qualified and understand the image acquisition guidelines and submission process as outlined 
in the CA20976K Imaging Manual provided by the central imaging vendor.
Screening and on study images should be acquired as outlined in Section 2, Schedule of Activities
Tumor assessments at other timepoints may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible. Unscheduled CT/MRI should be 
submitted to central imaging vendor. X-rays and bone scans that clearly demonstrate interval 
progression of disease, for example most commonly as unequivocal lesions that are unmistakably 
new since the prior CT/MRI, should be submitted to central imaging vendor. Otherwise, they do 
not need to be submitted centrally.
9.1.1.1
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known and/or suspected sites 
of disease (imaging of extremities for resected melanomas located in the extremities is not a 
requirement and may be conducted per local standard of care. Extremity imaging should be 
conducted in the event of a suspected locoregional relapse that is not clinically unequivocal) should 
be performed for tumor assessments. Images 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. 
If a participant has a contraindication for CT intravenous contrast, then 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. 
If a participant has a contraindication for both MRI and CT intravenous contrasts, then a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, then a non-contrast CT of the chest, abdomen, pelvis, 
and other known/suspected sites of disease is acceptable.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET CT 
is increasingly used in clinical care, and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans. However, if a site can document 
that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT 
(with IV and oral contrast), then the CT portion of the PET-CT can be used. Note, however, that 
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the PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.
Bone scans may be collected per local standards, as clinically indicated.
MRI of brain (with and without contrast) should be acquired as outlined in the Schedule of 
Activities for Arm 2 Participants. CT of the Brain (without and with contrast) can be performed if 
MRI is contraindicated.
For Arm 2 (Unresectable/Metastatic Disease) only:
Tumor measurements should be made by the same investigator or radiologist for each assessment, 
whenever possible. Changes in tumor measurements and tumor response to guide ongoing study 
treatment decisions will be assessed by the investigator using the RECIST v1.1 criteria 
(Appendix 7). 
Bone scan or PET scan are not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain 
nontarget organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
9.1.2
Investigator Assessment of Baseline Disease Status
Participant eligibility must be confirmed by investigator prior to randomization. 
9.1.2.1
General Considerations for Determining Recurrence
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 when the biopsy poses significant risks to the 
participant and/or may not be 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 a pathology 
report, lesion recurrence will be documented with a CT scan/MRI.
•
Tumor markers or auto-antibodies alone cannot be used to assess recurrence.
•
The goal is to identify lesions suspicious for recurrence of melanoma. If it is believed that a 
lesion is NOT malignant in nature (eg, infection, trauma), it should be noted in the medical 
records. The specified minimum size criteria should be combined with radiographic 
appearance consistent with recurrent tumor in the assessment of all suspicious lesions.
•
Non-melanoma primary cancer will be censored.
•
Equivocal recurrence is upgraded to unequivocal recurrence (except in cases of central nervous 
system [CNS] recurrence) by one or more of the following:
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A subsequent scan not earlier than 4 weeks from the time when recurrence was first 
suspected demonstrates that the lesion size is ≥ 5 mm over the size previously recorded, or 
the radiographic appearance of the lesion has become consistent with tumor recurrence. If 
this occurs, the date of recurrence will be the date when the lesion was first suspected.
−
Positive histology/cytology
•
Appearance of multiple new lesions in the same time point generally constitutes unequivocal 
recurrence, even though they may be from different organs (eg, one liver lesion, one lung 
lesion, and one enlarged lymph node).
9.1.2.2
Investigator Assessment of Recurrence (Nivolumab/Placebo-Blinded 
Treatment and Open-Label Nivolumab - Arm 1)
The same method of assessment used at Screening should be used for on-study timepoints. Post-
baseline assessments will be performed at the time points described below until disease recurrence 
confirmed by Investigator, death, or withdrawal from the study.
•
Tumor assessments for ongoing study treatment decisions will be completed by the 
Investigator.
•
Additional imaging of potential disease sites should be performed whenever disease recurrence 
or occurrence of a secondary malignancy is suspected.
•
Brain CT or MRI with and without contrast or bone imaging during on-study treatment and 
follow-up periods should be obtained if clinically indicated.
Criteria for Diagnosing Recurrences is presented in Table 9.1.2.2-1.
Table 9.1.2.2-1:
Criteria For Diagnosing Recurrence
Anatomic Sites
Criteria
Non-Nodal Soft 
Tissue 
Equivocal lesions include:
•
Solitary lesion measuring ≤10 mm in LD or with radiographic appearance equivocal 
for tumor recurrence.
Unequivocal lesions include:
•
One or more new lesions > 10 mm in LD with radiographic appearance consistent 
with tumor recurrence.
•
Positive histology/cytology
Bone Lesions
Equivocal lesions include:
•
Solitary lesion.
•
Lesions identified on radionuclide bone scan. Findings on radionuclide bone scan 
must be confirmed by CT, MRI, or plain films in order to be upgraded to 
unequivocal.
Unequivocal lesions include:
•
Two or more new lesions consistent with tumor recurrence.
•
Positive histology/cytology
Lymph Nodesa
Normal lymph nodes are defined as < 10 mm in the short-axis diameter (SAD).
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Table 9.1.2.2-1:
Criteria For Diagnosing Recurrence
Anatomic Sites
Criteria
Equivocal lymph nodes include
•
Lymph nodes measuring 10 – 14 mm SAD with radiographic appearance consistent 
with recurrence.
•
Lymph nodes ≥15 mm SAD without radiographic appearance consistent with 
recurrence.
Unequivocal proof of nodal recurrence includes:
•
One or more previously normal or equivocal lymph nodes that enlarge to ≥15 mm 
SAD and with radiographic appearance consistent with recurrence.
•
Positive histology/cytology
Fluid Collections
(eg, ascites, 
pleural/pericardial 
effusions)
•
Presence of fluid alone, without pathological confirmation, does not constitute 
equivocal or unequivocal recurrence.
•
Unequivocal proof of recurrence is positive pathology of malignant cells from 
fluid(s).
CNS
Unequivocal recurrence is defined as any new CNS lesion of any size on CT or MRI 
with a radiographic appearance consistent with tumor recurrence.
a For lymph node with short axis 10-15 mm, consider biopsy when lymph node is progressively enlarged as 
evidenced.
9.1.2.3
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.
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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 patients diagnosed with melanoma who 
experience recurrence.
9.1.2.4
Date of Recurrence
The first date when recurrence was observed is taken into account regardless of 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.
9.1.2.5
Investigator Assessment of Progression for Participants Receiving 
Open-Label Nivolumab (Arm 2: Unresectable/Metastatic Disease)
Tumor assessments should continue even if dosing is delayed or discontinued. Changes in tumor 
measurements and tumor responses will be assessed as per the protocol specified schedule by the 
same investigator or designee using RECIST 1.1 criteria. Investigators will report the number and 
size of new lesions that appear while on study. The time points of tumor assessments will be 
reported on the CRF based on the investigator’s assessment using RECIST 1.1 criteria (See 
Appendix 7 for specifics of RECIST 1.1 criteria to be used in this study). Assessments of PR and 
CR must be confirmed at least 4 weeks (28 days) after initial response. A BOR of SD requires a 
minimum of 78 days on study (date of first dose to the earliest date outlined in the Schedule of 
Activities for the first imaging assessment).
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9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
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.
All AEs/SAEs are to be graded and managed per CTCAE v5. 
(A) For Participants with Stage IIB/C Melanoma (Nivolumab or Placebo-blinded Portion)
For participants in the blinded portion of the trial, all AEs (serious and nonserious) will be collected 
for a minimum of 15 months (including Follow-Up Visits 1 and 2) following discontinuation of 
study treatment. The details are as follows:
Nonserious AEs: All nonserious AEs (not only those deemed to be treatment-related) must be 
collected continuously during the treatment period, starting from the initiation of study treatment, 
and until 100 days from the last dose of blinded study treatment. Beyond 100 days of 
discontinuation of blinded study treatment, only new-onset treatment-related nonserious AEs need 
to be reported. These events will continue to be collected for a minimum of 15 months (including 
Follow-Up Visits 1 and 2) following discontinuation of blinded study treatment. Nonserious 
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treatment-related AEs with an onset date beyond 100 days of discontinuation of blinded study 
treatment do not need to be reported, if the non-serious treatment-related AE has an onset date on 
or after the initiation of subsequent anti-cancer therapy.
SAEs: All SAEs (not only those deemed to be treatment-related) must be collected continuously 
during the treatment period, starting from the time of signing the consent, including those thought 
to be associated with protocol-specified procedures, and until 100 days from the last dose of 
blinded study treatment. Beyond 100 days of discontinuation of blinded study treatment, only new-
onset treatment-related SAEs need to be reported. These events will continue to be collected for a 
minimum of 15 months (including Follow-Up Visits 1 and 2) following discontinuation of blinded 
study treatment. Serious blinded study treatment-related or study procedure-related AEs with an 
onset date beyond 100 days of discontinuation of blinded study treatment must be reported, if the 
onset of the serious study treatment/procedure-related AE has an onset date on or after the initiation 
of subsequent anti-cancer therapy. 
Serious and nonserious AEs (SARS-CoV-2-associated): All serious and nonserious SARS-
CoV-2 infection (confirmed or suspected)-associated AEs must be collected from the time of 
signing the consent until 100 days following discontinuation of dosing.
(B) For Participants in the Open-Label Portion
Nonserious AEs: All nonserious AEs (not only those deemed to be treatment-related) must be 
collected continuously during the treatment period, starting from the initiation of study treatment, 
and until 100 days from the last dose of study treatment. Beyond 100 days of discontinuation of 
dosing, new-onset nonserious AEs do not need to be reported. 
SAEs: All SAEs (not only those deemed to be treatment-related) must be collected from the time 
of signing the open-label consent, including those thought to be associated with protocol-specified 
procedures and within 100 days of discontinuation of dosing. Beyond 100 days of discontinuation 
of dosing, new-onset SAEs do not need to be reported if subsequent anti-cancer therapy is initiated, 
unless the event is felt to be related to the CA20976K study treatment.
Serious and nonserious AEs (SARS-CoV-2-associated): All serious and nonserious SARS-
CoV-2 infection (confirmed or suspected)-associated AEs need to be collected from the time of 
signing the consent until 100 days following discontinuation of dosing.
For participants randomized and never treated with study drug, SAEs should be collected for 30 
days from the date of randomization.
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 CRF module.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
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•
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing AE and SAE causalities and the procedures for 
completing, reporting, and/or transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs 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 
AEs, when appropriate for the program or protocol.
Every AE 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 (including confirmed or suspected SARS-CoV-2 infection-associated 
nonserious AEs) should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs (including confirmed or suspected SARS-CoV-
2 infection-associated 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 (including confirmed or suspected SARS-CoV-2 infection-
associated 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.
All SAEs (including confirmed or suspected SARS-CoV-2 associated SAEs) 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), or for suspected cases, until SARS-
CoV-2 infection is ruled-out based on additional medical evaluation.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
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An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting 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 or designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor or designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy has ended), following approvals of participant /Sponsor 
/IRB/EC, as applicable.
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.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (e.g. vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner(s) must sign an informed consent form for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
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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).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2.1 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
2) AND
3) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
4) AND
5) 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. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3). 
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
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Participants will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the long-term follow-up phase (Table 2-3), 
toxicity assessments should be done in person for Follow-Up Visits 1 and 2. Following Visits 1 
and 2, additional in-person safety assessments will be conducted approximately every 12 weeks 
through 12 months (12 months counted from Follow-Up Visit 2) in randomized participants who 
received blinded therapy. For participants receiving open-label nivolumab monotherapy after 
recurrence, additional safety visits will be conducted approximately every 12 weeks through 12 
months (12 months counted from Follow-Up Visit 2). These additional safety assessments in 
participants being treated after recurrence (per protocol) may be accomplished by an in-person 
visit (eg, examination, laboratory tests) or by phone contact. Please refer to the Schedule of 
Activities, Table 2-3 for additional details regarding safety follow-up after discontinuation of study 
treatment.
Once participants reach the long-term follow-up phase, either in person (eg, during surveillance 
assessments) or documented telephone calls to assess the participant’s vital status are acceptable.
Adverse events, including laboratory abnormalities, will be reported and managed per NCI 
CTCAE v5. Some of the assessments may not be captured as data in the CRF. 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 (See Section 2).
9.4.2
Vital signs
Refer to Schedule of Activities (See Section 2).
9.4.3
Electrocardiograms
Refer to Schedule of Activities (See Section 2).
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report. See the Schedule of 
Activities (Section 2) for specific assessments and time points.
Hematology - CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Albumin at screening and as clinically 
indicated
Sodium
Potassium
Chloride
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Creatinine
Blood urea nitrogen (BUN) or serum urea
Glucose
Amylase at screening and as clinically indicated
Lipase at screening and as clinically indicated
Calcium
Phosphorus or phosphate
TSH, free T3 and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is 
abnormal - on treatment
Magnesium
Creatine kinase
Creatinine clearance (CLcr) - screening only
ACTH at screening and as clinically 
indicated
Cortisol at screening and as clinically 
indicated
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, HIV-1 and -2 antibody (screening 
only)
Hepatitis B/C (HBsAg, HCV antibody, or HCV RNA) - screening only
Note: Testing for HIV must be performed at sites where mandated locally.
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG as 
indicated in Section 2).
Follicle-stimulating hormone (FSH) (screening - only required to confirm menopause in 
women < age 55)
9.4.5
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. 
9.5
Pharmacokinetic and Immunogenicity Assessments
Samples for PK and immunogenicity assessments will be collected for all participants receiving 
nivolumab or placebo, and for participants receiving open-label nivolumab monotherapy after first 
recurrence as described in Table 9.5-1. Placebo PK and Anti-Drug Antibody (ADA) samples will 
not be analyzed. All timepoints are relative to the start of study drug administration. All on-
treatment timepoints are intended to align with days on which study drug is administered. If it is 
known that a dose is going to be delayed, then the predose sample should be collected just prior to 
the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, 
an additional predose sample should not be collected. Further details of sample collection, 
processing, and shipment will be provided in the laboratory procedures manual.
Blood samples should be drawn from a site other than the infusion site (ie, contralateral arm) on 
days of infusion for all pre-dose and end of infusion-PK (EOI-PK) samples. Exception: On 
sampling days where EOI-PK samples are NOT drawn, to minimize the number of needle 
sticks, the pre-dose sample can be drawn immediately from the same arm intended for study 
drug infusion from the catheter prior to IV insertion and prior to any saline or fluid flush 
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into the port to avoid diluting the blood sample. Nivolumab infusion is specified in the protocol 
for 30 minutes and is typically programmed for 30 minutes on the infusion pumps. Due to the 
nature by which the infusion pumps operate, there could be some residual dead volume in the IV 
tubing, and will be variable depending on the pump and IV tubing used. The EOI-PK sample is 
drawn with the intent of accurately estimating the Cmax, and as such should be drawn when all 
the study drug has been infused. If the site believes that all this drug was infused within the 30 
minutes, then the EOI-PK sample occurs within approximately 2 minutes of this 30-minute 
infusion. If a flush needs to be administered to clear the IV lines of the drug and deliver all drug, 
then the EOI-PK sample should be drawn approximately 2 minutes prior to end of the flush.
If the infusion was interrupted, the interruption details will also be documented on the CRF. Blood 
samples will be processed to collect serum and stored preferably at -70°C (samples may be stored 
at -20°C up to 2 months). Further details of pharmacokinetic sample collection and processing will 
be provided to the site in the lab manual. The serum samples will be analyzed for drug (nivolumab) 
and ADA (anti-nivolumab antibodies) by validated immunoassays. Samples with a positive ADA 
response may also be analyzed for neutralizing ADA response to nivolumab. 
In addition, selected serum samples may be analyzed by an exploratory method that measures 
nivolumab, or detect anti-drug antibodies for technology exploration purposes; exploratory results 
will not be reported. The corresponding serum samples designated for either PK, immunogenicity 
 assessments may also be used for any of those analyses, if required (eg, insufficient 
sample volume to complete testing or to follow-up on suspected immunogenicity related AE).
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Table 9.5-1:
Pharmacokinetic (PK) and Immunogenicity Sampling Collections for Blinded Nivolumab or Placebo-
Treated Participants or Participants Treated with Open-Label Nivolumab After First Recurrence
Study Daya
(1 Cycle = 4 weeks)
Time (Relative To 
Dosing) Hour
Time
(Relative To Dosing) 
Hour: Min 
Pharmacokinetic 
Serum Sample for 
Nivolumab
Immunogenicity 
Serum for 
Nivolumab
Cycle 1 Day 1
Predoseb
0:00
X
X
End of Infusionc
0:30
X
Cycle 2 Day 1
Predoseb
0:00
X
X
Cycle 3 Day 1
Predoseb
0:00
X
X
Cycle 6 Day 1
Predoseb
0:00
X
X
End of Infusionc
0:30
X
Cycle 9 Day 1
Predoseb
0:00
X
X
FU1
First 2 Follow-up visits (30 ± 7 days from the 
discontinuation of study drug)
N/A
N/A
X
X
FU2
First 2 Follow-up visits (100 ± 7 days from the 
discontinuation of study drug)
N/A
N/A
X
X
Abbreviation: FU1, Follow-Up Visit 1; FU2, Follow-Up Visit 2; Min, minutes.
a If a participant discontinues study drug treatment during the treatment/sampling period, they will move to sampling at the follow-up visits.
b Predose samples should be collected immediately before the administration of the drug (preferably within 30 minutes). If it is known that a dose is going to be 
delayed, then the predose sample should be collected immediately prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently 
delayed, an additional predose sample should not be collected.
c The end of infusion-PK sampling (EOI-PK) occurs when the entire nivolumab dose in the infusion bag is administered to the patient. If diluent will not be 
administered to flush the IV lines, this sample should be taken immediately prior to stopping the IV infusion (preferably within 2 minutes prior to the end of 
infusion). If diluent is used to flush the dose remaining in the infusion line, then the EOI-PK sample will occur when there is no dose remaining in the infusion 
line after a flush. If the end of IV infusion is delayed to beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly.
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9.6
Pharmacodynamics
 
9.7
Pharmacogenomics
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9.8.1
Additional Research Collection
This protocol will include residual sample storage for additional research (AR).
For All US sites:
Additional research is required for all study participants, except where prohibited by IRBs/ethics 
committees or academic/institutional requirements. Where one or more of these exceptions occurs, 
participation in the additional research should be encouraged but will not be a condition of overall 
study participation. 
If the IRB/ethics committees and site agree to the mandatory additional research retention and/or 
collection, then the study participant must agree to the mandatory additional research as a requirement 
for inclusion in the study.
If optional participation is permitted and approved, then the study participants may opt out of the 
additional research retention and/or collection.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection is 
prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs to 
the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc.
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Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study Sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
Residual P
 
 will also be retained for additional research purposes.
Samples kept for future research will be stored at the BMS Biorepository in 
 USA or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 9.8.1-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Timepoints for which residual samples will be 
retained
PK Serum
All 
Abbreviations: 
PK, pharmacokinetics.
9.8.2
Tissue Specimens
Pre-treatment tumor tissue specimens, not previously irradiated (“not previously irradiated” 
applies to participants with unresectable/metastatic disease recurrence entering open-label 
nivolumab), in the form of a paraffin embedded block to contain sufficient tissue for at least 15 
sections or a minimum of 15 unstained slides, preferably freshly cut, from the primary diagnostic 
biopsy must be shipped to the central lab prior to randomization or treatment assignment, for 
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blinded or open-label nivolumab treatment, respectively. If a minimum of 15 unstained slides or 1 
FFPE block cannot be provided, the eligibility should be discussed with the Medical Monitor or 
designee. This minimum quantity applies to tissue obtained prior to randomization/assignment to 
the open label portion as well as tissue obtained upon disease recurrence or progression.
The following tissue attributes for the samples prior to randomization of participants with Stage 
IIB/C melanoma are not mandatory, but considered desirable to optimize downstream 
 
analyses. The tissue biopsy samples should be from the primary diagnostic material (obtained for 
example by biopsy punch, shave, excision, incision, saucerization). If tissue from the primary 
diagnostic biopsy is insufficient, it may be supplemented by tissue from subsequent surgeries, 
provided at least 3 mm of tumor in smallest dimension is present. A dermatopathologist’s 
review/input is encouraged. Pathology samples acquisition guidelines and submission process will 
be outlined in the study Laboratory Manual.
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9.10
Other Assessments
Not applicable. 
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
10.1.1
RFS
The sample size of the study is based on a comparison of the RFS distribution between participants 
randomized to nivolumab and participants randomized to placebo.
 
 
 
 
Sample size calculations for this study design were done using EAST 
(v 6.4.1).
For this comparison of RFS between nivolumab and placebo in all randomized participants, 
approximately 154 RFS events would be required for a two-sided experiment-wise alpha = 0.05 
log-rank test, to show a statistically significant difference in RFS between the treatment arms with 
at least 90% power when the average hazard ratio (HR) of the nivolumab arm to the placebo arm 
is 
 
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Final analysis of RFS will be conducted when approximately 154 RFS events have occurred. 
 
 
 
One interim analysis of RFS will be conducted when approximately 123 RFS events (80% 
information fraction) have been reached among all randomized participants. 
 
 
 
 
 
 
 
 
10.1.2
Overall Survival
OS will be formally compared only if the null hypothesis for the primary endpoint (RFS) is 
rejected.
For the comparison of OS between nivolumab and placebo in all randomized participants, 
approximately 277 deaths would be required for a two-sided experiment-wise alpha = 0.05 log-
rank test, to show a statistically significant difference in OS with at least 79.6% power 
 
 
 
Although formal OS testing is planned at OS FA, descriptive statistics for OS will be prepared at 
RFS IA and/or RFS FA 
. If OS results (beyond the frequency of deaths 
per arm) including Kaplan-Meier (KM) curves are requested, an administrative alpha of 0.0001 
will be spent as alpha penalty. Should such analyses be conducted, only a BMS restricted team 
will have access to OS descriptive results.
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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 IRT.
All randomized participants
All participants who were randomized to any treatment arm 
in the study.
All treated participants
All participants who received at least one dose of study drug.
PK participants
All treated participants with available serum time-
concentration data.
Immunogenicity evaluable 
participants:
Nivolumab ADA evaluable 
participants
All treated participants with baseline and at least 1 post 
baseline 
pre-infusion 
nivolumab 
immunogenicity 
assessment
10.3
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before the first database lock 
for formal interim efficacy analysis, and will describe the selection of participants to be included 
in the analyses, and procedures for accounting for missing, unused, and spurious data. Below is a 
summary of planned statistical analyses of the primary and secondary endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups 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. For participants who remain alive and whose disease has not recurred or 
did not die, 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.
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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 vs placebo) using a two-
sided log-rank test stratified AJCC T-Stage at Screening at the overall significance level of 5% 
(two-sided) in all randomized participants.
The HR 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 factor.
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, 18, 24, 30, 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)
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 
12 weeks 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 vs placebo) using a two-sided log-rank test stratified by 
AJCC T-Stage at Screening at the overall significance level of 5% (two-sided) in all randomized 
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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, 18, 24, 30 and 36 months (and yearly after depending on follow-up) with two-sided 95% 
CIs using the log-log transformation will be computed.
Distant Metastasis-Free Survival (DMFS)
DMFS is defined as the time between the date of randomization and the date of first distant 
metastasis or date of death (whatever the cause), whichever occurs first. 
Censoring rules for the analysis of DMFS are presented in Table 10.3.1.2-1.
Table 10.3.1.2-1:
Censoring Scheme for Primary Definition of DMFS
Situation
Date of Event or Censoring
Outcome
Distant metastasis
Date of first distant metastasis
Event
Death without distant metastasis
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 distant metastasis and no death
Date of last evaluable disease assessment
Censored
DMFS will be analyzed using similar analyses methods as for RFS. No multiplicity adjustment 
will be applied.
Investigator-Assessed Outcomes on Next-Line Therapies
PFS2 is defined as the time from randomization to recurrence/objective disease progression after 
the start of the next-line of systemic anti-cancer therapy, or to the start of a second next-line 
systemic therapy, or to 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.
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.
Objective response rates and duration of treatment on next-line therapies will be summarized.
10.3.2
Safety Analyses
Safety and tolerability of nivolumab and placebo will be measured by the incidence of adverse 
events, serious adverse events, deaths, and laboratory abnormalities.
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Safety analyses will be performed in all treated participants. Descriptive statistics of safety will be 
presented using NCI CTCAE v5 by treatment group (for the nivolumab and placebo arms). All on-
study AEs, treatment-related AEs, SAEs, and treatment-related SAEs will be tabulated using worst 
grade per NCI CTCAE v5 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 v5 criteria.
10.3.3
Other Analyses
10.3.3.3
Pharmacokinetic Analyses
The nivolumab concentration data obtained in this study will be combined with data from other 
studies in the clinical development program to develop a population PK model. This model will 
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be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab. In 
addition, exposure-response analyses with selected efficacy and safety endpoints may be 
conducted. Results of population PK and exposure response-analyses will be reported separately.
10.3.3.5
Immunogenicity Analyses
Methodology for analysis of immunogenicity will be described in the statistical analysis plan.
10.3.3.6
Analyses of Follow-Up Data from Participants Receiving Optional Open-
Label Nivolumab Treatment
Methodology for analysis of follow-up data from participants receiving optional open-label 
nivolumab treatment will be described in the statistical analysis plan.
10.3.4
Interim Analyses
One formal interim analysis of RFS will be conducted when approximately 123 RFS events (80% 
information fraction) have been reached among all randomized participants. 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. With an 
interim RFS analysis at approximately 123 RFS events, the type I error would be 0.024 (two-
sided). The type I error to be used for final RFS analysis would be 0.043 (two-sided).
RFS and OS will be tested using a hierarchical procedure: RFS will be compared first in all 
randomized participants with an alpha allocation of 0.05 (two-sided). If significant, 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 when approximately 166 deaths (60% 
information fraction) have been reached among all randomized participants, which is expected to 
occur after the final analysis of RFS.
It is estimated this would occur when all participants have a minimum follow-up of approximately 
63 months from the randomization of the last participant. The estimated timing for this interim 
analysis is at 93 months. The stopping boundaries at the interim and final analyses will be derived 
based on the exact number of OS events using Lan-DeMets alpha spending function with O’Brien-
Fleming boundaries. With an interim OS analysis at approximately 166 deaths, the type I error 
would be 0.008 (two-sided), the power 30.7%, and an observed HR of 0.644 or less would result 
in a statistically significant improvement. The type I error to be used for final OS analysis would 
be 0.048 (two-sided).
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.
The Statistical Analysis Plan will further describe the planned interim analyses.
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11
REFERENCES
1
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3
BMS Internal Communication, data on file.
4
Leonardi G, Falzone L, Salemi R, et al. Cutaneous melanoma: From pathogenesis to therapy 
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5
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16 Averbook B, Lee S, Delman K, et al. Pediatric Melanoma: Analysis of an International 
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24 Ipilimumab US Package Insert; revised July 2018.
25 Hodi F, O’Day S, McDermott D, et al. Improved survival with ipilimumab in patients with 
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26 Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
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27 Maio M, Grob J, Aamdal S, et al. Five-year survival rates for Treatment-Naive Patients With 
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28 Nishino M, Giobbie-Hurder A, Ramaiya NH, et al. Response assessment in metastatic 
melanoma treated with ipilimumab and bevacizumab: CT tumor size and density as markers 
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29 Robert C, Long G, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF 
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30 Hodi F, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone 
versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a 
multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480–92.
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31 Wolchok J, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab 
and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377:1345-56.
32 Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice 
chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomized, 
controlled, phase 2 trial. Lancet Oncol. 2015;16:908-918. 
33 Robert C, Schachter J, Long G, et al. Pembrolizumab versus ipilimumab in Advanced 
Melanoma. N Engl J Med. 2015;372:2521-2532.
34 T-VEC (Imlygic) Package Insert, Revised 12/2018
35 Kaufman H, Amatruda T, Nemunaitis JJ, et al. Tumor size and clinical outcomes in melanoma 
patients (MEL pts) treated with talimogene laherparepvec (T-VEC). J Clin Oncol. 
2015;33:9074.
36 Schadendorf D, Long GV, Stroiakovski D, et al. Three-year pooled analysis of factors 
associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 
3 randomised trials. Eur J Cancer. 2017;82:45-55.
37 Flaherty L, Othus M, Atkins M, et al. Southwest Oncology Group S0008: a phase III trial of 
high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 
and interferon in patients with high-risk melanoma--an intergroup study of cancer and 
leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and
Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8.
38 Kirkwood J, Strawderman M, Ernstoff M, et al. Interferon Alfa-2b Adjuvant Therapy of High-
Risk Resected Cutaneous Melanoma: The Eastern Cooperative Oncology Group Trial EST 
1684. J Clin Oncol. 1996;14:7-17
39 Kirkwood J, Manola J, Ibrahim J, et al. A Pooled Analysis of Eastern Cooperative Oncology 
Group and Intergroup Trials of Adjuvant High-Dose Interferon for Melanoma. Clin Cancer 
Res. 2004;10:1670-1677.
40 Eggermont A, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b 
versus observation alone in resected stage III melanoma: final results of EORTC 18991, a 
randomised phase III trial. Lancet. 2008;372:117–26.
41 NCCN Clinical Practice Guidelines in Oncology-Melanoma, Version 2, 2019.
42 Lens M, Dawes M. Interferon Alfa Therapy for Malignant Melanoma: A Systematic Review 
of Randomized Controlled Trials. J Clin Oncol. 2002;20:1818-1825.
43 Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in 
Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19):1824-1835.
44 Eggermont A, Chiario-Sileni V, Grob J, et al. Prolonged Survival in Stage III Melanoma with 
Ipilimumab Adjuvant Therapy. N Engl J Med. 2016;375(19):1845–1855.
45 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
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46 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
47 Wheatley K, Ives N, Hancock B, et al. Does adjuvant interferon-a for high-risk melanoma 
provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treatment 
Reviews. 2003;29:241–252.
48 Hauschild A, Dummer R, Schadendorf D, et al. Longer Follow-Up Confirms Relapse-Free 
Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF 
V600–Mutant Stage III Melanoma. J Clin Oncol. 2018;36:1-9. 
49 Kirkwood J, Ibrahim J, Sondak V, et al. High- and Low-Dose Interferon Alfa-2b in High-Risk 
Melanoma: First Analysis of Intergroup Trial E1690/S9111/C9190. J Clin Oncol. 
2000;18:2444-2458.
50 Grob JJ, Dreno B, de la Salmoniere P, et al. Randomized trial of interferon α-2a as adjuvant 
therapy in resected primary melanoma thicker than 1·5 mm without clinically detectable node 
metastases. Lancet. 1998;351:1905-10.
51 Mocellin S, Lens MB, Pasquali S, et al. Interferon alpha for the adjuvant treatment of cutaneous 
melanoma. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD008955.
52 Ives N, Suciu S, Eggermont A, et al. Adjuvant interferon-a for the treatment of high-risk 
melanoma: An individual patient data meta-analysis. Ives et al. Eur J Cancer. 2017;82:171-
183.
53 Maio M, Lewis K, Demidov L, et al. Adjuvant vemurafenib in resected, BRAFV600 mutation-
positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, 
phase 3 trial, Lancet Oncol. 2018;19:510–20.
54 Buja A, Sartor G, Scioni M, et al. Estimation of Direct Melanoma-related Costs by Disease 
Stage and by Phase of Diagnosis and Treatment According to Clinical Guidelines. Acta Derm 
Venereol. 2018;98:218–224. 
55 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
56 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
57 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med.
2000;192(7):1027-34.
58 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
59 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20.
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60 Wilson M, Geskin L, Carvajal R, et al. Adjuvant nivolumab in high-risk stage IIb/IIc 
melanoma patients: Results from investigator initiated clinical trial. J Clin Oncol. 
2021;39(15_suppl):9583.
61 Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York: 
Springer; 2017.
62 Lee A, Droppelmann N, Panageas K, et al. Patterns and Timing of Initial Relapse in Pathologic 
Stage II Melanoma Patients. Ann Surg Oncol. 2017;24(4):939-946.
63 Dalal KM, Patel A, Brady MS, et al. Patterns of First-Recurrence and Post-recurrence Survival 
in Patients with Primary Cutaneous Melanoma After Sentinel Lymph Node Biopsy. Ann Surg 
Oncol. 2007;14(6):1934-1942.
64 Grob J, Garbe C, Ascierto P, et al. Adjuvant melanoma therapy with new drugs: should 
physicians continue to focus on metastatic disease or use it earlier in primary melanoma?
Lancet Oncol. 2018;19:e720-25.
65 OPDIVO (nivolumab) US Prescribing Information. Bristol-Myers Squibb, Princeton, NJ. 
February 2018.
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101 OPDIVO. Annex I Summary of Product Characteristics. Bristol-Myers Squibb Company. 
2018. 
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104 Centers for Disease Control (CDC), Criteria for Return to Work for Healthcare Personnel with 
Suspected or Confirmed COVID-19 (Interim Guidance) Updated May 5, 2020 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/return-to-work.html
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AR
additional research
AST
aspartate aminotransferase
AT
aminotransaminases
BICR
Blinded Independent Central Review
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CE
contrast enhanced
CFR
Code of Federal Regulations
cHL
Classical Hodgkin’s Lymphoma
cHR
critical hazard ratio
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CLcr
creatinine clearance
CMV
cytomegalovirus
CNS
central nervous system
COVID-19
coronavirus disease 2019
CRC
colorectal cancer
CRF
case report form
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Term
Definition
CSR
clinical study report
CT
computed tomography 
CTAg
Clinical Trial Agreement
CTLA-4
cytotoxic T-lymphocyte-associated protein-4 
cum
cumulative
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eCRF
electronic Case Report Form
eGFR
estimated glomerular filtration rate 
EHR
electronic health record
EMA
European Medicines Agency
EOI
end of infusion
EOI-PK
end of infusion-pharmacokinetics
EU
European Union
FA
final analysis
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin embedded
FPFT
first participant first treatment
FSH
follicle-stimulating hormone
FU1
Follow-Up Visit 1
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Term
Definition
FU2
Follow-Up Visit 2
GBS
Guillain-Barre syndrome
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator Brochure 
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
ie
id est (that is)
IEC
Independent Ethics Committee
IF
information fraction
IFN
interferon
IgG
Immunoglobin G
IMP
Investigational Medicinal Products
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUS
intrauterine hormone-releasing system
IV
intravenous
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Term
Definition
KM
Kaplan-Meier
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
mAb
monoclonal antibody
Mg++
magnesium
MG
myasthenia gravis
MID
minimally important difference
min
minute
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
MMIS
malignant melanoma in situ
MMR
mismatch repair 
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MRT
mean residence time
MSI-H
microsatellite instability-high
NCCN
National Comprehensive Cancer Network 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCI-SEER
National Cancer Institute Surveillance, Epidemiology, and End Results 
Program
NED
no evidence of disease
ng
nanogram
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer 
OS
overall survival
pAUCe
extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
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Term
Definition
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
PD-L1
programmed cell death ligand-1 
PEG-IFN
pegylated interferon
PET
positron emission tomography
PFS
progression-free survival 
PFS2
Progression-free survival through next-line therapy
PK
pharmacokinetics
PPK
population pharmacokinetics 
PT
prothrombin time
PTT
partial thromboplastin time
PVC
polyvinyl chloride
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
RCC
renal cell carcinoma
RFS
recurrence-free survival
RT-PCR
reverse transcription polymerase chain reaction
SAD
short-axis diameter 
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck 
SD
stable disease
SDV
source data verification
SEER
Surveillance, Epidemiology and End Results 
SJS
Stevens-Johnson syndrome
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Term
Definition
SLN
sentinel lymph node
SSC
Study Steering Committee
SUSAR
suspected unexpected serious adverse reaction 
T.bili
total bilirubin
TCR
T-cell receptor
TEN
toxic epidermal necrolysis
UK
United Kingdom
ULN
upper limit of normal 
US
United States 
VAS
visual analog scale
WBC
white blood cell
WHO
World Health Organization
WLE
wide local excision
WNOCBP
women not of childbearing potential
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
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
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
Guidelines
•
Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol,
any 
revisions/amendments,
and the participant
informed consent form (ICF) will receive 
approval/favorable 
opinion 
by 
Institutional 
Review 
Board/Independent 
Ethics 
Committee (IRB/IEC), and regulatory authorities according to applicable regulations prior to 
initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation) that is likely to affect, 
to a significant degree, one or more of the following: (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
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, Investigator’s Brochure, product labeling information, ICF, 
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants.
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
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•
ICH guidelines 
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union Directive 2001/20/EC; or
•
European Regulation 536/2014 for clinical studies (if applicable),
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable),
•
the IRB/IEC
•
and all other applicable local regulations
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 the local Health Authority), 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 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 the local Health Authority, must be sent to Bristol-Myers 
Squibb (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF 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.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, in accordance with 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 participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
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The Sponsor or designee will provide the investigator with an appropriate sample ICF, which will 
include all elements required by the ICH GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
The investigator or his/her representative must:
•
Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.
•
Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 
•
Explain the nature of the study to the participant or his/her legally acceptable representative
and answer all questions regarding the study.
•
Inform participant that his/her participation is voluntary. Participant or his/her legally 
acceptable representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.
•
Allow time necessary for participant or his/her legally acceptable representative to inquire 
about the details of the study.
Obtain an ICF signed and personally dated by participant or his/her legally acceptable 
representative and by the person who conducted the informed consent discussion. 
•
Include a statement in participant’s medical record that written informed consent was obtained 
before participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
•
Re-consent participant to the most current version of the ICF(s) during his/her participation in 
the study, as applicable.
Revise the ICF 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 his/her legally acceptable representative 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 participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA Authorization.
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records. 
In situations where consent cannot be given by participants, their legally acceptable representatives 
(as per country regulation) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
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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.
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 ICF 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 consent. Minors who 
reach the age of majority (legal adulthood) during the clinical trial must give their written consent.
Participant unable to give their written informed consent (eg, stroke or participants with 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 ICF 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 
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 participants are the most important considerations 
and should prevail over interests of science and society.
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
•
The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
•
Definitions of what constitutes source data can be found in the site procedure and document 
form.
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten 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 records/electronic health 
records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records.
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When paper records from such systems are used in place of an 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 INTERVENTION RECORDS
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
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 
standard 
operating 
procedures/standards of the sourcing pharmacy
BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs 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 the 
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 
the Sponsor or designee.
The confidentiality of records that could identify participants 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 and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For eCRFs, review and approval/signature is completed electronically through the 
BMS EDC tool. The investigator must retain a copy of the CRFs, including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the Sponsor or designee. User accounts are not to be shared or reassigned to other individuals.
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. In those instances where BMS staff is restricted from visiting the 
site, remote source data verification (SDV) is allowed where access to electronic health records
(EHRs) is permitted. 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.
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Certain CRF pages and/or electronic files may serve as the source documents. 
In addition, the study may be evaluated by the 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 the 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 its designee, whichever is longer. 
The investigator (or head of the study site in Japan) must contact BMS prior to destroying any 
records associated with the study.
BMS or its designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed-upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or its designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or 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 interventions supplied by 
BMS can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor, unless study treatments 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(eg, cytotoxics or biologics).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
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If
Then
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors; eg, study treatments 
sourced from the site’s 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 of study interventions, 
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 standard operating procedures 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 (eg, incinerator, licensed sanitary landfill, or licensed waste-disposal 
vendor) must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Study 
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.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
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Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
In the European Union (EU), the summary of results and summary for laypersons will be submitted 
within 1 year (6 months if pediatric participants are enrolled) of the end of trial in EU/European 
Economic Area and third countries.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR). 
For each CSR related to this protocol, the following criteria will be used to select the Signatory 
Investigator:
•
External Principal Investigator designated at protocol development
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the 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 the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
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external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study 
treatment that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, electrocardiograms, 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/serious adverse event (SAE) unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae and should specify “intentional overdose” as the verbatim 
term.
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE, even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
A 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 Bristol-Myers Squibb (BMS) clinical 
studies: 
•
A visit to the emergency room or other hospital department < 24 hours that does not result 
in admission (unless considered an important medical or life-threatening event).
•
Elective surgery, planned prior to signing consent.
•
Admissions as per protocol for a planned medical/surgical procedure.
•
Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy).
•
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.
•
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
•
Admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols).
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
Is an important medical event (defined as a medical event[s] that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm and 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.) 
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Pregnancy and DILI must follow the same transmission timing and processes to BMS as used for 
SAEs. (See Section 9.2.5 for reporting pregnancies.)
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint; if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration, 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure 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 the 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 the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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•
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
•
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
•
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of 
an event, and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports must include the same investigator term[s] initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the electronic case report 
form (eCRF).
−
The paper SAE Report Form is intended only as a back-up option when the electronic 
data capture 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 
transmission.
♦When paper forms are used, the original paper forms are to remain on site.
•
Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via 
email or confirmed facsimile transmission.
SAE Email Address: 
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 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.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels. 
•
1-week minimum for vaginal hormonal products (rings, creams, gels)
•
4-week minimum for transdermal products
•
8-week minimum for oral products
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation. (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol.)b
−
Oral (birth control pills)
−
Intravaginal (rings)
−
Transdermal
•
Combined (estrogen- and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy.
•
Progestogen-only hormonal contraception associated with inhibition of ovulation. (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol.)b
−
Oral
−
Injectable
•
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy.
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation. (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol.)b
•
Intrauterine device.
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Intrauterine hormone-releasing system (IUS). (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol.)b,c
•
Bilateral tubal occlusion.
•
Vasectomized partner 
A vasectomy is a highly effective contraception method provided that the participant 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 treatment. 
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.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy.
•
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 participant chooses to forego complete abstinence.
•
Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and 
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, 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. For information specific to this study regarding permissibility of 
hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.7.1 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone 
exposures from intrauterine devices do not alter contraception effectiveness. For information specific to this 
study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.7.1 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol.
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Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of > 1% per year when used consistently and correctly.
•
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. (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited.)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, postovulation methods).
•
Withdrawal (coitus interruptus).
•
Spermicide only.
•
LAM.
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 Appendix 3.
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APPENDIX 5
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low 
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 6
ECOG PERFORMANCE STATUS 
These scales are used by doctors and researchers to assess how a patient’s disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine appropriate 
treatment and prognosis. They are included here for healthcare professionals to assess.
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. 
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APPENDIX 7
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm)
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
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1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the participant is on-study for a minimum 
of 6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the participant is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the participant is considered to not have 
progressive disease.
REFERENCES
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 8
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
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 9
COUNTRY SPECIFIC REQUIREMENTS
Criteria for exclusion of HIV-positive participants in Argentina, Czech Republic, Germany, and 
any other countries where exclusion of HIV-positive participants is locally mandated.
Protocol Section
Revised Protocol Text
Table 2-1 Screening Procedural 
Outline (CA20976K)
Add “HIV testing” to list of laboratory tests.
Section 6.2 Exclusion Criteria, 1) 
Medical Conditions g)
Replace “Known history of testing positive for human immunodeficiency 
virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 
Testing for HIV must be performed at sites mandated by local 
requirements” with “Positive test for HIV”
Section 9.4.4 Clinical Safety 
Laboratory Assessments
Replace “Testing for HIV-1 and HIV-2 must be performed at sites where 
mandated by local requirements” with “Testing for HIV-1 and HIV-2 
must be performed.”
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APPENDIX 10
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 02, 15-Oct-2021
The protocol has been modified to align the management of adverse events (AEs) in trial 
participants, as well as the reporting of such AEs, per the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. The modification has been made since AE management in 
the previous version of the protocol (Revised Protocol 01, dated 16-Oct-2020) based on CTCAE 
v4 has been updated to CTCAE v5.
 
 
Other clarifications and editorial updates have been made throughout the protocol to improve 
clarity and readability and to keep consistency throughout the document.
This protocol amendment applies to all participants.
Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Title Page
Updated Medical Monitor 
information.
Administrative update.
Synopsis: Key 
Inclusion Criteria
• Updated criterion b) to 
indicate that in case 12 
weeks between 
complete resection and 
randomization is 
exceeded due to 
unforeseen 
circumstances, the 
eligibility should be 
discussed with the 
Sponsor. 
• Updated criterion g) to 
indicate that the 
eligibility should be 
discussed with the 
Sponsor in case the 
required tumor tissue 
content cannot be 
provided.
Additional text inserted to align these 
key criteria with criteria in the main 
body.
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Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Synopsis: Key 
Exclusion Criteria -
Prior/Concomitant 
Therapy
Section 6.2.1: 
Exclusion Criteria -
Blinded Nivolumab or 
Placebo Treatment
In criterion 2)b), added 
“radiation therapy” 
against the resected 
melanoma, as an example 
of an excluded treatment, 
amongst other excluded 
therapies.
Radiation therapy directed against the 
resected melanoma could confound the 
evaluation of recurrence.
Updated criterion 2)d) to 
(1) replace the 
terminology of “botanical 
preparations” with 
“complementary 
medications”, and (2) 
indicate that 
complementary 
medications are permitted 
if they are used as 
supportive care.
Terminology introduced to reflect the 
wider array of products that may be in 
use by trial participants. In addition, the 
use of such products is only a concern 
when used to treat the study entry 
melanoma, and not for supportive care 
purposes.
Table 2-1: Screening 
Procedural Outline 
CA20976K (Applies to 
All Participants: 
Blinded or Open-label 
Treatment)
Section 5.1.2: Optional 
On-Protocol Open-
Label Nivolumab 
Treatment After First 
Recurrence, 
Monitoring for Disease 
Recurrence/Progression
“Review of Pathology 
Report” row in Table 2-1 
and “Monitoring for 
Disease Recurrence/ 
Progression” subsection in 
Section 5.1.2, clarified 
that pathology reports sent 
to the central laboratory 
must be de-identified.
Clarification inserted to emphasize the 
importance of protecting participant 
privacy.
Table 2-2: On-
Treatment Assessments 
CA20976K (Applies to 
All Participants: 
Blinded or Open-label 
Treatment)
Table 2-3: Long-Term 
Follow-Up CA20976K 
In the “Adverse Event 
Assessment” row, edited 
text to clarify that the 
management and reporting 
of all AEs/serious adverse 
events (SAEs) is per 
CTCAE v5.
AE management in the previous 
version of the protocol based on 
CTCAE v4 has been updated to 
CTCAE v5.
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Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
(Applies to All 
Participants: Blinded or 
Open-label Treatment)
Table 2-3: Long-Term 
Follow-up CA20976K 
(Applies to All 
Participants: Blinded or 
Open-label Treatment)
Edited footnote “a” to 
indicate that Follow-up 
Visit 1 can be performed 
on the date of 
discontinuation if that date 
is greater than 37 days, 
instead of 42 days, from 
the last dose.
To correct the 42 days inserted in error.
Section 5.1.1: 
Nivolumab or Placebo 
Blinded Treatment
Clarified that 3 days was 
72 hours in the 
“Treatment” section.
To improve clarity.
In the “In the event of 
disease recurrence” 
section, clarified that 
pathology reports of 
biopsies confirming 
recurrence submitted to 
the central vendor need to 
be de-identified.
Clarification inserted to emphasize the 
importance of protecting participant 
privacy.
Section 5.4: Scientific
Rationale for Study 
Design
Updated text on the 
rationale for the 2:1 
randomization.
Provided additional rationale 
(specifically, additional safety 
information on the experimental arm) 
for the 2:1 randomization design 
implemented in the trial.
Section 6.1.1: Inclusion 
Criteria - Blinded 
Nivolumab or Placebo 
Treatment
Added text to criterion 
2)e)i) on addressing 
incidental findings (eg, 
indeterminate nodules 
noted on imaging).
Text inserted to provide sites with 
direction on handling incidental 
findings noted during the screening 
process.
Added text to criterion 
3)b) that allows additional 
time, up to 72 hours prior 
to start of study treatment, 
to obtain a negative serum 
or urine pregnancy test.
Provide sites with additional flexibility 
especially where results cannot be 
obtained within the standard 24-hour 
window.
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Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Criteria 3)c)-3)e): Deleted 
the requirement for male 
participants to use 
contraceptive measures.
Based on fetal and maternal exposure 
studies in rabbit and cynomolgus 
monkey models, excretion of 
monoclonal antibodies (mAbs) into 
semen, and male-mediated mAb drug 
transfer via seminal fluid does not 
present a health risk to a female 
partner, and mAbs present in seminal 
fluid are not bioavailable to the 
developing conceptus. Studies in 
healthy male volunteers demonstrated 
that the risk to a fetus exposed to a 
mAb via seminal fluid transfer to a 
pregnant partner is negligible and any 
theoretical fetal exposure that might 
occur is highly unlikely to be 
pharmacologically relevant.
Section 6.2.1: 
Exclusion Criteria -
Blinded Nivolumab or 
Placebo Treatment
In criterion 2)g), inserted 
clarification that the full 
dosing schedule of 
coronavirus disease 2019 
(COVID-19) vaccines 
should be completed, 
unless a delay would 
compromise the 
participant’s health or 
suitability for enrollment.
It is preferable for participants to 
complete the full dosing schedule of 
COVID-19 inactivated vaccines to 
allow for resolution of any vaccine-
induced side effects prior to initiating 
study treatment. New limited safety 
data on inactivated mRNA vaccines 
(eg, BNT162b2) indicate no new 
immune-mediated side effects or 
exacerbations of existing immune-
related side effects were observed in 
participants receiving concomitant 
checkpoint inhibitors and the 
BNT162b2 vaccine; therefore, 
allowance is made to accommodate 
participants who may not have 
completed their full COVID-19 vaccine 
schedule, if it is felt to be in the 
participant’s best interest, after 
discussion with the Sponsor and the 
investigator.
Section 7: Treatment
Deleted text that placebo 
should be sourced by 
investigative sites if 
Redundant, as this text already included 
in another paragraph.
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Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
available and permitted by 
local regulations.
Section 7.1.1: 
Treatment with 
Nivolumab or Placebo
Clarified that study 
treatment can be 
administered over 
approximately 30 minutes.
To align with infusion duration text in 
Section 5.1.1: Nivolumab or Placebo 
Blinded Treatment
Inserted text to indicate 
that the target interval of 
28 days for initiation of a 
subsequent cycle is 
always based on the actual 
date the study treatment 
was administered in the 
preceding cycle, unless 
the subsequent cycle 
needed to be delayed for 
safety reasons.
To provide clarity to sites that there 
should always be an interval of 28 days 
(± 3 days) between actual treatments, 
regardless of subsequent target visit 
dates that may have been charted out 
on calendar (for planning purposes) 
prior to or around the time of initiating 
the first study treatment.
Section 7.3.1: 
Unblinding: 
Emergency, 
Accidental, and in the 
Event of Disease 
Recurrence
Inserted text that in the 
case of accidental 
unblinding, the unblinded 
Clinical Trial Monitor 
assigned to the site should 
be contacted.
To prevent the inadvertent unblinding 
of blinded trial personnel (eg, the 
Medical Monitor or designee [Clinical 
Scientist]).
Section 7.3.2: 
Unblinding in the 
Event of Disease 
Recurrence
Inserted text that a 
member of the BMS study 
trial management team, in 
addition to a BMS site 
monitor, could assist the 
site with instructions 
related to unblinding the 
treatment arm through the 
Interactive Response 
Technology (IRT), in case 
of disease recurrence. 
Added additional BMS support to 
ensure that sites can unblind a 
participant’s treatment arm in a timely 
manner in the event of disease 
recurrence.
Section 7.4.1: Criteria 
to Delay, Resume, and 
Discontinue 
Nivolumab or 
Nivolumab-Placebo 
Criteria
Updated the section name 
from “Dose Delay 
Criteria” to “Criteria to 
Delay, Resume, and 
Discontinue Nivolumab or 
Nivolumab-Placebo”. 
The change was made since the criteria 
to delay, resume, and discontinue 
treatment were consolidated and 
reformatted into 1 section (Table 7.4.1-
1) for better readability.
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Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Revised Protocol 01 
Sections 7.4.3 (Criteria to 
Resume Treatment) and 
8.1.1 (Discontinuation of 
Nivolumab or Nivolumab-
Placebo) were moved to 
Section 7.4.1.
Updated text to clarify 
that the management and 
reporting of AEs will be 
based on CTCAE v5.
AE management in the previous 
version of the protocol based on 
CTCAE v4 was updated to CTCAE v5.
Section 7.4.2: 
Treatment of 
Nivolumab-Related 
Infusion Reactions
Deleted text that Grade 3 
or 4 infusion reactions 
need to be reported within 
24 hours to the BMS 
Medical Monitor/Study 
Director.
Redundant text, as sites are already 
directed to report Grade 3 or 4 infusion
reactions within 24 hours as an SAE, if 
reporting criteria are met.
Edited text to clarify that 
the management and 
reporting of infusion 
reactions is per CTCAE 
v5.
AE management in the previous 
version of the protocol based on 
CTCAE v4 was updated to CTCAE v5.
Inserted a note that in the 
case of Grade 2 infusion 
reaction symptoms, if the 
infusion rate cannot be 
safely increased to the 
original infusion rate, then 
a reduced infusion rate of 
50% of the original 
infusion rate or a reduced 
rate per local standards 
can be adopted for future 
infusions.
Flexibility provided to enable sites to 
manage subsequent infusion rates in 
participants who experience infusion 
reactions, in accordance with local 
practices.
Section 7.5: 
Preparation/Handling/S
torage/Accountability
Updated text to clarify 
that the unblinded Clinical 
Trial Monitor assigned to 
the site should be 
contacted if there are 
concerns about the quality 
To prevent the inadvertent unblinding 
of blinded trial personnel (eg, the 
Medical Monitor, Clinical Scientist, 
blinded site monitor, etc).
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Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
or appearance of the study 
treatment.
Section 7.6: Treatment 
Compliance
Deleted the following 
text: “Drug accountability 
should be reviewed by the 
site study staff at each 
visit.”
Redundant text.
Section 7.7: 
Concomitant Therapy
Inserted text that non-live 
COVID-19 vaccination is 
considered a simple 
concomitant medication 
and that the safety and 
efficacy of non-live 
vaccines (including 
COVID-19 vaccines) in 
participants receiving 
nivolumab is unknown. 
Non-live COVID-19 vaccines are 
considered a simple concomitant 
medication since a significant 
interaction between these vaccines and 
the study treatment is not anticipated. 
The safety and efficacy of non-live 
vaccines (including COVID-19 
vaccines) in participants receiving 
nivolumab continues to evolve.
Section 7.7.1: 
Prohibited and/or 
Restricted Treatments
Updated text to (1) replace 
the terminology of 
“botanical preparations” 
with “complementary 
medications”, and (2) 
indicate that 
complementary 
medications are permitted 
if they are used as 
supportive care.
Terminology introduced to reflect the 
wider array of products that may be in 
use by trial participants. In addition, the 
use of such products is only a concern 
when used to treat the study entry 
melanoma, and not for supportive care 
purposes.
Section 8.1: 
Discontinuation from 
Study Treatment
Inserted a cross-reference 
to Section 7.4.1 for details 
regarding discontinuation 
of nivolumab or 
nivolumab-placebo.
Reference to Section 7.4.1 inserted to 
direct the reader to Table 7.4.1-1 due to 
the reformatting of criteria to delay, 
resume, and discontinue study 
treatment.
Section 9.2.1: Time 
Period and Frequency 
for Collecting AE and 
SAE Information
Section 9.4: Safety
Edited text to clarify that 
the management and 
reporting of all AEs/SAEs 
is per CTCAE v5.
AE management in the previous 
version of the protocol based on 
CTCAE v4 was updated to CTCAE v5.
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BMS-936558
nivolumab
Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Section 9.4.4: Clinical 
Safety Laboratory 
Assessments
Added serum urea and 
phosphate as alternative 
laboratory assessments to 
blood urea nitrogen 
(BUN) and phosphorus, 
respectively. 
Change made to accommodate local 
laboratory testing practices.
Table 9.5-1: 
Pharmacokinetic (PK) 
and Immunogenicity 
Sampling Collections 
for Blinded Nivolumab 
or Placebo-Treated 
Participants or 
Participants Treated 
with Open-Label 
Nivolumab After First 
Recurrence
Added ± 7-day window to 
Follow-up Visits 1 and 2.
A window of ± 7 days was added to be 
consistent with the ± 7-day window for 
these visits.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Section 10.1.2: Overall 
Survival
Clarified that a formal 
interim OS analysis is not 
planned at the time of 
RFS analysis (interim or 
final).
Anticipated immaturity of OS data at 
the time of RFS analysis.
Inserted text to indicate 
that descriptive OS data 
will be provided at the 
time of significant RFS 
data (interim or final). In 
addition, the projected 
number of deaths at the 
time of the interim and 
final RFS analysis has 
been introduced.
 
Section 10.3.4: Interim 
Analyses
Type I error updated for 
the interim and final RFS 
analyses.
Correction made to be consistent with 
Section 10.1.1: RFS.
Section 11: References
List was updated.
Based on updates/additions as per 
Protocol Amendment 02.
Appendix 1: 
Abbreviations and 
Trademarks
Abbreviations list was 
updated.
For consistency within the protocol.
Appendix 2: Study 
Governance 
Considerations
Appendix was updated 
with standard language.
To align with current standards.
Appendix 3: Adverse 
Events and Serious 
Adverse Events: 
Appendix was updated 
with standard language.
To align with current standards.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Protocol Amendment 02
Section Number and 
Title
Description of Change
Brief Rationale
Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting
Appendix 4: Women of 
Childbearing Potential 
Definitions and 
Methods of 
Contraception
Appendix was updated 
with standard language.
To align with current standards.
Appendix 5: 
Management 
Algorithms for Studies 
Under CTCAE Version 
5.0
Algorithms were updated.
To align with most current version.
Throughout
Removed mention of 
“Study Director”
This title is no longer used.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Overall Rationale for the Revised Protocol 01, 16-Oct-2020
 
 
 
 
The protocol has been modified to incorporate this and other 
changes described below.
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Synopsis: Key 
Inclusion Criteria
Made a clarification in 
inclusion criterion “b” to 
include wording for timing of 
sentinel lymph node negativity 
assessment as it relates to the 
12-week window post complete 
resection with negative 
margins.
Due to the potential for 
geographic/institutional differences in 
the timing of sentinel lymph node 
assessment in relation to the wide local 
excision (WLE), the inclusion criterion 
was clarified that regardless of when 
the sentinel lymph node assessment 
was performed in relation to the 
surgery that documents the patient has 
negative margins, the 12-week clock is 
calculated from the time of this surgery 
to randomization. The clarification was 
provided to potentially reduce any bias 
in estimation of the RFS endpoint due 
to variability in sentinel lymph node 
assessment timing.
Clarification was made to 
inclusion criterion “c” to 
indicate that imaging of 
extremities for resected 
melanomas located in the 
extremities is not a requirement 
and may be conducted per local 
standard of care.
The current protocol requires baseline 
body imaging of chest, abdomen, pelvis 
(CT-chest/abdomen/pelvis or CT-chest 
and MRI-abdomen/pelvis), and all 
known sites of resected disease (lymph 
nodes ≥ 15 mm in short axis). Since the 
imaging of extremities by CT/MRI for 
primary extremity melanomas that have 
been resected is not generally done per 
standard of care in this patient 
population, and not recommended by 
major international guidelines, the 
criterion was clarified to indicate that 
the imaging of extremities was not 
mandatory and that the baseline 
evaluation could be conducted and 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
documented by the local standard of 
care.
Synopsis: Key 
Exclusion Criteria
To exclusion criterion “1.f”, 
additional direction regarding 
the evaluation of participants 
with prior SARS-CoV-2 
infection was added.
Exclusion criterion “1.f” excludes 
randomizing participants with serious 
or uncontrolled medical disorders. The 
text regarding the evaluation of 
participants with prior SARS-CoV-2 
infection was added to provide further 
clarity to sites on the handling of these 
situations.
To exclusion criterion “2.c” an 
exception was added that prior 
adjuvant treatment with 
interferon (for melanoma other 
than study entry melanoma) is 
allowed if completed ≥ 6 
months prior to randomization.
Prior treatment with interferon is not 
anticipated in this study population. In 
some countries, low-dose adjuvant 
treatment with interferon is approved in 
melanomas above 1.5 mm, although, 
the use of this agent is anticipated to be 
rare. The current protocol does not 
allow for the use of any systemic anti-
cancer therapy beyond surgical 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
resection for the study entry melanoma.
The prior use of this agent for a 
melanoma resected in the remote past is 
anticipated to have minimal to no 
impact on the evaluation of outcomes 
for the study entry melanoma.
Synopsis, Section 
4: Objectives and 
Endpoints
The “Endpoint” for the 
Secondary Objective regarding 
the safety and toxicity of 
nivolumab monotherapy was 
updated to “Occurrence and 
severity of AEs as defined by 
NCI CTCAE v5.”
Clarified endpoint language to be 
reflective of the broader scope of safety 
and toxicity evaluation.
Synopsis: Study 
Design
Clarified language regarding 
timeframe for participation of 
placebo and nivolumab 
treatment-assigned patients to 
participate in the open-label
portion of the trial in the event 
of recurrence on the blinded 
portion of the trial.
Editorially clarified the language to be 
consistent with text in the main body of 
the protocol.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Synopsis: 
Number of 
Participants
Number of participants was 
changed from 
 to 
Updated to allow adequate minimum 
follow-up time at the interim analysis 
of primary endpoint.
Synopsis: Study 
Treatments
Table was updated to list the 
nivolumab potency that will be 
used.
Text updated to reflect the intent of the 
column, which is to list the nivolumab 
potency, and not the presentation.
Synopsis: 
Statistical 
Considerations
Statistical section was updated.
Synopsis: 
References
References were updated.
Omitted in error.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
“Serious Adverse Event 
Assessment” row, inserted text 
that all AEs (SAEs or non-
serious AEs) associated with 
SARS-CoV-2 infection will be 
collected from time of consent.
Text inserted to document, at Baseline, 
AEs attributed specifically to SARS-
CoV-2 infection, thereby, facilitating 
the analysis and interpretation of 
downstream safety data during 
treatment and in follow-up.
“Body Imaging” row added 
clarification in the “Notes” 
column that “imaging of 
extremities for resected 
melanomas located in the 
extremities is not a requirement 
and may be conducted per local 
standard of care.”
The current protocol requires baseline 
body imaging of chest, abdomen, pelvis 
(CT-chest/abdomen/pelvis or CT-chest 
and MRI-abdomen/pelvis), and all 
known sites of resected disease (lymph 
nodes ≥ 15 mm in short axis). Since the 
imaging of extremities by CT/MRI for 
primary extremity melanomas that have 
been resected is not generally done per 
standard of care in this patient 
population, and is not recommended by 
major international guidelines, the 
criterion was clarified to indicate that 
the imaging of extremities was not 
mandatory and that the baseline 
evaluation could be conducted and 
documented by the local standard of 
care.
Section 2, Table 
2-2: On-
Treatment 
Assessments 
CA20976K 
(Applies to All 
“Targeted Physical 
Examination” row added “Pay 
special attention to skin and 
nodal examination.” in the 
“Notes” column.
Emphasis on nodal examination, in 
addition to skin examination, was 
added to align with the intent of 
identifying local/regional recurrences 
per recommendations made by national 
guidelines (as stated in Section 5.4.10 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Participants: 
Blinded or Open-
label Treatment)
“Rationale for Follow-up Clinic Visit 
Frequency”).
“Adverse Events Assessment” 
row, inserted text that all AEs 
(SAEs or non-serious AEs 
associated with SARS-CoV-2 
infection) will be collected 
continuously during treatment.
Introduced text that for 
reporting purposes, all 
AEs/SAEs are to be graded 
using CTCAE v5. However, for 
management, events must be re-
graded using CTCAE v4.
Text inserted to document, during 
treatment, AEs attributed specifically to 
SARS-CoV-2 infection, thereby, 
facilitating the analysis and 
interpretation of the overall safety data
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
“Body Imaging” row added 
clarification in the “Notes” 
column that “imaging of 
extremities for resected 
melanomas located in the 
extremities is not a requirement 
and may be conducted per local 
standard of care. Extremity 
imaging should be conducted in 
the event of a suspected 
locoregional relapse that is not 
clinically unequivocal.”
The current protocol requires baseline 
body imaging of chest, abdomen, pelvis 
(CT-chest/abdomen/pelvis or CT-chest 
and MRI-abdomen/pelvis), and all 
known sites of resected disease (lymph 
nodes ≥ 15 mm in short axis). Since the 
imaging of extremities by CT/MRI for 
primary extremity melanomas that have 
been resected is not generally done per 
standard of care in this patient 
population, and is not recommended by 
major international guidelines, the 
criterion was clarified to indicate that 
the imaging of extremities was not
mandatory and that the baseline 
evaluation could be conducted and 
documented by the local standard of 
care. In addition, the need to image the 
extremity was added to follow-up on a 
suspected locoregional relapse that is 
clinically equivocal.
Also from “Body Imaging” row 
“Notes” column, deleted text 
regarding imaging in the open-
label resectable disease arm 
(Arm 1) for participants in the 
Stage IIB/C participants in the blinded 
portion of the trial who relapse will 
most likely have recurrences that are 
most advanced in Stage (III/IV), 
therefore, the text referring to 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
blinded portion of the trial who 
have recurrent disease other 
than Stage III/IV.
recurrences other than Stage III/IV was 
deleted.
Section 2, Table 
2-3: Long-Term 
Follow-Up 
CA20976K 
(Applies to All 
Participants: 
Blinded or Open-
label Treatment)
Introduced text that for 
reporting purposes, all 
AEs/SAEs are to be graded 
using CTCAE v5. However, for 
management, events must be re-
graded using CTCAE v4.
Streamlined the AE/SAE 
section text.
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Text in this section was rearranged and 
streamlined to refer the reader to 
Section 9.2 (Adverse Events), where 
AE/SAE management (including 
details for AE/SAE handling for 
SARS-CoV-2 related infection) is 
described in greater detail.
“Pregnancy Test” row, in the 
“Notes” column option to have 
increased pregnancy testing 
beyond Follow-Up Visits 1 and 
2 was added.
Option added to comply with 
applicable local regulatory 
requirements for increased frequency of 
pregnancy testing.
“Body Imaging” row added 
clarification in the “Notes” 
column that “imaging of 
extremities for resected 
melanomas located in the 
extremities is not a requirement 
and may be conducted per local 
standard of care. Extremity 
imaging should be conducted in 
the event of a suspected 
locoregional relapse that is not 
clinically unequivocal.”
The current protocol requires baseline 
body imaging of chest, abdomen, pelvis 
(CT-chest/abdomen/pelvis or CT-chest 
and MRI-abdomen/pelvis), and all 
known sites of resected disease (lymph 
nodes ≥ 15 mm in short axis). Since the 
imaging of extremities by CT/MRI for 
primary extremity melanomas that have 
been resected is not generally done per 
standard of care in this patient 
population, and is not recommended by 
major international guidelines, the 
criterion was clarified to indicate that 
Protocol Amendment No.: 03
Date: 28-Apr-2022
204
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930137673
4.0
v
Approved
1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
the imaging of extremities was not 
mandatory and that the baseline 
evaluation could be conducted and 
documented by the local standard of 
care. In addition, the need to image the 
extremity was added to follow-up on a 
suspected locoregional relapse that is 
clinically equivocal.
Also from “Body Imaging” row 
“Notes” column, deleted text 
regarding imaging in the open-
label resectable disease arm 
(Arm 1) for participants in the 
blinded portion of the trial who 
have recurrent disease other 
than Stage III/IV.
Stage IIB/C participants in the blinded 
portion of the trial who relapse will 
most likely have recurrences that are 
most advanced in Stage (III/IV), 
therefore, the text referring to 
recurrences other than Stage III/IV was 
deleted.
Section 5.1: 
Overall Design
Updated schema to reflect 
sample size change from 
 
to 
 and accordingly 
adjusted the nivolumab arm 
Change made to align with revised 
sample size.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Approved
1.0
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
sample size from 
 to 
 
and placebo arm sample size 
from 
 to 
Section 5.1.1: 
Nivolumab or 
Placebo Blinded 
Treatment
In “Screening”, clarified that 
tumor tissue should be shipped 
to central lab prior to 
randomization and removed 
language stating that “receipt of 
minimum tissue requirement 
will be assessed by central lab 
prior to randomization.”
Deleted requirement for the central lab 
to confirm the receipt of Screening 
tumor tissue prior to randomization to 
eliminate delays in randomization since 
the information evaluated by the central
lab was not used for stratification 
purposes.
In “Screening”, deleted text that 
participants should not have 
received any systemic therapy 
after the date that the submitted 
tumor tissue was obtained.
Redundant text that is already covered 
in the eligibility criteria.
In “Treatment”, added text on 
“nodal examination” in addition 
to skin examination.
Emphasis on nodal examination, in 
addition to skin examination, was 
added to align with the intent of 
identifying local/regional recurrences 
per recommendations made by national 
guidelines (as stated in Section 5.4.10 
“Rationale for Follow-up Clinic Visit 
Frequency”).
Section 5.1.2: 
Optional On-
Protocol Open-
Label Nivolumab 
Treatment After 
First Recurrence
Section 5.1.3: 
Data Monitoring 
Committee and 
Other External 
Committees
Added text that a Study 
Steering Committee (SSC) has 
been established.
A SSC was selected to better guide the 
Sponsor on the scientific aspects of 
conducting the trial.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Section 5.2: 
Number of 
Participants
Changed number of participants 
from 
 to 
Change made to align with revised 
sample size, allowing higher 
information fraction and adequate 
minimum follow-up at interim analysis 
of primary endpoint.
Section 5.4.11: 
Rationale for 
Continued 
Adjuvant Therapy 
for Patients who 
are Diagnosed 
with Malignant 
Melanoma in Situ 
During Study 
Treatment
New section added with 
language for continued study 
treatment for participants who 
develop a malignant melanoma 
in situ (MMIS) during 
treatment.
Added to continue study treatment 
without unblinding in the event the 
participant develops MMIS lesions due 
to the excellent prognosis of this lesion 
with appropriate treatment per standard 
of care.
Section 6.1.1: 
Inclusion Criteria 
- Blinded 
Nivolumab or 
Placebo 
Treatment
In criterion “2.a”, inserted text 
that patients with Stage IIB/C 
melanoma who present with 
synchronous or metachronous 
Stage < 2 melanomas that have 
been completely resected will 
be allowed.
The inclusion criteria did not 
specifically address synchronous or 
metachronous melanomas. Patients 
with synchronous or metachronous 
melanomas that are below Stage II have 
an excellent 5-year melanoma-specific 
survival of greater than 95%, and the 
risk for melanoma recurrence is greater 
with the study entry Stage IIB/C 
melanoma; therefore, patients with 
synchronous or metachronous 
melanomas less than Stage II will be 
allowed on this trial.
Clarified inclusion criterion 
“2.b” to include wording for 
timing of sentinel lymph node 
negativity assessment as it 
relates to the 12-week window 
post complete resection with 
negative margins.
Due to the potential for 
geographic/institutional differences in 
the timing of sentinel lymph node 
assessment in relation to the wide local 
excision (WLE), the inclusion criterion 
was clarified that regardless of when 
the sentinel lymph node assessment 
was performed in relation to the 
surgery that documents the patient has 
negative margins, the 12-week clock is 
calculated from the time of this surgery 
to randomization. The clarification was 
provided to potentially reduce any bias 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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930137673
4.0
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Approved
1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
in estimation of the RFS endpoint due 
to variability in sentinel lymph node 
assessment timing.
Clarified inclusion criterion 
“2.e” to indicate that imaging of 
extremities for resected 
melanomas located in the 
extremities is not a requirement 
and may be conducted per local
standard of care.
The current protocol requires baseline 
body imaging of chest, abdomen, pelvis 
(CT-chest/abdomen/pelvis or CT-chest 
and MRI-abdomen/pelvis), and all 
known sites of resected disease (lymph 
nodes ≥ 15 mm in short axis). Since the 
imaging of extremities by CT/MRI for 
primary extremity melanomas that have 
been resected is not generally done per 
standard of care in this patient 
population, and is not recommended by 
major international guidelines, the 
criterion was clarified to indicate that 
the imaging of extremities was not 
mandatory and that the baseline 
evaluation could be conducted and 
documented by the local standard of 
care.
Protocol Amendment No.: 03
Date: 28-Apr-2022
208
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930137673
4.0
v
Approved
1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Section 6.2.1: 
Exclusion Criteria 
- Blinded 
Nivolumab or 
Placebo 
Treatment
To exclusion criterion “1.f”, 
additional direction regarding 
the evaluation of participants 
with prior SARS-CoV-2 
infection was added.
Exclusion criterion “1.f” excludes 
randomizing participants with serious 
or uncontrolled medical disorders. The 
text regarding the evaluation of 
participants with prior SARS-CoV-2 
infection was added to provide further 
clarity to sites on the handling of these 
situations.
To exclusion criterion “2.c” an 
exception was added that prior 
adjuvant treatment with 
interferon (for melanoma other 
than study entry melanoma) is 
allowed if completed ≥ 6 
months prior to randomization.
Prior treatment with interferon is not 
anticipated in this study population. In 
some countries, low-dose adjuvant 
treatment with interferon is approved in 
melanomas above 1.5 mm, although, 
the use of this agent is anticipated to be 
rare. The current protocol does not 
allow for the use of any systemic anti-
cancer therapy beyond surgical 
resection for the study entry melanoma. 
The prior use of this agent for a 
melanoma resected in the remote past is 
anticipated to have minimal to no 
impact on the evaluation of outcomes 
for the study entry melanoma.
Section 6.4.1: 
Retesting During 
Screening or 
Lead-In Period
Inserted text that testing for 
asymptomatic COVID-19 
infection, for example, by 
reverse transcription 
polymerase chain reaction (RT-
PCR) or viral antigen is not 
Testing by RT-PCR or viral antigens of 
all participants during Screening to 
identify asymptomatic infection with 
SARS-CoV-2 is not required due to the 
current limitations in molecular testing. 
Additional guidance on handling 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
required. In addition, inserted 
text to provide guidance on 
handling of participants who 
may develop suspected or 
confirmed symptomatic 
COVID-19 infection or be 
discovered to have 
asymptomatic COVID-19 
infection during the Screening 
period.
participants who may develop 
suspected or confirmed symptomatic 
COVID-19 infection or be discovered 
to have asymptomatic COVID-19 
infection during the Screening period 
has been inserted based on the Center 
for Disease Control (CDC) guidance 
for return to work for healthcare 
workers.
Section 7: 
Treatment
Table 7-1 was updated to list 
the nivolumab potency that will 
be used and the ‘Packaging’ and 
‘Storage Conditions’ 
information was also updated.
Text updated to reflect the intent of the 
column, which is to list the nivolumab 
potency, and not the presentation, as 
well as the packaging and storage 
conditions.
Section 7.2.1: 
Blinded 
Nivolumab or 
Placebo 
Treatment
Removed language regarding 
receipt of minimum tissue 
requirement to be assessed by 
central lab prior to 
randomization.
Deleted requirement for the central lab 
to confirm the receipt of Screening 
tumor tissue prior to randomization to 
eliminate delays in randomization since 
the information evaluated by the central 
lab was not used for stratification 
purposes.
Section 7.4.1: 
Dose Delay 
Criteria
Added text that for dose delays, 
events will be reported per 
CTCAE v5, and re-graded using 
CTCAE v4 for management.
Added bullet point to delay 
dosing for SARS-CoV-2 
infection (confirmed or 
suspected).
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Text added in the interest of ensuring 
trial participant safety.
Section 7.4.2: 
Treatment of 
Nivolumab-
Related Infusion 
Reactions
Added text that infusion 
reactions will be reported per 
CTCAE v5, and re-graded using 
CTCAE v4 for management.
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Section 7.4.3: 
Criteria to 
Resume 
Treatment
Added text that AEs will be re-
graded per NCI CTCAE v4 to 
determine resuming treatment. 
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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4.0
v
Approved
1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Added criteria to resume 
treatment for participants with 
suspected or confirmed 
SARS-CoV-2 infection.
Criteria added to provide guidance to 
sites on resuming study treatment for 
participants in whom study treatment 
was held due to suspected or confirmed 
SARS-CoV-2 infection.
Section 7.7.1: 
Prohibited and/or 
Restricted 
Treatments
Added section reference for 
permitted corticosteroid
therapy.
To provide further information and 
direct the reader to the section for 
permitted corticosteroid therapy.
Section 7.8.1: 
Treatment 
Beyond Disease 
Progression
Section 7.8.1.1: Blinded 
Nivolumab/Placebo Participants 
and Participants Receiving 
Optional Open-Label 
Nivolumab Monotherapy After 
Recurrence (in Arm 1 
[resectable disease]), and its 
associated text referring to the 
appearance of a melanoma in 
situ lesion as a progression 
event was deleted.
This section in the protocol is reserved 
for the classical pseudoprogression 
phenomenon reported with 
immunotherapy treatment in patients 
with unresectable/metastatic disease. 
The development of a MIS does not fit 
the definition of classic 
pseudoprogression, and hence the text 
has been deleted.
Section 8.1.1: 
Discontinuation of 
Nivolumab or 
Nivolumab-
Placebo
Added text that for dose 
discontinuations, events will be 
reported per CTCAE v5, and re-
graded using CTCAE v4 for 
management.
The current toxicity management 
guidelines in the protocol are based on
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Reference to “Recurrence” in 
the context of “Treatment 
Beyond Disease Progression” 
was deleted from the reference 
to Section 7.8.1 in the first 
bullet point.
Update was made consequent to 
deleting Section 7.8.1.1 above.
Modified text addressing study 
treatment discontinuations due 
to dose delays > 8 weeks for 
non-drug related reasons to 
include COVID-19 as a non-
drug-related reason.
Added text to provide guidance to sites 
regarding continuing treatment in 
participants whose study treatment 
were delayed beyond 8 weeks from the 
previous dose due to COVID-19 related 
reasons.
Protocol Amendment No.: 03
Date: 28-Apr-2022
211
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4.0
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Approved
1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Section 9.1.1.1: 
Methods of 
Measurement
Language regarding imaging of 
extremities added/clarified as 
follows: Imaging of extremities 
for resected melanomas located 
in the extremities is not a 
requirement and may be 
conducted per local standard of 
care. Extremity imaging should 
be conducted in the event of a 
suspected locoregional relapse 
that is not clinically 
unequivocal.
The current protocol requires baseline 
body imaging of chest, abdomen, pelvis 
(CT-chest/abdomen/pelvis or CT-chest 
and MRI-abdomen/pelvis), and all 
known sites of resected disease (lymph 
nodes ≥ 15 mm in short axis). Since the 
imaging of extremities by CT/MRI for
primary extremity melanomas that have 
been resected is not generally done per 
standard of care in this patient 
population, and is not recommended by 
major international guidelines, the 
criterion was clarified to indicate that 
the imaging of extremities was not 
mandatory and that the baseline 
evaluation could be conducted and 
documented by the local standard of 
care. In addition, the need to image the 
extremity was added to follow-up on a 
suspected locoregional relapse that is 
clinically equivocal.
Section 9.1.2.1: 
General 
Considerations for 
Determining 
Recurrence
The original title of Section 
9.1.2.1, “Investigator 
Assessment of Recurrence 
(Nivolumab/Placebo Blinded 
Treatment and Open-Label 
Nivolumab - Arm 1)” was 
rearranged as Section 9.1.2.2, 
and Section 9.1.2.1 was 
renamed with the title “General 
Considerations for Determining 
Recurrence”. In addition, the 
content in each of these sections 
was rearranged.
Changes made for better flow and 
readability.
New text added to Section 
9.1.2.1 to provide direction 
regarding cytological and/or 
histological confirmation of 
melanoma recurrence.
Provide greater clarity on situations 
where cytological and/or histological 
confirmation or recurrence is 
mandatory. In addition, emphasized the 
need at attempting cytological and/or 
histological confirmation of all 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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4.0
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Approved
1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
recurrences when clinically feasible, 
per regulatory agency feedback.
Section 9.1.2.4: 
Date of 
Recurrence
Added a new section to specify 
how the date of recurrence will 
be determined for the primary 
endpoint evaluation.
To add clarity.
Section 9.2.1: 
Time Period and 
Frequency for 
Collecting AE 
and SAE 
information
Introduced text that for 
reporting purposes, all 
AEs/SAEs are to be graded 
using CTCAE v5. However, for 
management, events must be re-
graded using CTCAE v4. 
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Separated AE/SAE reporting 
requirements for the Blinded 
Nivolumab/Placebo portion and 
the Open-Label portion.
Change made for better readability.
Inserted text that all AEs (SAEs 
or nonserious AEs) related to 
SARS-CoV2 infection will be 
collected during the blinded 
nivolumab/placebo portion of 
the trial, as well as the open-
label portion of the trial, with 
reporting intervals for each of 
these portions.
Text inserted to outline the collection 
time period for AEs attributed 
specifically to SARS-CoV-2 infection, 
to better facilitate the analysis and 
interpretation of the overall safety data.
In the blinded portion, inserted 
language that new-onset serious 
AEs do not need to be reported 
beyond 100 days of 
discontinuation of study 
treatment, if subsequent anti-
cancer therapy is initiated, 
Initiation of subsequent anti-cancer 
therapy could confound the 
evaluation/attribution of the serious AE 
to CA20976K study therapy. An 
option, however, is still provided to 
report the event if it is felt to be related 
to the CA20976K study therapy to 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
unless the event was felt to be 
related to the CA20976K study 
treatment. In addition, inserted 
text that nonserious treatment-
related AEs do not need to be 
reported with an onset date on 
or after initiation of subsequent 
anti-cancer therapy. For the 
open-label portion clarified that 
nonserious AEs do not need to 
be reported beyond 100 days of 
discontinuation of study 
treatment.
completely capture the SAE profile of 
the study treatment.
Section 9.2.2: 
Method of 
Detecting AEs 
and SAEs
Deleted text regarding the 
frequency of reporting 
nonserious AEs, as well as 
reference to the Schedule of 
Assessments and Long-term 
Follow-up tables for further 
details.
AE/SAE reporting details have been 
captured in Section 9.2.1; hence, text 
was deleted to reduce redundancy.
Section 9.2.3: 
Follow-up of AEs 
and SAEs
Inserted text stating that follow-
up and recording of nonserious 
AEs and SAEs applies to AEs 
related to SARS-CoV-2 
infection as well.
Text added for clarification that SARS-
CoV-2 associated AEs will be collected 
during follow-up and to align with text 
in earlier safety sections.
Section 9.4: 
Safety
Updated text to state that AEs, 
including laboratory 
abnormalities, will be reported 
per NCI CTCAE v5, and re-
graded using NCI CTCAE v4 
for management.
The current toxicity management 
guidelines in the protocol are based on 
CTCAE v4 and will be updated in the 
future to CTCAE v5.
Section 9.5: 
Pharmacokinetic 
and 
Immunogenicity 
Assessments
Added text giving the 
nivolumab infusion and 
sampling timepoints.
Provide additional clarity to sites on the 
timing of End of Infusion blood draws 
to accommodate flushing of residual 
study treatment in intravenous (IV) 
lines.
Table 9.5-1: Clarified footnote 
“c” regarding timing of sample 
draw for End of Infusion 
timepoint.
Provide additional clarity to sites on the 
timing of End of Infusion blood draws 
to accommodate flushing of residual 
Protocol Amendment No.: 03
Date: 28-Apr-2022
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1.0
v

Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
study treatment in intravenous (IV) 
lines.
Section 9.8.1: 
Additional 
Research 
Collection
Inserted additional text 
regarding residual sample 
storage for additional research 
for US sites. In addition, 
updated Table 9.8.1-1 as well.
Text added to clarify coverage to 
ensure all sample types and derived 
materials are available for additional 
research.
Protocol Amendment No.: 03
Date: 28-Apr-2022
215
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
Section 10.1.2: 
Overall Survival 
(OS)
Adjusted the sample size from
 to 
 participants.
Sample size was adjusted from 
 to 
 participants to align with revised 
statistical parameters.
.
 
Section 10.3.1.2: 
Secondary 
Endpoint 
Analyses
Under ‘Investigator-Assessed 
Outcomes on Next-Line 
Therapies’, removed “These 
endpoints will be analyzed 
using a two-sided log-rank test 
at the overall significance level 
of 5% (two-sided) in all 
No formal testing will be done on next-
line therapy.
Protocol Amendment No.: 03
Date: 28-Apr-2022
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Clinical Protocol
CA20976K
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 01
Section Number 
and Title
Description of Change
Brief Rationale
randomized participants” and 
“No multiplicity adjustment 
will be applied”.
Section 10.3.4: 
Interim Analyses
Updated the IA for RFS 
analysis to be conducted at 
increased number of events 
To ensure adequate maturity of the data 
at the time of IA.
Removed language regarding 
OS interim analysis.
OS interim analysis deleted due to data 
immaturity.
Appendix 1: 
Abbreviations 
and Trademarks
List updated with additional 
abbreviations used.
Newly added text in the protocol.
Appendix 5: 
Management 
Algorithms
Updated the algorithms and 
added the Myocardial 
algorithm.
Program updates.
All
Minor formatting and 
typographical corrections.
Minor, therefore have not been 
summarized.
Protocol Amendment No.: 03
Date: 28-Apr-2022
217
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Approved
1.0
v