A Double-Blind, Randomized, Two Arm Phase 2 Study of Nivolumab in Combination With Ipilimumab Versus Nivolumab in Combination With Ipilimumab Placebo in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA209714
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 25-May-2018
2
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 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
 
 
 
 
 
 
 
5.0
Approved
930101794
5.0
v
Revised Protocol No.: 04
Date: 25-May-2018
4

Clinical Protocol
CA209714
BMS-936558
nivolumab
SYNOPSIS
Clinical ProtocolCA209714
Protocol Title: A Double-Blind, Randomized, Two Arm Phase 2 Study of Nivolumab in Combination with 
Ipilimumab versus Nivolumab in Combination with Ipilimumab Placebo In Recurrent or Metastatic Squamous Cell 
Carcinoma of the Head and Neck (SCCHN) (CheckMate 714: CHECKpointpathway and nivoluMAb clinical Trial 
Evaluation 714)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 
Nivo and Ipi combo Arm A: 
Nivolumab 3 mg/kg IV will be administered every 2 weeks (3days) 
Ipilimumab 1 mg/kg IV will be administered every 6 weeks (3days) following the administration of nivolumab.
(1 Cycle =6 Weeks)
Nivo and Ipi-placebo Arm B:
Nivolumab 3 mg/kg IV will be administered every 2 weeks (3days).
Ipi-Placebo IV will beadministered every 6 weeks (3days) following the administration of nivolumab.
(1 Cycle =6 Weeks)
Study Phase: II
Study Population:
Subjects must have metastatic or recurrent disease that is not amenable to therapy with curative intent (surgery or 
radiation therapy with or without chemotherapy). Subjects that refuse potentially curative salvage surgery for recurrent 
disease are ineligible.
Two subgroups will be enrolled into this study. Subjects will be classified as platinum refractory or platinum eligible:
Platinum refractory subgroup (n=approximately 216): subjects with histologically confirmed SCCHN that has 
recurred during or less than 6 months after completion of previous platinum-based chemotherapy, given as 
adjuvant or neoadjuvanttreatment or as part of multimodal treatment (chemotherapy, surgery, radiotherapy) for 
locally advanced disease. Subjects should have not received systemic anti-cancer therapy in the recurrent or 
metastatic setting.
Platinum eligible subgroup (n= approximately 180): subjects with histologically confirmed SCCHN who are 
platinum naive, or have recurred 6 months or more after completion of previous platinum-based chemotherapy, 
given as adjuvant or neoadjuvant treatment or as part of multimodal treatment (chemotherapy, surgery, 
radiotherapy) for locally advanced disease. Subjects should have not received systemic anti-cancer therapy in the 
recurrent or metastatic setting.
Research Hypothesis: 
In patients with recurrent or metastatic SCCHN,the administration of nivolumab in combination with ipilimumab 
as first-line therapy in the platinum refractory setting will improve objective response rate (ORR) and duration of 
response (DOR) compared to nivolumab in combination with ipilimumab placebo. 
Revised Protocol No.: 04
Date: 25-May-2018
7
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Study Population: 
For entry into the study, the following criteria MUST be met:
Key Inclusion Criteria (See Protocol Section 3.4.1 for full list of criteria)
a) Histologically confirmed head and neck squamous cell carcinoma (SCCHN), from any of the following
primary sites only: oral cavity, oropharynx, hypopharynx and larynx or unknown primary location (if p-16 
positive).  
b) Subjects must have metastatic or recurrent disease that is not amenable to therapy with curative intent 
(surgery or radiation therapy with or without chemotherapy). Subjects that 
refuse potentially curative salvage 
surgery for recurrent disease are ineligible.
c) Subjects will be classified as platinum refractory (n=approximately 216) or platinum eligible (n=
approximately 180). Definitions of the subgroups are found above. 
d) Eastern Cooperative Oncology Group (ECOG) Performance Status of 1 (See Appendix 1)
e) Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 
criteria. 
f) Documentation of HPV p-16 status is required for SCCHN tumor of the oropharynx. Subjects with unknown 
primary location must have documented positive p-16 status. 
g) Documentation of PD-L1 status by IHC performed by the central lab at randomization. 
h) Screening laboratory values must meet the following criteria (using CTCAE v4):
i) WBC
2000/uL
ii) Neutrophils
1500/uL
iii)Platelets
100x103/uL
iv)-Hemoglobin
9.0 g/dL
Arm A
N
ivolumab 3 mg/kg IV Q2wks 
+ Ipilimumab 1 mg/kg IV Q6wks
Randomized
2:1
Stratify by:
•Platinum refractory 
subgroup  (yes/no)
•PD-L1 status
•HPV p-16
Arm B
N
ivolumab 3mg/kg IV Q2 wks
+ Ipi-Placebo IV Q6wks
Follow-up: 
Data collection for 
primary endpoint 
ORR as we
l
l as 
Follow-up Visits for 
Safety and Survival
SCCHN First-l
ine
1) Platinum eligible subgroup
(N = approxim
ate
ly 180)  
• Histologically conf
irmed SCCHN
• Platinum naïve or recurrence ≥ 
6 m after completion of prior 
platinum based chemotherapy 
(ad
juvant/neo-ad
juvant/mu
lt
i-
modal therapy) 
• No prior systemic therapy for 
recurrent or metastatic disease
2) Platinum refractory subgroup 
(N = approximately216)
• H
istologicallyconfirmed SCCHN 
recurrence < 6 m after completion 
of prior platinum based 
chemotherapy (ad
juvant/neo-
ad
juvant/mu
lt
i-modal)
• No prior systemic therapy for 
recurrent disease
Note: Tumor issue required for PD-L1 
and HPV p-16 (oropharyngeal cancer 
and unknown primary) tesing prior to 
randomization. 
Treat until progression,* 24 month from
 first dose, withdrawal of informed consent, or 
unacceptable toxicity
*Treatment beyond initial 
investigatorassessed RECIST 1.1defined progression will be 
considered in subjects experiencing investigator
-assessed clinical benefit and tolerating 
study therapy. This is to a maximum o
f 24 months from date of first dose. Such
 subjects 
must discontinue therapy when
 further progression is documented.
Revised Protocol No.: 04
Date: 25-May-2018
10
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
v) Serum creatinine
1.5 x ULN or calculated creatinine clearance > 40 mL/min (using the Cockcroft 
Gault formula)
Female CrCl = (140-age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl = (140-age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
vi)
AST
3.0 x ULN 
vii)
ALT
3.0 x ULN 
Total Bilirubin
1.5 x ULN (except subjects with Gilbert Syndrome who must have a total 
bilirubin level of < 3.0x ULN). 
i) Subjects must have an estimated life expectancy of at least 3 months.
Key Exclusion Criteria (See Protocol Section 3.4.2 for full list of criteria)
1. Target Disease Exceptions
a) Recurrent or metastatic carcinoma of the nasopharynx, paranasal sinus, squamous cell carcinoma that 
originated from the skin and salivary gland or non-squamous histologies (eg,mucosal melanoma). 
b) Subjects with untreatedcentral nervous system (CNS) metastases. 
Subjects are eligible if CNS metastases have been adequately treated and have neurologically returned to 
baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to 
randomization. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of 
10 mg daily prednisone (orequivalent) for at least 2 weeks prior to randomization.
c) Subjects with carcinomatous meningitis.
d) Any prior treatment with any non-platinum containing systemic therapy regimen for SCCHN (adjuvant, 
neoadjuvant, or multi-modal treatment). 
2. Medical History and Concurrent Diseases
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-programmed death ligand 2 (PD-L2), anti-cytotoxic 
T-lymphocyte associated protein 4 (anti-CTLA-4) antibody, or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways.
3. Physical and Laboratory Test Findings
a) 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).
b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).
Revised Protocol No.: 04
Date: 25-May-2018
11
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Product 
Description / 
Class and 
Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions
(per label)
BMS-936558-01 
(Nivolumab) 
Solution for 
Injection
100 mg (10 
mg/mL)
IP
Open-labela
10 mL/vial (5 or 
10vials/carton)
Store at 
2°-8°C.
Protect from 
light and 
freezing.
Ipilimumab 
Solution for 
Injection
200 mg
(5 mg/mL)
IP
Open-labela
40 mL/vial 
(4vials/carton)
Store at 2°-8°C. 
Protect from 
light and 
freezing.
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
a Theterm “open label” refers to the medication as it is upon receipt at the pharmacy. The trial will be conducted in 
a double-blinded fashion
Study AssessmentsThe primary objective is to compare the ORR of nivolumab in combination with ipilimumab vs 
nivolumab in combination with ipilimumab placebo, as determined by BICR using RECIST 1.1 criteria in platinum 
refractory subjects with recurrent or metastatic SCCHN. SubjectswillbeassessedforresponsebyCT orMRI
beginning6weeks(7days)afterfirst doseandcontinuingevery6weeks(7days)untilWeek48andthenevery
12weeks(7days)untilprogression.TumorassessmentsmustcontinueperprotocoluntilRECIST1.1progression
hasoccurred.For the best response determination, confirmation of complete or partial response isrequired. Subjects 
withclinical progressionmust continue to be scanned per protocol schedule until radiographic PD is documented. 
SubjectswillbefollowedforSurvivalevery3 monthsviainpersonor telephonecontactafter thesubjecthas
discontinuedstudydrugtreatment.Allrandomizedsubjectswill befollowed
Statistical Considerations:
Sample Size: 
Approximately 396subjects (approximately 216platinum refractory subjects and 
approximately180 platinum eligible 
subjects) will be randomized to either nivolumab in combination with ipilimumab or nivolumab in combination with 
ipilimumab placebo in a 2:1 ratio. 
A sample size of 216randomized platinum refractory subjects (144and 72,respectively) will provide 84% power for 
testing the odds ratio of nivolumab in combination with ipilimumab or over nivolumab in combination with 
ipilimumab placebo, with a 0.050 two-sided significance level, assuming ORR of 35% and 15% (odds ratio of 3.051) 
in the nivolumab in combination with ipilimumab or and nivolumab in combination with ipilimumab placebo 
treatment groups respectively (odds ratio of proportions test using EAST v6).
Approximately 180 subjects (120 and 60,respectively) will be randomized in the platinum eligible subgroup. For a 
sample size of 120 subjects randomized to nivolumab plus ipilimumab, the maximum width of the exact two-sided 
95% confidence interval (CI) is 18.6% when the ORR is expected to be in the 10% to 55% range. About 60 subjects 
will be randomized into nivolumab and ipilimumab placebo arm.
Revised Protocol No.: 04
Date: 25-May-2018
12
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Endpoints:
Primary Endpoint
The primary objective in the study isto compare the ORR and assess DoR of the treatment of nivolumab in 
combination with ipilimumab vs. nivolumab in combination with ipilimumab placebo, as determined by a blinded 
independent central review (BICR) using RECIST 1.1 criteria, for first-line treatment of recurrent or metastatic 
SCCHN in the platinum refractory setting. ORR is defined as the number of subjects with a BOR of a CR or PR 
divided by the number of randomized subjects for each treatment group The BOR is defined as the best response 
designation, as determined by BICR, recorded between the date of randomization and the date of progression, as 
assessed by BICR per RECIST 1.1 or the date of subsequent anticancer therapy (includingtumor-directed radiotherapy 
and tumor-directed surgery), whichever occurs first. For subjects without evidence of RECIST 1.1 progression or 
subsequent anticancer therapy, all available response designations will contribute to the BOR assessment. For subjects 
who continue treatment beyond progression, the BOR will be determined based on response designations up to the 
time of initial RECIST 1.1 progression. 
ORR will be further characterized by DOR and Time to Response (TTR). DOR is defined as the time between the 
date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due 
to any cause, whichever occurs first. TTR is defined as the time from randomization to the date of the first confirmed 
CR or PR. DOR and TTR will be evaluated for responders (confirmed CR or PR) only.
Subjects who neither progress nor die are censored on the date of theirlast evaluable tumor assessment. Subjects who 
start subsequent anti-cancer therapy without a prior reported progression are censored at the last evaluable tumor 
assessments prior to or on initiation of the subsequent anti-cancer therapy.
Secondary Endpoints:
The secondary objective of this study is to estimate the ORR and assess DoR of the treatment of nivolumab in 
combination with ipilimumab vs nivolumab in combination with ipilimumab placebo, as determined by BICR using 
RECIST 1.1 criteria, for first line treatment of recurrent or metastatic SCCHN in the platinum eligible setting.
The BICR-assessed PFS is defined as the time from randomization to the date of first documented disease progression, 
as assessed by the BICR using RECIST 1.1 criteria, or death due to any cause, whichever occurs first. Subjects who 
died without a reported progression will be considered to have progressed on the date of their death. Subjects who did 
not progress or die will be censored on the date of their last evaluable tumor assessment. Subjects who did not have 
any on study tumor assessments and did not die will be censored on the date they were randomized. Subjects who 
started any subsequent anti-cancer therapy, including tumor-directed radiotherapy and tumor-directed surgery, without 
a prior reported progression will be censored at the last evaluable tumor assessment prior to/on initiation of the 
subsequent anti-cancer therapy. 
OS is defined as the time between the date of randomization and the date of death. For subjects without documentation 
of death, OS will be censored on the last date the subject was known to be alive.
PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100evaluable tumor 
cells per validated Dako PD-L1 IHC assay.  Analysis of the secondary endpoints will be performed at the same time 
as the primary endpoint analysis.
Analyses:
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized by treatment arm as randomized using descriptive 
statistics using all randomized population.
Efficacy Analyses
Efficacy analyses will be performed using all randomized subjects by treatment group as randomized.
Revised Protocol No.: 04
Date: 25-May-2018
13
5.0
Approved
930101794
5.0
v

9.3 Clinical Study Report and Publications 
............................................................ 
10. LIST OF ABBREVIATIONS 
................................................................................. 
 
 
 
..
 
APPENDIX 3 RECIST 1.1 GUIDELINES 
.................................................................. 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
..................................................................... 
APPENDIX 5 HEAD AND NECK SQUAMOUS CELL CARCINOMAS 
CLASSIFIED AS FOLLOWS: 
............................................................................... 
APPENDIX 6 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY 
........ 
APPENDIX 7 COUNTRY-SPECIFIC REQUIREMENTS 
......................................... 
101
103
108
113
114
122
130
133
134
137
5.0
Approved
930101794
5.0
v
Clinical Protocol
BMS-936558
CA209714
nivolumab
Revised Protocol No.: 04
Date: 25-May-2018
18

Clinical Protocol
CA209714
BMS-936558
nivolumab
1.3
Study Population:
Subjects must have metastatic or recurrent disease that is not amenable to therapy with curative 
intent (surgery or radiation therapy with or without chemotherapy). Subjects that refuse potentially 
curative salvage surgery for recurrent disease are ineligible.
Two subgroups will be enrolled into this study. Subjects will be classified as platinum refractory 
or platinum eligible:
Platinum refractory subgroup (n = approximately 216): subjects with histologically confirmed 
SCCHN that has recurred during or less than 6 months after completion of previous platinum-
based chemotherapy, given as adjuvant or neoadjuvant treatment or as part of multimodal 
treatment (chemotherapy, surgery, radiotherapy) for locally advanced disease. Subjects should 
have not received systemic anti-cancer therapy in the recurrent or metastatic setting.
Platinum eligible subgroup (n = approximately 180): subjects with histologically confirmed 
SCCHN who are platinum naive, or have recurred 6 months or more after completion of 
previous platinum-based chemotherapy, given as adjuvant or neoadjuvant treatment or as part 
of multimodal treatment (chemotherapy, surgery, radiotherapy) for locally advanced disease. 
Subjects should have not received systemic anti-cancer therapy in the recurrent or metastatic 
setting.
1.4
Research Hypothesis 
In patients with recurrent or metastatic SCCHN, the administration of nivolumab in 
combination with ipilimumab as first-line therapy in the platinum refractory setting will 
improve objective response rate (ORR) and duration of response (DOR) compared to 
nivolumab in combination with ipilimumab placebo.
1.5
Objectives(s)
1.5.1
Primary Objectives
To compare the ORR and assess DOR of the treatment of nivolumab in combination with 
ipilimumab vs nivolumab in combination with ipilimumab placebo, as determined by a blinded 
independent central review (BICR) using RECIST 1.1 criteria, for first-line treatment of 
recurrent or metastatic SCCHN in the platinum refractory setting 
1.5.2
Secondary Objectives
To estimate the ORR and assess DOR of the treatment of nivolumab in combination with 
ipilimumab vs nivolumab in combination with ipilimumab placebo, as determined by BICR 
using RECIST 1.1 criteria, for first-line treatment of recurrent or metastatic SCCHN in the 
platinum eligible setting
To assess progression-free survival (PFS), as determined by BICR, of nivolumab in 
combination with ipilimumab vs nivolumab in combination with ipilimumab placebo for 
first-line treatment of recurrent or metastatic SCCHN in the platinum eligible and platinum 
refractory settings, separately and overall
Revised Protocol No.: 04
Date: 25-May-2018
29
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
2.
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with consensus ethical principles derived from 
international guidelines including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines Good Clinical 
Practice (GCP), as defined by the International Conference on Harmonisation (ICH) in accordance 
with the ethical principles underlying European Union Directive 2001/20/EC, United States Code 
of Federal Regulations, Title 21, Part 50 (21CFR50), and applicable local requirements. 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP (occurring in any country)in connection 
with the study or the protocol, which is likely to affect, to a significant degree, the safety or 
physical or mental integrity of 1 or more subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg,advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports,updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(asper country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
Revised Protocol No.: 04
Date: 25-May-2018
34
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
Allow time necessary for subject or subject
's legally acceptable representative to inquire about 
the details of the study.
Obtain an informed consent signed and personally dated by the subject or the subject
's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject
's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject
's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject
's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF and, in the 
US, the subjects’ signed HealthInsurance Portability and Accountability Act (HIPAA) 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information torefuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
Revised Protocol No.: 04
Date: 25-May-2018
35
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
3.
INVESTIGATIONAL PLAN
3.1
Study Subgroups
CA209714 will recruit patients with recurrent or metastatic first line SCCHN. 
Subjects must have metastatic or recurrent disease that is not amenable to therapy with curative 
intent (surgery or radiation therapy with or without chemotherapy). Subjects that refuse potentially 
curative salvage surgery for recurrent disease are ineligible.
Two subgroups will be enrolled into this study. Subjects will be classified as platinum refractory 
or platinum eligible:
Platinum refractory subgroup (n = approximately 216): subjects with histologically 
confirmed SCCHN that has recurred during or less than 6 months after completion of previous 
platinum-based chemotherapy, given as adjuvant or neoadjuvant treatmentor as part of 
multimodal treatment (chemotherapy, surgery, radiotherapy) for locally advanced disease. 
Subjects should have not received systemic anti-cancer therapy in the recurrent or metastatic 
setting.
Platinum eligible subgroup (n = approximately 180): subjects with histologically confirmed 
SCCHN who are platinum naive, or have recurred 6 months or more after completion of 
previous platinum-based chemotherapy, given as adjuvant or neoadjuvant treatment or as part 
of multimodal treatment (chemotherapy,surgery, radiotherapy) for locally advanced disease. 
Subjects should have not received systemic anti-cancer therapy in the recurrent or metastatic 
setting.
Enrollment to each cohort will close when the predetermined number of patients in each cohort 
has been reached. If one cohort closes recruitment as it has reached the predefined number of 
patients in that particular subgroup (216or 180), enrollment of patients into the other subgroup 
will remain open until it has completed enrollment.
3.2
Study Design andDuration
Protocol CA209714 is a randomized (2:1), double blinded, Phase 2 trial in subjects 18 years old 
with untreated metastatic SCCHN or recurrent SCCHN that is not amenable to curative therapy, 
evaluating nivolumab in combination with ipilimumab vs.nivolumab in combination with 
ipilimumab placebo as a first-line treatment. 
HPV p-16 status (pos or neg/non-oropharyngeal), PD-L1 status (expressing or non-expressing/non 
evaluable/indeterminate) and platinum-refractory subgroup (yes/no) will be needed prior to 
randomization. Subjects will undergo screening evaluations to determine eligibility prior to 
randomization. 
Subjects will be treated with one of the following:
Arm A: Nivo/Ipi Combo 
Nivolumab 3 mg/kg IV will be administered every 2 weeks (3 days).
Ipilimumab 1 mg/kg IV will be administered every 6 weeks (3 days) following the 
administration of nivolumab.
Revised Protocol No.: 04
Date: 25-May-2018
36
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Arm B: Nivo and Ipilimumab-placebo 
Nivolumab 3 mg/kg IV will be administered every 2 weeks (3 days).
Ipilimumab-Placebo IV will be administered every 6 weeks (3 days) following the 
administration of nivolumab.
The study design schematic is presented in Figure 3.2-1.
Figure 3.2-1:
Study Design Schematic: A Double-Blind, Randomized, Two Arm 
Phase 2 Study of Nivolumab in Combination with Ipilimumab versus 
Nivolumab in combination with Ipilimumab placebo in Recurrent or 
Metastatic Squamous Cell Carcinoma of the Head and Neck 
(SCCHN)
Approximately 396subjects will be randomized to the two treatment arms in a 2:1 ratio and 
stratified by the following factors:
Platinum refractory subgroup (yes vs no).
PD-L1 status (expressing vs non-expressing or non-evaluable or indeterminate). PD-L1 status 
is set to expressing when tumor cell PD-L1 expression 1%. Up to 20% of randomized subjects 
can be included into the study as “non-evaluable” or indeterminate. After this point, subjects 
with non-evaluable/indeterminate results will not be permitted to be randomized; the site 
would need to submit an additional tumor tissue for testing with either a result of “expressing” 
or “non-expressing” in order to randomize the subject. 
Arm A
N
ivolumab 3 mg/kg IV Q2wks 
+ Ipilimumab 1 mg/kg IV Q6wks
Randomized
2:1
Stratify by:
•Platinum refractory 
subgroup  (yes/no)
•PD-L1 status
•HPV p-16
Arm B
N
ivolumab 3mg/kg IV Q2 wks
+ Ipi-Placebo IV Q6wks
Follow-up: 
Data collection for 
primary endpoint 
ORR as we
l
l as 
Follow-up Visits for 
Safety and Survival
SCCHN First-l
ine
1) Platinum eligible subgroup
(N = approxim
ate
ly 180)  
• Histologically conf
irmed SCCHN
• Platinum naïve or recurrence ≥ 
6 m after completion of prior 
platinum based chemotherapy 
(ad
juvant/neo-ad
juvant/mu
lt
i-
modal therapy) 
• No prior systemic therapy for 
recurrent or metastatic disease
2) Platinum refractory subgroup 
(N = approximately216)
• H
istologicallyconfirmed SCCHN 
recurrence < 6 m after completion 
of prior platinum based 
chemotherapy (ad
juvant/neo-
ad
juvant/mu
lt
i-modal)
• No prior systemic therapy for 
recurrent disease
Note: Tumor issue required for PD-L1 
and HPV p-16 (oropharyngeal cancer 
and unknown primary) tesing prior to 
randomization. 
Treat until progression,* 24 month from
 first dose, withdrawal of informed consent, or 
unacceptable toxicity
*Treatment beyond initial 
investigatorassessed RECIST 1.1defined progression will be 
considered in subjects experiencing investigator
-assessed clinical benefit and tolerating 
study therapy. This is to a maximum o
f 24 months from date of first dose. Such
 subjects 
must discontinue therapy when
 further progression is documented.
Revised Protocol No.: 04
Date: 25-May-2018
37
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
HPV p-16 status (oropharyngeal Cancer HPV Positive vs oropharyngeal Cancer HPV Negative 
/non-oropharyngeal Cancer) -For subjects with oropharyngeal cancer, sites defined in 
Appendix5.
Tumor progression or response endpoints will be assessed using Response Evaluation Criteria In 
Solid Tumors (RECIST 1.1) criteria. Treatment with study medication will continue until RECIST 
1.1 defined progression, unacceptable toxicity, 24 months of treatment, or withdrawal of consent. 
See Section 3.6for full details of discontinuation of study drug treatment.
Dose reductions will not be allowed for nivolumab, ipilimumab, or ipilimumab-placebo. 
Treatment beyond initial investigator-assessed progression (either clinical or radiographical) is 
permitted for nivolumab and ipilimumab or ipilimumab-placebo up to a maximum of 24 months 
from date of first dose if the subject has an investigator-assessed clinical benefit and is tolerating 
study drug (see Section 4.5.6.1).
A Data Monitoring Committee (DMC) will be established and meet regularly during the study to 
ensure that subject safety is carefully monitored and to provide oversight regarding safety and 
efficacy considerations in protocol CA209714, see Section 7.
The ORR analyses foreach of the platinum eligible and platinum refractory subgroups will be 
conducted when the sufficient number of randomized subjects in that subgroup have been followed 
at least 9 months. The accrual duration will be approximately 13 months. Survival follow-up may 
continue for up to 5 years from the time of this analysis. The study will end once survival follow-
up has concluded.
The study design schematic is presented in Figure 3.2-1.
This study will consist of three phases: screening, treatment, and follow-up.
Screening Phase 
Begins by establishing the subject’s initial eligibility and signing of the Informed Consent 
Form (ICF).
Subject is enrolled using the Interactive Voice Response System (IVRS).
Tumor tissue (archival or recent tumor biopsy) must be submitted by the site to the central lab 
for determination of PD-L1 status. Additional tumor tissue may be required by Central Lab if 
initial testing is unevaluable. Subjects will be stratified on PD-L1 status (expressing/non-
expressing or non-evaluable or indeterminate). Up to 20% of randomized subjects can be 
included into the study as “non-evaluable” orindeterminate, after this point subjects with non-
evaluable results will not be permitted to be randomized; the site would need to submit an 
additional tumor tissue for testing with either a result of “expressing” or “non-expressing” in 
order to randomizethe subject.
o A patient’s tumor will be classified as non-evaluable if the tumor tissue sample was not 
optimally collected or prepared. Some examples that would yield a non-evaluable result 
are: a) specimen contains <100 viable tumor cells, b) sections arefolded/fragmented, c) 
specimen is excessively thick, or d) specimen is excessively necrotic or hemorrhagic.
o A patient’s tumor will be classified as indeterminate if the tumor cell membrane staining 
hampered for pre-specified reasons attributed to the biology of the tumor tissue sample, 
Revised Protocol No.: 04
Date: 25-May-2018
38
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
such as high melanin content or high cytoplasmic staining, and not because of improper 
sample preparation or handling.
A communication will be sent to the site to inform that a PD-L1 result is available at the 
IVRS system.
HPV p-16 status (in subjects with Oropharyngeal cancer) must be available prior to 
randomization. If it is not available locally, then this will need to be tested by central lab and 
resulted prior to randomization. A communication will be sent to the site to provide HPV p-16 
result, if this test is being performed at the central lab.
Subject is assessed for study eligibility.
All screening assessments and procedures must be performed within 28 days prior to treatment.
Treatment Phase  
The treatment begins with the contact to the IVRS to randomize the subject.
First treatment dose should occur within 3 calendar days following the randomization (after 
results of PD-L1 for all SCCHN and HPV p-16 status, in oropharyngeal cancer, are available).  
Nivo/Ipi Combo Arm:
Nivolumab 3 mg/kg IV will be administered every 2 weeks (3 days).
Ipilimumab 1 mg/kg IV will be administered every 6 weeks (3 days) following the 
administration of nivolumab.
On the day of infusion, nivolumab is to be administered first. Thesecond infusion will always 
be ipilimumab and will start at least 30 minutes after completion of the nivolumab infusion.
Nivolumab 3 mg/kg Q2 weeks and ipilimumab 1 mg/kg Q6 weeks will be continued until the 
progression of disease, discontinuation due to toxicity, withdrawal of consent, 24 months of 
treatment, or study closure. Subjects may discontinue only ipilimumab and continue treatment 
with nivolumab if certain circumstances are met.
Treatment beyond initial investigator-assessed RECIST 1.1-defined progression is permitted 
if the subject has investigator-assessed clinical benefit and is tolerating treatment.
Study assessments are to be collected as outlined in Table 5.1-2
Nivo and Ipilimumab-placebo Arm:
Nivolumab 3 mg/kg IV will be administered every 2 weeks (3 days).
Ipilimumab-Placebo IV will be administered every 6 weeks (3 days) following the 
administration of nivolumab.
On the day of infusion, nivolumab is to be administered first. The second infusion will always 
be Ipilimumab-Placebo and will start at least 30 minutes after completion of the nivolumab 
infusion.
Nivolumab 3 mg/kg Q2 weeks and Ipilimumab-Placebo 1 mg/kg Q6 weeks will be continued 
until the progression of disease, discontinuation due to toxicity, withdrawal of consent, 24 
months of treatment, or study closure. Subjects may discontinue only Ipilimumab-Placebo and 
continue treatment with nivolumab if certain circumstances are met.
Revised Protocol No.: 04
Date: 25-May-2018
39
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Treatment beyond initial investigator-assessed RECIST 1.1-defined progression is permitted 
if the subject has investigator-assessed clinical benefit and is tolerating treatment.
Study assessments are to be collected as outlined in Table 5.1-2:
Follow-up Phase
The post-treatment follow-up begins when the decision to discontinue a subject from all 
treatment is made.
Subjects who discontinue treatment for reasons other than disease progression will continue to 
have tumor assessments (if clinically feasible) according to the schedule in Table 5.1-3until 
progression.
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for minimum of 
100 days after the last dose of study medications.
Subjects who discontinue study drug must continue to be followed for collection of outcome 
and/or survival follow-up data until death or the conclusion of the study.
Survival Follow-up visits may be performed by phone contact or office visit. BMS may request 
that survival data be collected on all subjects outside of the protocol defined window. At the 
time of this request, each subject will be contacted to determine their survival status unless the 
subject has withdrawn consent for all contact.
3.2.1
Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumor types in the nivolumab and ipilimumab development program 
indicate that most of the responses occur early, with a median time to response of 2 to 4 
months,44,45,46,47,48and emerging data suggests that benefit can be maintained in the absence of 
continued treatment. A recent analysis in a melanoma study suggests the majority of patients who 
discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of 
further treatment.49Furthermore, a limited duration of ipilimumab, including only 4 induction 
doses, resulted in long term survival in patients with metastatic melanoma, with a sustained plateau 
in survival starting around 2 years after the start of treatment.
50
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 participants were alive > 5 years and remained progression-free without any 
subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, 
with an OS rate of 25% at 2 years and 18% at 3 years.51These survival outcomes are similar to 
phase 3 studies in previously treated NSCLC, in which nivolumab treatment was continued until 
progression or unacceptable toxicity (2 year OS rates of 23% and 29%, and 3 year OS rates of 16% 
to18% for squamous and non-squamous NSCLC, respectively).
52
Revised Protocol No.: 04
Date: 25-May-2018
40
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in participants with previously treated, PD-L1-positive, advanced 
NSCLC which specified a  maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47patients completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.53
Keynote-006 was a randomized phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.54
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2years is low.
In contrast, a shorter duration ofnivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.55
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
3.3
Post Study Accessto Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration specified in 
protocol Section 4.5.1.1. Study drug will be provided via an extension of the study, a rollover study 
Revised Protocol No.: 04
Date: 25-May-2018
41
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS. BMS reserves the right to terminate access to BMS supplied 
study drug if any of the following occur: a) the marketing application is rejected by responsible 
health authority; b) the study is terminated due to safety concerns; c) the subject can obtain 
medication from a government sponsored or private health program; or d) therapeutic alternatives 
become available in the local market.
3.4
Study population
For entry into the study, the following criteria MUST be met:
3.4.1
Inclusion Criteria
1. Signed Written Informed Consent
a. Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care.
b. Subjects must be willing and able to comply with scheduled visits, treatment schedule, and 
laboratory testing.
2. Target Population
a. Histologically confirmed head and neck squamous cell carcinoma (SCCHN) from any of 
the following primary sites only: oral cavity, oropharynx, hypopharynx and larynx 
(including squamous cell carcinoma of unknown primary arising from head and neck if 
HPV p-16 positive).
b. Must have metastatic or recurrent disease that is not amenable to therapy with curative 
intent (surgery or radiation therapy with or without chemotherapy). Subjects that refuse 
potentially curative salvage surgery for recurrent disease are ineligible. 
c. Two subgroups will be enrolled into this study, as detailed above. Subjects will be 
classified as platinum refractory or platinum eligible.
No prior treatment with systemic anti-cancer therapy for recurrent or metastatic SCCHN, 
except if given as adjuvant or neoadjuvant chemotherapy, or chemotherapy as part of 
multimodal (chemo, radiation) treatment for locally advanced disease.
i.
Platinum refractory subgroup (n = approximately 216): subjects with histologically 
confirmed SCCHN that has recurred during or less than 6 months after completion of 
previous platinum based chemotherapy, given as adjuvant or neoadjuvant treatment or 
as part of multimodal treatment (chemotherapy, surgery, radiotherapy) for locally 
advanced disease.
ii.
Platinum eligible subgroup (n = approximately 180): subjects with histologically 
confirmed SCCHN who are platinum naive or have recurred 6 months or more after 
completion of previous platinum-based chemotherapy, given as adjuvant or 
neoadjuvant treatment or as part of multimodal treatment (chemotherapy, surgery, 
radiotherapy) for locally advanced disease.
[As of Revised Protocol 03, this criterion has been moved to 2.c]  No prior treatment with 
systemic anti-cancer therapy for recurrent or metastatic SCCHN, except if given as adjuvant 
or neoadjuvant chemotherapy, or chemotherapy as part of multimodal (chemo,radiation) 
treatment for locally advanced disease. 
Revised Protocol No.: 04
Date: 25-May-2018
42
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
d. Eastern Cooperative Oncology Group (ECOG) Performance Status of 1
e. Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) 
per RECIST 1.1 criteria; radiographic tumor assessment performed prior 
to randomization.
i.
Target lesions may be located in a previously irradiated field if there is documented 
(radiographic) disease progression in that site after the completion of radiation therapy.
f. Documentation of HPV p-16 status is required for SCCHN tumor of the oropharynx. 
Subjects with unknown primary location must have documented positive p-16 status
Note: If results are not available, then a sample (tissue on microscopic slides, tissue block 
or a fresh tissue biopsy in formalin) should be sent to the central laboratory for analysis. 
g. Documentation of PD-L1 status by IHC performed by the central lab at randomization. 
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections (archival or recent: within 6 months), with an associated pathology report, must 
be submitted for biomarker evaluation prior to randomization. Biopsy should be excisional, 
incisional, or core needle. Fine needle aspiration is insufficient. 
h. Prior palliative or curative radiotherapy must have been completed at least 2 weeks prior 
to randomization regardless of site that was irradiated.
i. If patient received prior chemotherapy
, the prior chemotherapy should be completed at 
least 4 weeks prior to randomization.
j. All toxicities attributed to prior cancer therapy (systemic anti-cancer therapy, radiation or 
surgery) other than alopecia and fatigue must have resolved or returned to baseline at least 
2 weeks before randomization.
k. Subject Re-enrollment: This study permits the re-enrollment ofa subject who has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has 
not been treated). If re-enrolled, the subject must be re-consented.
l. Screening laboratory values must meet the following criteria (using CTCAE v4):
WBC
2000/uL
Neutrophils
1500/uL
Platelets
100x103/uL
Hemoglobin 9.0 g/dL
Serum creatinine 1.5 x ULN or calculated creatinine clearance 
>40mL/min (using the Cockcroft Gault formula)
Female CrCl = (140-age in years) x weight in kg x 0.85
                               
72 x serum creatinine in mg/ dL
Male CrCl = (140-age in years) x weight in kg x 1.00
                                        72 x serum creatinine in mg/ dL
AST
3.0 x ULN 
ALT
3.0 x ULN 
Revised Protocol No.: 04
Date: 25-May-2018
43
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Total Bilirubin1.5 x ULN (except subjects with Gilbert Syndrome who 
must have a total bilirubin level of < 3.0x ULN).
m. Subjects must have an estimated life expectancy of at least 3 months.
3. Age and Reproductive Status
a. Males and Females, ages 18 years of age
b. Women of childbearingpotential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c. Women must not be breastfeeding
d. WOCBP must agree to follow instructions for method(s) of contraception for a period of 
30 days (duration of ovulatory cycle) plus the time required for the investigational drug to 
undergo approximately five half-lives. WOCBP randomized/assigned to receive 
nivolumab should use an adequate method to avoid pregnancy for 5 months (30 days plus 
the time required for nivolumab to undergo approximately five half-lives) after the last 
dose of investigational drug.
e. Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the 
time required for the investigational drug to undergo approximately five half-lives.
f. Males randomized to receive nivolumab who are sexually active with WOCBP must 
continue contraception for 7 months (90 days plus the time required for nivolumab to 
undergo approximately five half-lives) after the last dose of investigational drug.
g. Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in these sections.
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active 
with WOCBP on the use of highly effective methods of contraception. Highly effective 
methods of contraception (see Appendix 4) which have a failure rate of < 1% when used 
consistently and correctly.
At a minimum, subjects must agree to use one highly effective method of contraception as 
listed in Appendix 4. Local laws and regulations may require use of alternative and/or 
additional contraception methods
3.4.2
Exclusion Criteria
1. Target Disease Exceptions
a. Recurrent or metastatic carcinoma of the nasopharynx, paranasal sinus squamous cell 
carcinoma that originated from the skin and salivary gland or non-squamous histologies 
(eg, mucosal melanoma).
b. Subjects with untreatedCentral Nervous system (CNS) metastases. 
Subjects are eligible if CNS metastases have been adequately treated and have 
neurologically returned to baseline (except for residual signs or symptoms related to the 
CNS treatment) for at least 2 weeks prior to randomization. In addition, subjects must be 
Revised Protocol No.: 04
Date: 25-May-2018
44
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
either off corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone 
(orequivalent) for at least 2 weeks prior to randomization.
c. Subjects with carcinomatous meningitis.
d. Any prior treatment with any non-platinum containing systemic therapy regimen for 
SCCHN (adjuvant, neoadjuvant, or multi-modal treatment). 
2. Medical History and Concurrent Diseases
a. Women who are pregnant or breastfeeding
b. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2,anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways.
c. Other active malignancy requiring concurrent intervention.
d. Subjects with previous malignancies (except non-melanoma skin cancers and the following 
in situ cancers: bladder, gastric, colon, esophageal endometrial, cervical/dysplasia, 
melanoma, or breast) unless a complete remission was achieved at least 2years prior to 
study entry AND no additional therapy is required during the study period.
e. Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
f. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily 
prednisone equivalent are permitted in the absence of active autoimmune disease.
g. Not applicable per Amendment 05/Revised Protocol 02.Subjects with interstitial lung 
disease that is symptomatic or may interfere with the detection or management of suspected 
drug-related pulmonary toxicity.
h. Known medical condition that, in the investigator
's opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results.
i. Participantswho have received a live / attenuated vaccine within 30 days of first treatment.
3. Physical and Laboratory Test Findings
a. Any positive testresult 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).
b. Known history of positive testing for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
c. History of allergy or hypersensitivity to study drug components. In case of history of 
allergy or hypersensitivity to platinum containing compounds, please discussthese 
individual cases with the medical monitor.
4. Other Exclusion Criteria
a. Prisoners or subjects who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a subject. Strict 
conditions apply and Bristol-Myers Squibb approval is required.
Revised Protocol No.: 04
Date: 25-May-2018
45
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
b. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria. Subjects not meeting the inclusion/exclusion criteria must not be enrolled into 
the study. There can be no exceptionsto this rule.
Subject Re-enrollment: This study permits the re-enrollment of a subject who has discontinued the 
study as a pre-treatment failure (ie, subject has not been randomized/has not been treated). If 
re-enrolled, the subject must be re-consented.
3.4.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone (FSH) level 
>40 mIU/mL to confirm menopause.
*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 
FSHlevel. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermalproducts
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSHlevel 
is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
3.5
Concomitant Treatments
3.5.1
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 (except as stated in Section 3.5.2)
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of cancer
Revised Protocol No.: 04
Date: 25-May-2018
46
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Surgical resection of tumor
Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
Caution should be used regarding the use of herbal medications as there may be as yet unknown 
interactions with nivolumab and/or ipilimumab. Discontinuation of the use of herbal medications 
prior to study enrollment is encouraged. Except for the permitted procedures specified as palliative 
local therapies (Section 3.5.3), all other radiation therapy or surgery to any tumor lesion is not 
permitted during study treatment. Subjects who require such non-palliative procedures must be 
discontinued from study treatment.
3.5.2
Other Restrictions and Precautions
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment 
are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, allergy 
history, diabetic history and renal status), the appropriate imaging modality and contrast regimen 
for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. If CT is contraindicated 
for a subject because of an iodinated contrast allergy, then a contrast enhanced MRI of the neck, 
chest, abdomen and pelvis will be performed.
Specific to MRI, subjects with severe renal insufficiency (ie, estimated glomerular filtration rate 
(eGFR) < 30 mL/min/1.73m
2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast 
should not be given to this subject population. In addition, subjects are excluded from MRI if they 
have tattoos, metallic implants, pacemakers, etc. The ultimate decision to perform MRI in an 
individual subject in this study rests with the site radiologist, the investigator and the standard set 
by the local Ethics Committee.
3.5.3
Permitted Therapy
Subjects 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.
Regular concomitant use of bisphosphonates and receptor activator of nuclear factor kappa B 
ligand (RANK-L) inhibitors for prevention or reduction of skeletal-related events in subjects with 
Revised Protocol No.: 04
Date: 25-May-2018
47
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
bone metastases is allowed if initiated prior to first dose of study therapy. Prior palliative 
radiotherapy must have been completed at least 2 weeks prior to randomization.
Prior palliative or curative radiotherapy must have been completedat least 2 weeks prior to 
randomization regardless of site that was irradiated. On study palliative radiotherapy is only 
allowed for treatment of painful bone lesions. Palliative surgical resection of tumor sites is not 
permitted. Subjects requiring palliative radiotherapy should be evaluated for objective evidence of 
disease progression prior to the initiation of such therapy, particularly if the most recent tumor 
assessment was more than 4weeks prior to the start of local therapy. If progression per RECIST 
1.1 is identified on any tumor assessments prior to the initiation of palliative local therapy, then 
subjects must either discontinue study drug treatment or they must meet criteria to continue 
treatment beyond progression (Section4.5.6.1) in order to resume immunotherapy after palliative 
local therapy. 
The potential for overlapping toxicities with radiotherapy and nivolumab/ipilimumab currently is 
not known; however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and 
nivolumab/ipilimumab have not been formally evaluated, in cases where palliative radiotherapy is 
required for a tumor lesion, then nivolumab and ipilimumab or ipilimumab-placebo should be 
withheld for at least 1 week before, during, and 1 week after radiation. Subjects should be closely 
monitored for any potential toxicity during and after receiving radiotherapy, and AEs should 
resolve to Grade 1 prior to resuming nivolumab or nivolumab plus ipilimumab or 
ipilimumab-placebo.
3.6
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
Subject’s request to stop study treatment
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
Termination of the study by Bristol-Myers Squibb (BMS)
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note:Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
Pregnancy*
*In the case of pregnancy, the investigator must immediately (within 24 hours of awareness of the 
pregnancy) notify the BMS Medical Monitoror designee of this event. In most cases, the study 
treatmentwill be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety)(see Appendix 7). Refer to Section 6.4Pregnancy.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5.1. The only exception to this requirement is when a subject 
Revised Protocol No.: 04
Date: 25-May-2018
48
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.7
Post Study Drug Study Follow up
Subjects who discontinue study drug must continue to be followed for collection of outcome and/or 
survival follow-up data as required and in line with Section 5.1until death or the conclusion of the 
study. Follow-Up Visit 1 to occur 30 days from the last dose (7 days) or Follow-Up Visit 1 can 
be performed on date of discontinuation if it is greater than 42 days from last dose. Follow-Up 
Visit 2 to occur 90 days from Follow-Up Visit 1 (7 days). Survival Follow-Up Visits to occur 
approximately every 3 months (7 days) from Follow-Up Visit 2. Survival Follow-up visits may 
be performed by phone contact or office visit.
BMS may request that survival data be collected on all subjects outside of the protocol defined 
window (Table 5.1-3). At the time of this request, each subject will be contacted to determine their 
survival status unless the subject has withdrawn consent for all contact.
3.7.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, if possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study drug only or also from study procedures and/or 
post treatment study follow-up, and entered on the appropriate CRF page. In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with local 
law.
3.7.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
Revised Protocol No.: 04
Date: 25-May-2018
49
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4.
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
Table 4-1:
Study Drugs for CA209714
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions
(per label)
BMS-936558-01 
(Nivolumab) Solution 
for Injection
100 mg
(10 mg/mL)
IP
Open-labela
10 mL/vial (5 or 
10vials/carton)
Store at 
2°-8°C.
Protect from 
light and 
freezing.
Ipilimumab Solution for 
Injection
200 mg
(5 mg/mL)
IP
Open-labela
40 mL/vial 
(4vials/carton)
Store at 2°-8°C. 
Protect from 
light and 
freezing.
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
a The term “open label” refers to the medication as it is upon receipt at the pharmacy. The trial will be conducted in 
a double-blinded fashion
Premedications or medications used to treat infusion-related reactions should be sourced by the 
investigative sites if available and permitted bylocal regulations. Solutions used as diluent or 
placebo (ie, 0.9% Sodium Chloride Injection or 5% Dextrose Injection) should also be sourced by 
investigative sites if available and permitted by local regulations.
4.1
Investigational Product
An investigationalproduct, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorizationbut 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.
Revised Protocol No.: 04
Date: 25-May-2018
50
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
Nivolumab
Ipilimumab
Placebo for ipilimumab (0.9% sodium chloride injection or 5% dextrose injection)
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
Please refer to the current version of the Investigator Brochure (IB) and/or pharmacy reference 
sheets for complete storage, handling, dispensing, and infusion information for nivolumab, 
ipilimumab, and matching placebo.
The unblinded pharmacist will obtain treatment assignment by interactive voice response system 
(IVRS) and prepare blinded drug. 
Please refer to Section 9.2for guidance on IP records and documentation.
4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has beenobtained, the 
subject must be enrolled into the study by an IVRS to obtain the subject number. Every subject 
that signs the informed consent form must be assigned a subject number in IVRS. Specific 
instructions for using IVRS will be provided to the investigational site in a separate document. The 
Revised Protocol No.: 04
Date: 25-May-2018
51
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
Date that informed consent was obtained
Date of birth
Gender at birth
Once enrolled in IVRS, enrolled subjects that have met all eligibility criteria will be ready to be 
randomized through IVRS. PD-L1 expression data will be transferred directly from analyzing lab 
to IVRS. The local HPV p-16 result will be entered by the site directly into IVRS for the 
oropharyngeal cancer and unknown primary with p-16 positive subjects during the randomization 
call. The following information is required for subject randomization:
Subject number
Date of birth
HPV p-16 status (oropharyngeal HPV p-16 pos vs oropharyngeal HPV p-16 neg or 
nonoropharyngeal)
Oropharyngeal CA sites defined in Appendix 5
Tumor 
Cell 
PD-L1 
expression status at 1%  cutoff: 
(expressing/non-
expressing/non-evaluable/indeterminate)
Positive (1% expressing) vs Negative (<1% expressing)/not evaluable/indeterminate)
Platinum refractory subgroup status (yes vs no)
Subjects meeting all eligibility criteria will be stratified by PD-L1 status (expressing vs 
nonexpressing/non-evaluable/indeterminate), HPV p-16 status (oropharyngeal HPV p-16 positive 
vs oropharyngeal HPV p-16 negative/non-oropharyngeal) and platinum refractory subgroup status 
(yes vs no). Subjects will be randomized in a 2:1 ratio to nivolumab + ipilimumab (Arm A) vs 
nivolumab +ipilimumab-placebo (Arm B).
Enrollment will stop once approximately 396subjects have been randomized.
The exact procedures for using the IVRS will be detailed in the IVRS manual.
4.5
Selection and Timing of Dose for Each Subject
The dosing schedule is detailed below in Section 4.5.1. 
All subjects will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay, interruption, discontinuation) will be based on specific laboratory 
and adverse event criteria, as described in Sections 4.5.2, 4.5.3, 4.5.4and 4.5.5.
Revised Protocol No.: 04
Date: 25-May-2018
52
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
4.5.1
Dosing
Table 4.5.1-1:
Study Drugs for CA209714
Cycle 1
Day 1 3 Days
Cycle 1
Day 15 3 Days
Cycle 1
Day 293 Days
Arm A:a
Nivolumab 3 mg/kg q 2 
weeks
+ Ipilimumab 1mg/kg q 6 
weeksa
Nivolumab
+
Ipilimumab
Nivolumab
Nivolumab
Arm B:b
Nivolumab 3 mg/kg q 2 
weeks
+ Ipi-placebo 1mg/kg q 6 
weeksb
Nivolumab
+
Ipilimumab-placebo
Nivolumab
Nivolumab
a Arm A: Both nivolumab and ipilimumab should be administered as 30 minute infusions. nivolumab is to be 
administered first. The second infusion will be ipilimumab and will start at least 30 minutes after completion of the 
nivolumab infusion 
b Arm B: Both nivolumab and ipilimumab-placebo should be administered as 30 minute infusions. nivolumab is to 
be administered first. The second infusion will be ipilimumab-placebo and will start at least 30 minutes after 
completion of the nivolumab infusion
4.5.1.1
Nivolumab plus Ipilimumab or ipilimumab-placebo
Subjects are randomized to receive treatment with nivolumab as a 30 minute infusion 3mg/kg 
every 2 weeks (3 calendar days) and ipilimumab or ipilimumab-placebo as a 30 minute infusion 
1mg/kg every 6 weeks (3 calendar days), but no less than 12 days of the previous dose starting 
on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months from the first 
dose of treatment, or the study ends, whichever occurs first.
When study drugs (nivolumab and ipilimumab) are to be administered on the same day, nivolumab 
is to be administered first and separate infusion bags and filters should be used for each infusion. 
Nivolumab infusion must be promptly followed by a flush of diluent to clear the line of nivolumab 
before starting the ipilimumab infusion. The second infusion will always be the ipilimumab study 
drug and will start after the infusion line has been flushed, filters changed, and subject has been 
observed to ensure no infusion reaction has occurred. The time in between infusions is expected 
to be at least 30 minutes. Nivolumab and ipilimumab or ipilimumab-placebo may be diluted in 
0.9% Sodium Chloride Solution or 5% Dextrose solution.
Dosing calculations should be based on the body weight. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the prior dose, the dose must be 
recalculated. Doses canbe rounded per institutional standards. There will be no dose escalations 
or reductions of nivolumab and ipilimumab or ipilimumab-placebo allowed.
Revised Protocol No.: 04
Date: 25-May-2018
53
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Subjects may be dosed with nivolumab no less than 12 days from the previous dose. There are no 
premedications recommended. Subjects may be dosed with Ipilimumab or Ipilimumab-placebo no 
less than 6 weeks from the previous dose.
Doses of nivolumab and/or ipilimumab or ipilimumab-placebo may be interrupted, delayed, or 
discontinued depending on how well the subject tolerates the treatment. For more details, see 
Sections 4.5.2(dose delays), 4.5.4(resuming treatment), and 4.5.5(discontinuation).
4.5.2
Dose Delays
4.5.2.1
Nivolumab and Ipilimumab/ipilimumab-placebo
Dose delay criteria apply for all drug-related AEs. Treatment delay up to 6 weeks for nivolumab 
and up to 12 weeks for ipilimumab or ipilimumab-placebofrom the last dose are allowable 
(anydose delays greater than these will require approval from the medical monitor).
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed. 
Nivolumab and ipilimumab or ipilimumab-placebo administration should be delayed for the 
following:
Any Grade 2 non-skin, drug-related adverse event, except of fatigue 
Any Grade 2 drug-related creatinine, AST, ALT, and/or Total Bilirubin abnormalities
Grade 3 skin, drug-related AE
Any Grade 3 drug-related laboratory abnormality with the following exceptions:
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
Grade 3 AST, ALT, total bilirubin will require dose discontinuation (see Section 4.5.5)
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Subjects receiving ipilimumab or ipilimumab-placebo in combination with nivolumab that 
have drug-related toxicities that meet the criteria for dose delay, should have both drugs 
(ipilimumab or ipilimumab-placebo and nivolumab) delayed until retreatment criteria are met. 
(Exceptions apply to the retreatment criteria after dose delay of ipilimumab or 
ipilimumab-placebo and nivolumab for Grade 3 amylase and lipase abnormalities that are 
not associated with symptoms or clinical manifestations of pancreatitis and that are attributed 
to ipilimumab or ipilimumab-placebo alone.)
Rescheduling:
Nivolumab may be delayed until the next planned ipilimumab or ipilimumab-placebo dose if 
the next ipilimumab or ipilimumab-placebo dose is scheduled within the next 12 days. This 
will permit periodic ipilimumab or ipilimumab-placebo dosing to besynchronized with 
nivolumab dosing.
Ipilimumab or ipilimumab-placebo should be dosed at the specified interval regardless of any 
delays in intervening nivolumab doses. However, in order to maintain periodic synchronized 
dosing of ipilimumab or ipilimumab-placebo and nivolumab, the dosing days of nivolumab 
and ipilimumab or ipilimumab-placebo may be adjusted within the permitted 3 day window, 
as long as consecutive nivolumab doses are given at least 12 days apart. Ipilimumab may be 
delayed beyond the 3 day window if needed to synchronize with the next nivolumab dose.
Revised Protocol No.: 04
Date: 25-May-2018
54
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
If an ipilimumab or ipilimumab-placebo dose is delayed beyond 6 weeks from the prior 
ipilimumab or ipilimumab-placebo dose, then subsequent ipilimumab or ipilimumab-placebo 
doses should be rescheduled to maintain the 6 week interval between consecutive ipilimumab 
or ipilimumab-placebo doses.
A dose delay of ipilimumab or ipilimumab-placebowhich results in no ipilimumab or 
ipilimumab-placebo dosing for > 12 weeks requires ipilimumab or ipilimumab-placebo 
discontinuation, with exceptions as noted in Section 4.5.5.2.
Participants who require delay of nivolumab should be re-evaluated weeklyor more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
4.5.3
Dose Reductions
4.5.3.1
Nivolumab or Ipilimumab/ipilimumab-placebo
There will be no dose reductions for nivolumab or ipilimumab or ipilimumab-placebo allowed.
4.5.4
Criteria to Resume Treatment
4.5.4.1
Criteria to Resume Nivolumab Treatment
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade 
1 or baseline, with the following exceptions:
Subjects may resume treatment in the presence of Grade 2 fatigue.
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
For subjects with Grade 2 AST/ALT and/or total bilirubin values, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete. 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
Subjects with drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor (or 
designee). Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
4.5.4.2
Criteria to Resume Ipilimumab/ipilimumab-placebo Dosing
Subjects may resume treatment with nivolumab and ipilimumab or ipilimumab-placebo when 
drug-related AE(s) resolve(s) to Grade 1 or baseline value, with the following exceptions:
Subjects may resume treatment in the presence of Grade 2 fatigue.
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
Revised Protocol No.: 04
Date: 25-May-2018
55
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT or total bilirubin.
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (Section 4.5.5.2) should have treatment permanently discontinued.
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.
Subjects who received systemic corticosteroids for management of any drug-related toxicity 
must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
10mg/day.
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor.
Dose delay of ipilimumab or ipilimumab-placebo which results in no ipilimumab or 
ipilimumab-placebo dosing for > 12 weeks requires ipilimumab or ipilimumab-placebo 
discontinuation, with exceptions as noted in Section 4.5.5.2.
Ipilimumab may not be resumed sooner than 6 weeks (5days) after the prior ipilimumab or 
ipilimumab-placebodose.
In general, subjects who meet criteria to resume ipilimumab or ipilimumab-placebo will also 
have met criteria to resume nivolumab, so it should be feasible to synchronize dosing of both 
drugs when resuming ipilimumab or ipilimumab-placebo. In order to facilitate this, the dosing 
days of nivolumab and ipilimumab or ipilimumab-placebo may be adjusted within the 
permitted 5 day window, as long as consecutive nivolumab doses are given at least 12 days 
apart.
One exception to note is when ipilimumab or ipilimumab-placebo and nivolumab doses are 
delayed due to drug-related Grade 3 amylase or lipase abnormalities not associated with 
symptoms or clinical manifestations of pancreatitis. If the investigator assesses the Grade 3 
amylase or lipase abnormality to be related to ipilimumab or ipilimumab-placebo and not 
related to nivolumab, nivolumab may be resumed when the amylase or lipase abnormality 
resolves to Grade < 3 but ipilimumab or ipilimumab-placebo may only be resumed when the 
amylase or lipase abnormality resolves to Grade 1 or baseline. Investigator attribution of this 
toxicity to the ipilimumab or ipilimumab-placebo dosing must be clearly noted in the subject’s 
medical chart. The BMS Medical Monitor should be consulted prior to resuming nivolumab in 
such subjects.
4.5.5
Treatment Discontinuation Criteria
For all subjects, global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time will be captured on the health outcomes 
questionnaires. Tumor assessments for subjects who discontinue study treatment without 
radiographic progression should continue as per protocol until radiographic progression is 
determined.
Revised Protocol No.: 04
Date: 25-May-2018
56
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
4.5.5.1
Nivolumab Dose Discontinuation
Treatment with nivolumab should be permanently discontinued for any of the following:
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, myocarditis, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation
Grade 3 drug-related endocrinopathies,adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment will be 
permanently discontinued. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion 
between the investigator and the BMS Medical Monitor/designee must occur.
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events, which do not 
require discontinuation:
Grade 4 neutropenia 7 days
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
Grade 4 drug-related endocrinopathy adverse events, such as, hyper-or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
Revised Protocol No.: 04
Date: 25-May-2018
57
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
Prior to re-initiating treatment in a participant with a dosing delay lasting >6 weeks, the BMS 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 6weeks or more frequently if clinically indicated during such dosing 
delays.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab or ipilimumab-placebo. Although there is overlap among 
the discontinuation criteria, if discontinuation criteria are met for ipilimumab but not for 
nivolumab, treatment with nivolumab may continue if ipilimumab or ipilimumab-placebois 
discontinued.
If a subject meets criteria for discontinuation and investigator is unable to determine whether the 
event is related to both or one study drug, the subject should discontinue both nivolumab and 
ipilimumab or ipilimumab-placeboand be taken off the treatment phase of the study. Continuation 
of ipilimumab or ipilimumab-placeboafter discontinuation of nivolumab is not allowed on study.
4.5.5.2
Ipilimumab/ipilimumab-placebo Dose Discontinuation
Ipilimumab or ipilimumab-placeboshould be permanently discontinued if any of the following 
criteria are met:
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond totopical 
therapy and does not improve to Grade 1 severity within 2 weeks OR requires systemic 
treatment;
Any Grade 3 bronchospasm or other hypersensitivity reaction;
Any other Grade 3 non-skin, drug-related adverse event with the following exceptions for
laboratory abnormalities, grade 3 nausea and vomiting, grade 3 neutropenia and 
thrombocytopenia, and symptomatic endocrinopathies which resolved (with or without 
hormone substitution);
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation:
AST or ALT > 8 x ULN
Total bilirubin > 5 x ULN
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
Revised Protocol No.: 04
Date: 25-May-2018
58
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:
Grade 4 neutropenia 7 days
Grade 4 lymphopenia or leukopenia
Isolated Grade 4 amylase or lipase abnormalities which are not associated with symptoms 
or clinical manifestations of pancreatitis. The BMS Medical Monitor should be consulted 
for Grade 4 amylase or lipase abnormalities.
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
Any treatment delay resulting in no ipilimumab or ipilimumab-placebo dosing for > 12 weeks 
with the following exceptions: Dosing delays to manage drug-related adverse events, such as 
prolonged steroid tapers, are allowed. Prior to re-initiating treatment in a subject with a dosing 
delay lasting >12weeks, the BMS medical monitor must be consulted. Tumor assessments 
should continue as per protocol even if dosing is delayed.
Dosing delays resulting in no ipilimumab or ipilimumab-placebo dosing for > 12 weeks that 
occur for non-drug-related reasons may be allowed if approved by the BMS medical monitor. 
Prior to re-initiating treatment in a subject with a dosing delay lasting > 12 weeks, the BMS 
medical monitor must be consulted. Tumor assessments should continue as per protocol even 
if dosing is delayed.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued ipilimumab 
or ipilimumab-placebo dosing.
The assessment for discontinuation of ipilimumab or ipilimumab-placebo should be made 
separately from the assessment made for discontinuation of nivolumab. Although there is overlap 
among the discontinuation criteria, if discontinuation criteria are met for ipilimumab or 
ipilimumab-placebo but not for nivolumab, treatment with nivolumab may continue if ipilimumab 
or ipilimumab-placebo is discontinued.
If a subject meets criteria for discontinuation and investigator is unable to determine whetherthe 
event is related to both or one study drug, the subject should discontinue both nivolumab and 
ipilimumab or ipilimumab-placebo and be taken off the treatment phase of the study.
4.5.6
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-
oncology agents in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
Gastrointestinal
Renal
Pulmonary
Hepatic
Endocrinopathy
Skin
Revised Protocol No.: 04
Date: 25-May-2018
59
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Neurological
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures, as 
well as in Appendix 2.
4.5.6.1
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progression of disease (PD).
56
Subjects will be permitted to continue on nivolumab + ipilimumab or ipilimumab-placebo for 
treatment beyond initial RECIST 1.1 defined PD, assessed by the investigator for up to a maximum 
of 24 months from the date of the first dose as long as they
 meet the following criteria:
Investigator-assessed clinical benefit and no rapid disease progression
Tolerance of study drug 
Stable performance status
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
Subject provides written informed consent prior to receiving additional nivolumab and 
ipilimumab or ipilimumab-placebotreatment, using an ICF describing anyreasonably 
foreseeable risks or discomforts, or other alternative treatment options. The decision to 
continue treatment beyond initial investigator-assessed progression should be discussed with 
the BMS Medical Monitor and documented in the study records. 
In cases where the subject is treated beyond investigator-assessed progression which is not 
confirmed by BICR, the subject should continue to be scanned following the study imaging 
schedule (every 6 weeks until week 48 and every 12 weeks thereafter). If the subject is treated 
beyond investigator-assessed progression that is confirmed by BICR a follow-up scan should 
be performed within six (6) weeks 5 days of original PD to determine whether there has been 
a decrease in the tumor size, or continued progression of disease. In this case, subsequent scans 
should be performed every twelve (12) weeks until further progression is determined.
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Time and Events Schedule in Table 5.1-1, Table 5.1-2, and Table 5.1-3.
For the subjects who continue study therapy beyond progression, further progression is defined as 
an additional 10% increase in tumor burden 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. Nivolumab and ipilimumab or ipilimumab-placebo treatment should be 
discontinued permanently upon documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15mm). 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 
Revised Protocol No.: 04
Date: 25-May-2018
60
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15mm). 
In situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
4.5.7
Treatment of Infusion Reactions
4.5.7.1
Nivolumab or Ipilimumab Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo-or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE 
if criteria are met. Infusion reactions should be graded according to National Institute of cancer 
(NCI) common terminology criteria for adverse event (CTCAE, Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated)
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab or ipilimumab-placebo administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24hours)
Stop the nivolumab or ipilimumab or ipilimumab-placebo infusion, begin an IV infusion of 
normal saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor subject until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30minutes, the rate may be increased to 100% of the original infusion rate. Monitor subject 
closely. If symptoms recur, then no further nivolumab or ipilimumab or ipilimumab-placebo 
will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at 
bedside and monitor the subject until resolution of symptoms. The amount of study drug 
infused must be recorded on the electronic case report form (eCRF).
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
Revised Protocol No.: 04
Date: 25-May-2018
61
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
should be administered at least 30 minutes before nivolumab or ipilimumab or ipilimumab-
placebo infusions. If necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may 
be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory support indicated).
Immediately discontinue infusion of nivolumab or ipilimumab or ipilimumab-placebo. Begin 
an IV infusion of normal saline and treat the subject as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg 
of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg 
IV withmethylprednisolone 100 mg IV (or equivalent), as needed. Subject should be 
monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab 
or ipilimumab or ipilimumab-placebo will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.6
Blinding/Unblinding
The Sponsor, subjects, investigator and site staff will be blinded to the study drug administered 
(ipilimumab + nivolumab ornivolumab plus ipilimumab-placebo). 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. 
Before breaking the blind of an individual subject
's treatment during the blinded portion of the 
study, the investigator should determine that the unblinded information is necessary, ie, that it will 
alter the subject
's immediate management. In many cases, particularlywhen the emergency is 
clearly not related to the investigational product, the problem may be properly managed by 
assuming that the subject is receiving active product. It is highly desirable that the decision to 
unblind treatment assignment be discussed with the Medical Monitor; but, the investigator always 
has ultimate authority for the decision to unblind during the blinded portion of the study. The 
Principal Investigator should only call for emergency unblinding during the blinded portion of the 
study AFTER the decision to discontinue the subject has been made.
For both cohorts, the Sponsor will remain blinded until the time of planned interim analysis of the 
primary endpoint. However, due to the nature of the study design and corresponding data 
collection, the Sponsor’s central protocol team (including but not limited to clinical, statistics, and 
data management) may have knowledge of an individual subjects’ treatment assignment once 
subject-level unblinding occurs.
Revised Protocol No.: 04
Date: 25-May-2018
62
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
For this study, the method of unblinding is through the Interactive Response Technology (IRT). 
For information on how to unblind for emergency, please consult the IRT manual.
Any request to unblind a subject for non-emergency purposes during the blinded portion of the 
study should be discussed with the Medical Monitor.
Subjects may not resume initial treatment once unblinded.
4.6.1
Unblinding for emergency purposes
During the blinded portion of the study, blinding of treatment assignment is critical to the integrity 
of clinical study. However, in the event of a medical emergency or pregnancy in an individual 
subject in which knowledge of the investigational product is critical to the subject’s management, 
the blind for that subject may be broken by the investigator during the blinded portion of the study. 
The subject’s safety takes priority over any other considerations in determining if a treatment 
assignment should be unblinded during the blinded portion of the study.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountabilityas well as the subject’s medical 
record and eCRF.
4.8
Destruction or Return of Investigational Product
For this study, 
IP (those supplied by BMS, a vendor or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics).
On-site destruction is allowed provided the following minimal standards are met:
On-site disposal practices must not expose humans to risks from the drug.
On-site disposal practices and procedures are in agreement with applicable lawsand 
regulations, including any special requirements for controlled or hazardous substances.
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensedwaste disposal vendor 
must be documented.
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
Revised Protocol No.: 04
Date: 25-May-2018
63
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
and institutional guidelines and procedures, and provi
ded that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provi
ded that appropriate records of disposal are 
kept.
Arrangements for the return of study drug will be made by the responsible StudyMonitor.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not Applicable. 
Revised Protocol No.: 04
Date: 25-May-2018
64
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
5.
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209714)
Procedure
Screening
Notes
Eligibility Assessments
Informed Consent
X
Original IC in screening for protocol participation; Study allows for re-enrollment 
of a subject that has discontinued the study as a pre-treatment failure. If re-
enrolled, the subject must be re-consented and assigned a new subject number 
from IVRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed 
prior to first dose
Medical History
X
Tumor Tissue Sample
X
A Tumor sample prior to therapy is mandatory for PD-L1 testing (to be shipped to 
Central Lab) and HPV p-16 testing for subjects with oropharyngeal CA and 
unknown primary location (sample either tested locally or shipped to Central 
Lab). If a recent tumor sample (obtained within 6months of enrollment) is not 
available at screening, a fresh biopsy will be taken at any point prior to 
randomization. Sufficient tumor tissue should be submitted either one full block 
or minimum of 15 slides, obtained from core biopsy, punch biopsy, excisional 
biopsy or surgical specimen.
Screening/Baseline Tumor Assessment
X
Should be performed within 28 days prior to first dose. 
CT with IV contrast or MRI of Neck, Chest, Abdomen, Pelvis and all known or 
suspected sites of disease should be imaged at the screening visit. MRI with 
Gadolinium may be obtained if CT iodinated contrast is contraindicated.
MRI of brain without and with Gadolinium is required to rule out brain metastases 
in cases where there is clinical suspicion of intracranial involvement.  CT of the 
Brain (with or without contrast) can be performed if MRI is contraindicated or 
unavailable. 
TAs following RECIST 1.1 criteria.1.1 criteria.
Prior Medications
X
Dates and doses of platinum-based therapy plus prior medications subjects 
received to treat cancer including and radiotherapy given.
Revised Protocol No.: 04
Date: 25-May-2018
65
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209714)
Procedure
Screening
Notes
ECOG Performance Status
X
Within 72 hours prior to first dose 
Safety Assessments
Physical Measurements/Physical Examination
X
Height and Weight. Within 14 days prior to first dose
Vital Signs
X
Including BP, HR, temperature. Obtain vital signs within 28 days prior to first 
dose.
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Concomitant Medication Collection
X
Within 14 days prior to first dose
ECG
X
12 lead ECG required at Screening
Adverse Events Assessment
X
Laboratory Tests
X
CBC w/differential,
Chemistry panel including: Albumin , LDH, AST, ALT, ALP, T.Bili, BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, phosphate, glucose, amylase, 
lipase, TSH, Free T4, Free T3. 
Within 14 days prior to first dose.
Hepatitis B surface antigen (HBV sAg),and hepatitis C antibody (HCV Ab) or 
Hepatitis C RNA (HCV RNA).
Within 28 days prior to first dose.
Subjects who test positive for hepatitis C but have undetectable HCV RNA are 
allowed to enroll.
Pregnancy Test (WOCBP only) 
X
Serum or urine within 24 hours of first dose
Biomarker Assessment
Tumor Biopsy Sample
X
See Table 5.6-1
Study Drug
Enrollment in IRT
X
Those supplied by BMS or sourced by the investigator
Revised Protocol No.: 04
Date: 25-May-2018
66
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (CA209714)
Procedure
Each 
Cycle 
Day1 3 
Each 
Cycle 
Day 15 3
Each 
Cycle 
Day 29 3
Notes
Safety Assessments
Targeted Physical Examination
X
X
X
Vital Signs
X
X
X
Including BP, HR, and temperature. 
Physical measurements 
(including performance status)
X
X
X
Weight and ECOG status. The dosing calculations should be 
based on the body weight. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the 
dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram.
Adverse Events Assessment
X
X
X
Laboratory Tests
X
X
X
On-studylocallaboratoryassessmentsshouldbedonewithin72
hourspriortoeachdose, CBCw/differential,(Albuminif
clinicallyindicated),LFTs(ALT,AST,totalbilirubin,alkaline
phosphatase),BUNorserumurealevel,creatinine,Ca,Mg,Na,
K,Cl,LDH,phosphate,glucose,amylase,lipase,TSHwith
reflexiveFreeT4,FreeT3.
(ThyroidFunctionTestingtobeevaluatedevery6weeks)
Pregnancy Test (WOCBP only) 
See note
Serum or urine within 24 hours prior to first dose and then every 
4weeks (1 week) regardless of dosing schedule.
Revised Protocol No.: 04
Date: 25-May-2018
67
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Table 5.1-3:
Follow-Up Period (all treatment groups)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-Up 
Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related issues
Vital Signs
X
Adverse Events Assessment
X
In survival periodonly to include toxicities from study therapy.
Review of Concomitant Medication
X
X
Document Subsequent Cancer Therapy
Laboratory Tests
X
CBC w/ differential, LFTs, BUN or serum urea level, creatinine, Ca, 
Mg, Na, K, Cl, LDH, Glucose, amylase, lipase, TSH (+ reflex Free T4 
and Free T3)
To be done at FU1, to be repeated at FU2, if study related toxicity 
persists.
Pregnancy Test (WOCBP only)
X
Serum or urine on the 2 the first follow up visits
Efficacy Assessments
Tumor Assessment
X
X
Only for subjects without progression.
-Tumor assessments should occur every 6 weeks (1week) for the first 
48 weeks, then every 12 weeks (1week) until disease progression or 
treatment is discontinued (whichever occurs later).
-CT or MRI of neck, chest, abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at screening/baseline.
-Subjects with a history of brain metastasis should have surveillance 
MRI approximately every 12 weeks from first dose, or sooner if 
clinically indicated
 
5.0
Approved
930101794
5.0
v
Revised Protocol No.: 04
Date: 25-May-2018
70

Clinical Protocol
CA209714
BMS-936558
nivolumab
Table 5.1-3:
Follow-Up Period (all treatment groups)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-Up 
Visitsb
Notes
Subject Status
Survival Status
X
X
Every 3 months after FU 2; may be accomplished by visit, phone 
contact or email, to include assessment of subsequent anti-cancer 
therapy
a Follow-up visit 1 (FU1) = 30 days from the last dose (7) days or Follow up visit 1 can be performed on the date of discontinuation if it is greater than 42 days 
from last dose. Follow-up visit 2 (FU2) = 90 days (7 days) from follow-up visit 1(7 days).
b Every 3 Months (7 days) from FU2.
Revised Protocol No.: 04
Date: 25-May-2018
71
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments during the Screening or Lead-in 
period will be permitted (this does not include parameters that require a confirmatory result).
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter 
is clinically relevant.
5.2
Study Materials
NCI CTCAE version 4
Nivolumab Investigator Brochure
Ipilimumab Investigator Brochure
Pharmacy Binder
Laboratory manuals for collection and handling of blood (including PK, biomarker and 
immunogenicity) and tissue specimens
Site manual for operation of IVRS, including enrollment worksheets
Manual for entry of local laboratory data
Pregnancy Surveillance Forms
RECIST 1.1 pocket guide
Study Imaging Manual
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), and temperature at rest, and should be performed within 28 days prior to 
first dose. Baseline signs and symptoms are those that are assessed within 14 days prior to first 
dose. Concomitant medications will be collected from within 14 days prior to the first dose through 
the study treatment period (see Section 5.1).
Baseline local laboratory assessments should be done within 14 days prior to first dose and are to 
include: complete blood count (CBC) w/differential, liver function tests (LFTs: ALT, AST, total 
bilirubin, alkaline phosphatase), blood urea nitrogen (BUN) or serum urea level, creatinine, 
albumin, calcium (Ca++), magnesium (Mg++), sodium (Na+), potassium (K+), chloride (Cl-), 
phosphate, lactate dehydrogenase (LDH), glucose, amylase, lipase. Thyroid function tests includes 
thyroid stimulating hormone (TSH), free thyroxine (T4), and free triiodothyronine (T3).
The following baseline local laboratory assessments should be done within 28 days prior to first 
treatment: Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA).
Revised Protocol No.: 04
Date: 25-May-2018
72
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the Day1 
of first dose and then every 4 weeks 1 week regardless of dosing Cycle.
While on-study the following local laboratory assessments are to be done within 3 days prior to 
each dose: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, albumin (if clinically indicated), Ca,Mg, Na, K, Cl, phosphate, 
LDH, glucose, amylase, and lipase. Thyroid function testing is to be done every 6 weeks regardless 
of treatment arm.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Table 5.1-3) 
toxicity assessments should be done in person. Once subjects reach the survival follow-up phase 
either in person or documented telephone calls to assess the subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
On-study weight,ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to dosing. Vital signs should also be taken as per institutional standard of care prior to, 
during and after infusions. The start and stop time of the study therapy infusions should be 
documented.
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
Additional measures, including non-study 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.
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.
5.3.1
ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status will be evaluated and 
documented at Screening within 72 hours prior to first dose and within 72 hours prior to each 
dosing visit as outlined in Section 5.1. See Appendix 1 for description of ECOG status.
5.3.2
Pregnancy Testing
WOCBP are required to have pregnancy tests performed. WOCBP must exhibit a negative serum 
or urine pregnancy (minimum sensitivity 25 IU/L or equivalent units) of HCG within 24hours 
prior to Day 1 of first dose and then every 4 weeks (1 week) during the treatment period and first 
2 follow-up visits. Pregnancy testing will be done locally and as outlined in Section 5.1. An 
extension up to 72 hours prior to start of study drug may be permissible in situations where results 
Revised Protocol No.: 04
Date: 25-May-2018
73
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
cannot be obtained within the standard hour window. This is subject to medical monitor/MST 
Chair approval.
5.3.3
Thyroid Function Testing
Local thyroid function testing will be performed as outlined in Section 5.1.
At Screening, thyroid function testingis to include TSH, free T3 and free T4. At subsequent time 
points, thyroid function testing consists of TSH only. However, if the TSH is abnormal, reflexive 
testing of free T3 and free T4 are to be performed.
Management algorithms for suspected endocrinopathy adverse events (including abnormal thyroid 
function) can be found in the nivolumab investigator brochure and Appendix 2 of the protocol.
5.3.4
Electrocardiogram (ECG)
All subjects who have met the eligibility criteria are required to have a 12-lead ECG performed at 
Screening. If clinically indicated, additional ECGs may be obtained during the study.
5.4
Efficacy Assessments
Study radiologic tumor evaluations will take place in accordance with T & E tables according to 
RECIST 1.1 Appendix 3. 
Sites will be trained prior to scanning the first study subjects. Images will be submitted to an 
imaging third-party radiology vendor for central review as they are performed. Image acquisition 
guidelines and submission process will be outlined in the study Imaging Manual to be provided by 
the radiology vendor. 
Screening (baseline) tumor assessments are to be performed within 28 days prior to first dose. In 
addition to the neck, chest, abdomen, pelvis, and all known / suspected sites of disease should be 
assessed at baseline.Subsequent assessments should include neck, chest, abdomen, pelvis, and all 
known / suspected sites of disease using the same imaging method and technique as was used at 
baseline. 
A Screening MRI (or CT with contrast if MRI is contraindicated) of the brain without and with 
contrast should be done for all subjects with suspected brain involvement, including base of skull 
involvement, in order to rule out active metastatic disease.
Radiographic tumor response will be assessed every 6 weeks (1 week) after the first dose for the 
first 12 months (until week 48) and every 12 weeks (1 week) thereafter, until disease progression 
or subsequent therapy (whichever occurs later). Previously treated CNS metastases are not 
considered measurable lesions for purposes of RECIST 1.1 determined response. Subjects with a 
history of brain metastasis should have surveillance MRI approximately every 12 weeks from the 
date of first dose, or sooner if clinically indicated.
CT with PO/IV contrast or contrast enhanced MRI are thepreferred imaging modalities for 
assessing radiographic tumor response. If a subject has a known allergy to contrast material, local 
prophylaxis standards may be used to obtain the assessment with contrast if at all possible, or use 
the alternate modality. In cases where contrast is strictly contraindicated, a non-contrast scan will 
Revised Protocol No.: 04
Date: 25-May-2018
74
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
suffice. Should a subject have a contraindication for CT IV contrast, contrast enhanced MRI of the 
neck, chest, abdomen and pelvis may be obtained. Every attempt should be madeto image each 
subject using an identical acquisition protocol on the same scanner for all imaging time points.
Use of CT component of a PET/CT scanner: Combined modality scanning such as with 
fluorodeoxyglucose-positron emission tomography (FDG PET)/CT isincreasingly 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 FDG-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 for anatomically based RECIST measurements. However, 
if a site can document that the CT performed as part of a FDG-PET/CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast) then the CT portion of the FDG-PET/CT can 
be used for RECIST 1.1 measurements. Note, however, that the FDG-PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially performed.
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities arethe sole modality used to assess certain non 
target organs, those non-target organs may be evaluated less frequently. For example, bone scans 
may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed or 
discontinued. Tumor measurements should be made by the same investigator or radiologist for 
each assessment whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the Investigator using the RECIST 1.1 
criteria (Appendix 3). 
All radiographic assessments performed for study purposes will be submitted to the third-party 
radiology vendor for central review. Tumor assessments should be submitted to the third-party 
radiology vendor as they are performed on an ongoing basis. At the time of investigator-assessed 
disease progression, the site must request a Blinded Independent Central Review (BICR) from the 
third-party radiology vendor. For details on the timelines and associated process requirements refer 
to the imaging manual. 
Subjects whose disease progression is not confirmed by the BICR will be required to continue 
tumor assessments (if clinically feasible) according to the protocol-specified schedule, in order to 
ensure of the primary and key secondary endpoints of the study (BICR assessed ORR and PFS) 
are assessed. In this situation, the decision on whether to discontinue therapywill be the 
responsibility of investigator. Subsequent tumor assessments must be submitted to the third party 
radiology vendor for BICR and may be discontinued when the investigator and BICR both assess 
the subject to have met RECIST 1.1 criteria for progression. 
If clinically acceptable, subsequent therapy should begin only after RECIST1.1 progression has 
been assessed by BICR.
Revised Protocol No.: 04
Date: 25-May-2018
75
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
At the time of investigator-assessed disease progression, the site must complete the tumor 
assessment pages in TAO (Trial AccessOnline) documenting disease progression and submit a 
fresh biopsy sample to Central Lab for biomarker analysis as specified in Section5.6.
If thesubject is offered treatment beyond progression, the biopsy should be performed when they 
are taken off therapy, at the point after RECIST progression when they meet the criteria for 
discontinuation as defined in the protocol
In addition, subjects receiving nivolumab or ipilimumab or ipilimumab-placebo treatment beyond 
progression must continue tumor assessments until such treatment has been discontinued.
5.4.1
Primary Efficacy Assessment
The primary endpoint is objective response rate (ORR) in the platinum refractory subgroup (See 
Section 8.3.1for the definitions of ORR). All randomized subjects will be monitored by 
radiographic assessment on an every 6 week schedule every 6 weeks (7 days) from first dose for 
the first 12months (until week 48) and every 12 weeks (7 days) thereafter (beginning from the 
first on-study assessment on week 6 [7 days]), to determine changes in tumor size. RECIST 1.1 
criteria will be used for the assessment. For details regarding the response criteria using RECIST 
1.1 refer to Appendix 3.
5.4.2
Secondary Efficacy Assessment
The secondary endpoint of ORR in platinum eligible subgroup is defined similarly as described 
for the primary endpoint.
The BICR-assessed PFS is defined as the time from randomization to the date of first documented 
disease progression, as assessed by the BICR using RECIST 1.1 criteria, or death due to any cause, 
whichever occurs first. Subjects who died without a reported progression will be considered to 
have progressed on the date of their death. Subjects who did not progress or die will be censored 
on the date of their last evaluable tumor assessment. Subjects who did not have any on study tumor 
assessments and did not die will be censored on the date they were randomized. Subjects who 
started any subsequent anti-cancer therapy, including tumor-directed radiotherapy and tumor-
directed surgery, without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to/on initiation of the subsequent anti-cancer therapy. 
Every effort will be made to collect survival data on all randomized subjects including subjects 
withdrawn from treatment for any reason, who are eligible to participate in the study and who have 
not withdrawn consent for survival data collection. If the death of a subject is not reported, all 
dates in this study representing a date of subject contact will be used in determination of the 
subject’s last known date alive.
PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 
100evaluable tumor cells per validated Dako PD-L1 IHC assay.
Analysis of the secondary endpoints will be performed at the same time as the primary endpoint 
analysis.
Revised Protocol No.: 04
Date: 25-May-2018
76
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
To determine changes in tumor size. RECIST 1.1 criteria will be used for the assessment. .For 
details regarding response criteria using RECIST 1.1 refer to Appendix 3.
 
 
 
 
 
 
 
 
 
 
 
 
 
  
5.0
Approved
930101794
5.0
v
Revised Protocol No.: 04
Date: 25-May-2018
77

Clinical Protocol
CA209714
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.
ADVERSE EVENTS
An Adverse Event(AE)is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
Thecausal relationship to study drug is determined by a physician and should be used to assess all 
AE. The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term “reasonable causal relationship” means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. Care should be taken not to introduce bias when collecting 
5.0
Approved
930101794
5.0
v
Revised Protocol No.: 04
Date: 25-May-2018
84

Clinical Protocol
CA209714
BMS-936558
nivolumab
AEs and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in the 
context of known adverse events,when appropriate for the program or protocol. 
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.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE)is any untoward medical occurrence that at any dose: 
results in death
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect 
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
elective surgery, planned prior to signing consent
admissions as per protocol for a planned medical/surgical procedure
routine health assessment requiring admission for baseline/trending of health status 
(eg,routine colonoscopy)
Revised Protocol No.: 04
Date: 25-May-2018
85
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. 
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing, except in cases where a study participant has started a new anti-
neoplastic therapy. However, any SAE occurring after the start of a new treatment that is suspected 
to be related to study treatment by the investigator will be reported. If applicable, SAEs must be 
collected that relate to any later protocol specified procedure (eg, a follow-up skin biopsy).  For 
subjects randomized/assigned to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of randomization/treatment assignment. The investigator must 
report any SAE that occurs after these time periods and that is believed to be related to study drug 
or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAEReport Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to Sponsor 
or designee within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. 
In this case, the paper formsare to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address:Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
Revised Protocol No.: 04
Date: 25-May-2018
86
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or ifnew information 
becomes available, the SAE report must be updated and submitted within 24 hours to Sponsor or 
designee using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
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 systemis not functioning.
Any laboratory test result that is clinically significant or meets the definition of an SAE 
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
Revised Protocol No.: 04
Date: 25-May-2018
87
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5half 
lives after product administration, the investigator must immediately notify the Sponsor 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 Section 6.1.1.
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/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 BMS 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.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section6.1.1for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section6.1.1for reporting details).
Revised Protocol No.: 04
Date: 25-May-2018
88
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Potential drug induced liver injury
 is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
6.7.1
Adverse Events of Interest
Definition of immune-mediated adverse events (IMAEs)
Immune-mediated AEs are specific events (that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
(adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis) for which 
subjects received immunosuppressive medication for treatment of the event, with the exception of 
endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, 
adrenal insufficiency), which are included regardless of treatment since these events are often 
managed without immunosuppression.
IMAEs include events, regardless of causality, occurring within 100 days of the last dose. This list 
is subject to change based on Health Authority feedback or change of Medical Dictionary for 
Regulatory Activities (MedDRA) version. The final list used will be described in the clinical study 
report (CSR).
Table 6.7.1-1below provides a summary of the IMAEs category and their respective preferred 
terms (PTs). This list is subject to change based on Health Authority feedback or change of 
MedDRA version. The final list used will be described in the CSR.
Table 6.7.1-1: 
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Pneumonitis
Pneumonitis, Interstitial lung disease
Diarrhea/Colitis
Diarrhea, Colitis, Enterocolitis
Revised Protocol No.: 04
Date: 25-May-2018
89
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Table 6.7.1-1: 
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs included under IMAE Category
Hepatitis
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune 
hepatitis, AST increased, ALT increased, Bilirubin 
increased, ALP increased
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, Thyroiditis
Thyroiditis acute (collapsed with thyroiditis for 
frequency), Autoimmune thyroiditis (collapsed with 
thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, Diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, Nephritis allergic, Tubulointerstitial 
nephritis, Acute renal failure, Renal failure, Increased 
creatinine
Rash
Rash, Rash maculopapular
7.
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will be utilized to provide general oversight and safety 
considerations for this study. The DMC will provide advice to the Sponsor regarding actions the 
committee deems necessary for the continuing protection of subjects enrolled in this study. The 
DMC will be charged with assessing such actions in light of an acceptable risk/benefit profile for 
nivolumab in combination with placebo, and nivolumab in combination with ipilimumab. The 
DMC will act in an advisory capacity to BMS and will monitor subject safety data for the study 
approximately every 6 months for the duration of the trial.
The DMC will be advisory to the clinical study leadership team. The clinical study leadership will 
have responsibility for overall conduct of the study including managing the communication of 
study data. The group will be responsible for promptly reviewing the DMC recommendations, for 
providing guidance regarding the continuation or termination of the study, and for determining 
whether amendments to the protocol or changes to the study conduct are required.
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
Revised Protocol No.: 04
Date: 25-May-2018
90
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
8.
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The primary objective is to compare the ORR of nivolumab in combination withipilimumab vs 
nivolumab in combination with ipilimumab placebo, as determined by BICR using Response 
Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria in platinum refractory subjects with 
recurrent or metastatic SCCHN. The alpha level for the ORR is adjusted for one planned interim 
analysis using Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. Given that 
the interim analysis for the primary endpoint is expected to be performed when 70% of platinum 
refractory subjects have reached 6 months follow up after randomization, the alpha level is 
expected to be 0.015 for the interim analysis and 0.045 for the final analysis.
Approximately 396subjects (216platinum refractory subjects and 180 platinum eligible subjects) 
will be randomized to either nivolumab plus ipilimumab or nivolumab in combination with 
ipilimumab placebo in a 2:1 ratio. 
A sample size of 216randomized platinum refractory subjects (144and 72, respectively) will 
provide 84% power for testing the odds ratio of nivolumab plus ipilimumab over nivolumab in 
combination with placebo, with a 0.050 two-sided significance level, assuming ORR of 35% and 
15% (odds ratio of 3.051) in the nivolumab plus ipilimumab and nivolumab in combination with 
ipilimumab placebo treatment group, respectively (odds ratio of proportions test using EAST v6). 
The first secondary objective is to estimate the ORR of the treatment of nivolumab in combination 
with ipilimumab vs nivolumab in combination with ipilimumab placebo, as determined by BICR 
using RECIST 1.1 criteria for first-line treatment of recurrent 
or metastatic SCCHN in the platinum 
eligible setting.
Approximately 180 subjects (120 and 60, 
respectively) willbe randomized in the platinum eligible 
subgroup. For a sample size of 120 subjects randomized to nivolumab plus ipilimumab, the 
maximum width of the exact two-sided 95% confidence interval (CI) is 18.6% when the ORR is 
expected to be in the 10% to 55% range. The table below summarizes the 95% exact CI when 
observed ORRs are between 10% and 55% respectively.
Table 8.1-1:
Observed ORR with Exact 95% CI in Platinum Eligible 
Subjects randomized to nivolumab plus ipilimumab (N=120)
Observed ORR 
95% Exact CI
10% 
(5.3%, 16.8%)
20% 
(13.3%, 28.3%)
30% 
(22.0%, 39.0%)
40% 
(31.2%, 49.3%)
50% 
(40.7%, 59.3%)
55%
(45.7%, 64.1%)
Revised Protocol No.: 04
Date: 25-May-2018
91
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
About 60 subjects will be randomized to nivolumab plus ipilimumab placebo arm. The following 
table summarizes the 95% exact CI whenobserved ORRs are between 10% and 55%.
Table 8.1-2:
Observed ORR with Exact 95% CI in Platinum Eligible 
Subjects randomized to nivolumab plus ipilimumab placebo 
(N=60)
Observed ORR 
95% Exact CI
10% 
(3.8%, 20.5%)
20% 
(10.8%, 32.3%)
30% 
(18.8%, 43.2%)
40% 
(27.6%, 53.5%)
50% 
(36.8%, 63.2%)
55%
(41.6%, 67.9%)
8.2
Populations for Analyses
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IRS. 
All Randomized Subjects: All subjects who were randomized to any treatment arm in the study. 
This is the primary dataset for analyses of study conduct, study population, and efficacy.
All Treated Subjects: All subjects who received at least one dose of nivolumab, or ipilimumab, 
or nivolumab in combination with ipilimumab placebo.
All pharmacokinetic (PK) Subjects: All subjects with available serum time-concentration data
Immunogenicity Evaluable Subjects:
Nivolumab ADA Evaluable Subjects: all treated subjects with baseline and at least 
1post-baseline pre-infusion nivolumab immunogenicity assessment. 
Ipilimumab ADA Evaluable Subjects: all treated subjects with baseline and at least 
1post-baseline pre-infusion ipilimumab immunogenicity assessment. 
All PD-L1 Tested subjects: All subjects, randomized or not, who had a tumor biopsy specimen 
available for PD-L1 expression testing. This includes both randomized and screen failure 
subjects.
A description of the participant population will be included in the statistical output reported, 
including subgroup of age, gender, and race.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective in the study will be measured by the primary endpoint of ORR in Platinum 
Refractory subgroup. ORR is defined as the number 
of subjects with a best 
overall response (BOR) 
of a complete response (CR) or partial response (PR) divided by the number of randomized 
subjects for each treatment group. The BOR is defined as the best response designation, as 
determined by BICR, recorded between the date of randomization and the date of progression, as 
Revised Protocol No.: 04
Date: 25-May-2018
92
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
assessed by BICR per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-
directed radiotherapy and tumor-directed surgery), whichever occurs first. For subjects without 
evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available response 
designations will contribute to the BOR assessment. For subjects who continue treatment beyond 
progression, the BOR will be determined based on response designations up to the time of initial 
RECIST 1.1 progression. 
ORR will be further characterized by Duration of Response (DOR) and Time to Response (TTR). 
DOR is defined as the time between the date of first confirmed response to the date of the first 
documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs 
first. Subjects who neither progress nor die will be censored on the date of their last evaluable 
tumor assessment. Subjects who started any subsequent anti-cancer therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to or on 
initiationof the subsequent anti-cancer therapy. TTR is defined as the time from randomization to 
the date of the first confirmed CR or PR. DOR and TTR will be evaluated for responders 
(confirmed CR or PR) only.
The final analysis of the primary endpoint will occurat least 9 months after the last subject in the 
platinum refractory subgroup has been randomized. 
8.3.2
Secondary Endpoint(s)
The secondary endpoint of ORR and DOR in platinum eligible subgroup is defined similarly as 
described for the primary endpoint.
The BICR-assessed PFS is defined as the time from randomization to the date of first documented 
disease progression, as assessed by the BICR using RECIST 1.1 criteria, or death due to any cause, 
whichever occurs first. Subjects who died without a reported progression will be considered to 
have progressed on the date of their death. Subjects who did not progress or die will be censored 
on the date of their last evaluable tumor assessment. Subjects who did not have any on study tumor 
assessments and did not die will be censored on the date they were randomized. Subjects who 
started any subsequent anti-cancer therapy, including tumor-directed radiotherapy and tumor-
directed surgery, without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to/on initiation of the subsequent anti-cancer therapy. 
OS is defined as the time between the date of randomization and the date of death. For subjects 
without documentation of death, OS will be censored on the last date the subject was known to be 
alive.
PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 
100evaluable tumor cells per validated Dako PD-L1 IHC assay.
The final analysis of the ORR in each of platinum eligible and platinum refractory subgroups will 
occur at least 9 months after the sufficient number of subjects in that subgroup have been 
randomized (approximately 180 in platinum eligible and 216in platinum refractory subgroups). 
Analysis of the PFS and OS will also be performed at the sametime as the ORR analysis.
Revised Protocol No.: 04
Date: 25-May-2018
93
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
 
 
 
 
8.4
Analyses
Safety and tolerability will be measured by the incidence of deaths, adverse events, serious adverse 
events, adverse events leading to discontinuation, immune-mediated adverse events, select adverse 
events, adverse events leading to dose delay, and specific laboratory abnormalities (worst grade) 
in each treatment group. Toxicities will be graded using the NCI CTCAE version 4.0.
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized by treatment arm as randomized 
using descriptive statistics using all randomized population.
8.4.2 
Efficacy Analyses
Efficacy analyses will be performed by treatment for each of platinumeligible and platinum 
refractory sub-group as randomized and for all randomized subjects.
8.4.2.1
Method for primary endpoint
The comparison of ORR between nivolumab in combination with ipilimumab vs nivolumab in 
combination with ipilimumab placebo in platinum refractory randomized subjects will be carried 
out using a two-sided Cochran Mantel Haenszel (CMH) test stratified by the stratification factors 
as recorded in the IVRS. The significance level will be adjusted for an interim analysis which will 
be performed when around 70% of platinum-refractory subjects have been followed for at least 6 
months after randomization. Using Lan DeMets alpha spending function with O’Brien-Fleming 
boundaries, the significance level for this comparison will be determined by the fraction of subjects 
included in the interim analysis. If the analysis is performed when exactly 70% of platinum 
refractory subjects have reached 6 months follow up after randomization, the alpha level is 0.015 
for the interim and 0.045 for the final. An associated odds ratio and corresponding CIs (98.5% CI 
for interim and 95.5% CI for final) will be calculated. ORR will be summarized by a binomial 
response rate and its corresponding two-sided exact CIs using Clopper-Pearson method for each 
treatment group. An estimate of the difference in ORRs and corresponding CIs will be calculated 
using CMH methodology and adjusted by the stratification factors as recorded in the IVRS. 
Summary statistics of TTR will be provided for each treatment group for subjects who achieve PR 
or CR. Duration of response (DOR) in each treatment group will be estimated using KM product-
limit method for subjects who achieve PR or CR. Median values along with two-sided 95% CI 
will be calculated.
5.0
Approved
930101794
5.0
v
Revised Protocol No.: 04
Date: 25-May-2018
94

Clinical Protocol
CA209714
BMS-936558
nivolumab
 
 
 
 
 
9.
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. If a deviation or change to a protocol is implemented to eliminate an 
immediate hazard(s) prior to obtaining relevant approval/favorable opinion(s), the deviation or 
change will be submitted as soon as possible to:
IRB/IEC 
Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS. If an 
amendment substantially alters the study design or increases the potential risk to the subject: (1)the 
consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by BMS 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 BMS. 
5.0
Approved
930101794
5.0
v
Revised Protocol No.: 04
Date: 25-May-2018
98

Clinical Protocol
CA209714
BMS-936558
nivolumab
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.2
Records
9.2.1
Records Retention
The investigator (or head of the study site in Japan)must retain all study records and source 
documents for the maximum period requiredby applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan)must contact BMS or designee prior to destroying 
any records associated with the study.
BMS or designeewill notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s) Records or logs must comply with applicable 
regulations and guidelines and should include:
Revised Protocol No.: 04
Date: 25-May-2018
99
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
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 
subject, including unique subject 
identifiers
amount transferred to another area/site for 
dispensing or storage
nonstudy disposition (eg, lost, wasted) 
amount destroyed at study site, if 
applicable
amount returned to BMS
retain samples for 
bioavailability/bioequivalence, if 
applicable 
date and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
label identification number or batch 
number 
amount dispensed to and returned by each 
subject, including unique 
subject 
identifiers
date and initials of person responsible for 
Investigational 
Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
Revised Protocol No.: 04
Date: 25-May-2018
100
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effortto enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFswill be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. Subinvestigators in Japan may not
be delegated the CRF approval task.For electronic CRFs, review and approval/signature is 
completed electronically through the BMS electronic data capture tool. The investigator must 
retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not tobe shared or reassigned to other 
individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
Subject recruitment (eg, among the top quartile of enrollers)
Involvement in trial design
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
Revised Protocol No.: 04
Date: 25-May-2018
101
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limitedto, submitting proposed publications to 
BMS at the earliest practicable time prior to submission or presentation and otherwise within the 
time period set forth in the CTA.
Revised Protocol No.: 04
Date: 25-May-2018
102
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
10.
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ACTH
adrenocorticotropic hormone
AIDS
Acquired Immune Deficiency Syndrome
ALP
Alkaline phosphatase
ALT
alanine aminotransferase
AR
Additional research
AST
aspartate aminotransferase
BID, bid
bis in die, twice daily
BICR
Blinded Independent Central Review
BMS
Bristol-Myers Squibb
BOR
Best Overall Response
BP
blood pressure
BUN
blood urea nitrogen
CA
cancer
Ca++
calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CHO
Chinese hamster ovary
CI
confidence interval
C1-
chloride
cm
centimeter
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CR
Complete Response
CRC
Clinical Research Center
CRF
Case Report Form
CSR
Clinical Study Report
CTA
Clinical Trial Agreement
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Revised Protocol No.: 04
Date: 25-May-2018
103
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Term
Definition
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
D/C
discontinue
DCR
Disease Control Rate
DILI
Drug Induced Liver Disease
Dl
deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
Duration of Response
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4thEdition)
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
EGFR
Estimated glomerular filtration rate
EQ-5D
EuroQol five-dimension scale
ESR
Expedited Safety Report
5-FU
Fluoracil
FACT-G
FACT-general
FACT-HN
Functional Assessment of Cancer Therapy-Head & Neck
FHNSI-10
FACT Head and Neck Symptom Index
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescent in-situ hybridization
FU-1
Follow upvisit 1
FU-2
Follow up visit 2
FSH
follicle stimulating hormone
Revised Protocol No.: 04
Date: 25-May-2018
104
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Term
Definition
g
Gram
GCP
Good Clinical Practice
h
Hour
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HCG
Human chorionic gonadotrophin
HIV
HumanImmunodeficiency Virus
HIPAA
Health Insurance Portability and Accountability Act
HLA
human leukocyte antigen
HNC
Head and Neck carcinoma
HPV
Human Papilloma Virus
hr
Hour
HR
Hazard Ratio
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICF
Informed Consent Form
ICH
International Conference on Harmonization 
ie
id est (that is)
IEC
Independent Ethics Committee
IMA
Immune-mediated adverse events
IMP
investigational medicinal products
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
IVRS
Interactive Voice Response System
Revised Protocol No.: 04
Date: 25-May-2018
105
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Term
Definition
K+
potassium
kg
kilogram
L
Liter
LDH
lactate dehydrogenase
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
Mg++
magnesium
min
minute
Ml
milliliter
MRI
Magnetic resonance imaging
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NaCl
Sodium Chloride
NCI
National Cancer Institute
ng
nanogram
NIMP
non-investigational medicinal products 
NSCLC
Non-small cell lung cancer
OPC
Oropharynx
ORR
Objective Response Rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cells
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PET
positron emission tomography
PFS
Progression free survival
Revised Protocol No.: 04
Date: 25-May-2018
106
5.0
Approved
930101794
5.0
v

Clinical Protocol
CA209714
BMS-936558
nivolumab
Term
Definition
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PR 
Partial Response
PRO-CTCAE
Common Terminology Criteria for Adverse Events
PT
Preferred term
QD, qd
quaque die, once daily
RANK-L
Receptor activator of nuclear factor kappa-B ligand
RBC
red blood cell
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
serious adverse event
SCCHN
Squamous Cell Carcinoma Head and Neck
SD
standard deviation
SmPC
summary of product characteristics
SNP
Single nucleotide polymorphisms
SOP
Standard Operating Procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Time
T3
triiodothyronine
T4
thyroxine
TAO
Trial Access Online
TOI
Trial Outcome Index
TID, tid
ter in die, three times a day
TMB
Tumor mutational burden
TTSD
Time To Symptom deterioration
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
VAS
Visual Analog Scale
WBC
white blood cell
WOCBP
women of childbearing potential
Revised Protocol No.: 04
Date: 25-May-2018
107
5.0
Approved
930101794
5.0
v