Clinical trial NCT02741570
Conditions: Head and Neck Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2016-10-05; Completion date: 2022-09-22
Enrollment: 947 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to compare nivolumab and ipilimumab with the extreme regimen as first line treatment in patients with recurrent or metastatic squamous cell of the head and neck cancer

Detailed description:

Arms: arm 1: Specified dose on specified days arm 2: Specified dose on specified days
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Cetuximab/Erbitux intervention 4: Cisplatin/Platinol intervention 5: Carboplatin/Paraplatin intervention 6: Fluorouracil/Adrucil
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None

Protocol documents:
Prot_002.pdf: 
Page:
1
Protocol Number:
CA209651
IND Number:
125872
Ex-US
Non-IND
EUDRACT Number
2016-000725-39
Date:
23-Mar-2016
Revised Date:
19-Dec-2019
Clinical Protocol CA209651
An Open Label, Randomized, Two Arm Phase III Study of Nivolumab in Combination with 
Ipilimumab versus Extreme Study Regimen (cetuximab + cisplatin/carboplatin + fluorouracil) as 
First Line Therapy in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
(SCCHN)
(CheckMate 651: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 651)
Revised Protocol Number: 05
Incorporated: Administrative Letter 05 and Administrative Letter 07
Study Director
Medical Monitor
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
2
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).
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 05
19-Dec-2019
•
Removed second interim analysis of OS
•
Added a Myocarditis adverse event management algorithm
Administrative 
Letter 07
11-Nov-2019
•
Corrected typographical error in the statistical section to address the 
inconsistency in the number of death events required for interim 
analysis
Administrative 
Letter 05
23-Aug-2019
•
Made changes to the Medical Monitor and Study Director and added 
abbreviation “EGFR, epidermal growth factor receptor” to Section 10, 
List of Abbreviations
Revised 
Protocol 04
20-Jun-2019
•
The primary objectives were changed to compare: 
−
OS for participants who are receiving nivolumab + ipilimumab 
versus EXTREME regimen in participants with PD-L1 CPS ≥ 20 
(changed from tumor PD-L1 ≥ 1) and 
−
OS for participants who are receiving nivolumab + ipilimumab 
versus EXTREME regimen in all study participants (irrespective 
of PD-L1 expression).
•
Description of the statistical analyses were changed based on the 
changes in objectives
•
Key secondary objective was changed to OS in subject with PD-L1 
CPS ≥1.
•
Efficacy evaluation based on biomarker subgroups were added to 
exploratory objectives.
•
Added supporting data for change in objectives from recent years and 
updated literature references
•
Updated protocol to align with current standards for BMS clinical 
studies.
•
Minor formatting and typographical corrections.
Revised 
Protocol 03
01-May-2018
•
The primary objectives were changed from PFS and OS in all 
randomized subjects to PFS and OS in subjects with PD-L1 expressing 
tumors.
•
PFS and OS in all study subjects moved to secondary endpoints.
•
The hierarchy for the analysis was updated – PFS in all study subjects 
would be tested hierarchically after PFS in subjects with PD-L1 
expressing tumors. OS in all study subjects would be tested 
hierarchically after OS in subjects with PD-L1 expressing tumors.
•
The sample size was increased to allow for evaluation of the updated 
primary end-points. The sample size determination was updated 
accordingly.
•
Added brief description of the analysis of TMB data.
•
Change in medical monitor and study director for the study 
(Administrative Letter 04 (date of issue:20-Mar-2018))
•
Added that nivolumab should be permanently discontinued in case of 
grade 3 drug-related myocarditis.
•
Minor formatting and typographical corrections.
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
4
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
26-Oct-2017
•
The sample size was increased. 
•
A maximum duration of nivolumab and ipilimumab treatment of 24
months from the start of treatment was added. 
•
Duration of response has been changed from an exploratory objective 
to a secondary objective based on the expected improvement in 
duration of response as seen in other nivolumab trials. Response to first 
therapy after disease progression was changed to an exploratory 
endpoint to limit the secondary objectives only to critical endpoints. 
•
Exploratory biomarker objectives were added in order to evaluate the 
potential associations between efficacy outcomes (such as objective 
response rate, PFS, and OS) with select biomarkers, including tumor 
mutational burden, from tumor tissue and peripheral blood. 
Administrative 
Letter 03
06-Oct-2016
Change in medical monitor for the study
Administrative 
Letter 02
14-Sep-2016
Change to section 5.8, Additional Research section modified
Revised 
Protocol 01
22-Jun-2016
Incorporates Amendment 02
Amendment 02
22-Jun-2016
Week 7 biopsy optional instead of required, Section 5.8 “Additional 
Research” added, PK and IMG Follow up visit samples no longer required 
to be collected, Radiographic Imaging wording updated for clarification. 
Updated Algorithms for Renal, Pulmonary and Skin to match with 
updated Nivolumab IB v15 (includes Nivo IB 15 erratum update).  Other 
minor edits, clarifications, corrections
Original 
Protocol
23-Mar-2016
Not applicable
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 05:
Changes were made based on discussions with the 
. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & Title
Description of Change
Brief Rationale
Title Page
Made updates to Study Director 
and Medical Monitor names.
Personnel change
Synopsis, Statistical 
Considerations
Section 8.1 Sample Size 
Determination
Table 8.1-1 Statistical 
Assumption and Power 
Calculation
Section 8.5 Interim Analyses
Removed second interim analysis 
and associated statistical 
assumptions.
Corrected typographical error to 
ensure proper alignment in the 
approximate number of death 
events required for the interim 
analysis.
The analysis plan contained two formal 
interim analyses at 80% and 90% 
information fraction prior to the final 
analysis. Upon 
 
recommendation, the analysis at 90% 
information was dropped. The new 
analysis plan has one formal interim 
analysis at 80% information fraction 
(approximately 593 events in all 
randomized participants) followed by 
final analysis.
Section 10 List of 
Abbreviations
Added abbreviation “epidermal 
growth factor receptor (EGFR)” to 
distinguish it from “estimated 
glomerular filtration rate (eGFR).”
Correction of error
Section 11 References
Removed “References for the use 
of condoms with spermicide” and 
the two listed references.
Correction of error, as the references are 
not applicable to the protocol.
Appendix 2 Management 
Algorithms
Added Myocarditis algorithm and
revised date of the other algorithms 
to 2019.
Provided Myocarditis algorithm per 
recent Nivolumab Investigator Brochure.
Revised Protocol No.: 05
Date: 19-Dec-2019
5
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
SYNOPSIS
Clinical Protocol CA209651
Protocol Title: An Open Label, Randomized, Two Arm Phase III Study of Nivolumab in Combination with 
Ipilimumab versus Extreme Study Regimen (cetuximab + cisplatin/carboplatin + fluorouracil) as First Line Therapy 
in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)
(CheckMate 651: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 651)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
Nivo/Ipi Combo Arm (Arm A):
•
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) until 24 months from first nivolumab treatment, disease progression or 
unacceptable toxicity. 
(1 Cycle =6 Weeks)
EXTREME regimen Arm (Arm B):
•
Cetuximab 400 mg/m2 IV once only, then 250 mg/m2 weekly + cisplatin (100 mg/m2) or carboplatin (Area Under 
the Curve of 5 mg per milliliter per minute) on day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 
3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly until disease 
progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
(1 Cycle = 3 weeks).
Study Phase: III
Research Hypothesis:
•
Participants with Programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥ 20 who receive nivolumab 
in combination with ipilimumab for first-line treatment of recurrent or metastatic SCCHN will have longer overall 
survival (OS) than comparable participants who receive the EXTREME regimen
•
Participants who receive nivolumab in combination with ipilimumab for first-line treatment of recurrent or 
metastatic SCCHN will have longer OS than comparable participants who receive the EXTREME regimen 
Objectives: 
Primary Objectives:
•
To compare the OS of participants with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab 
to those receiving EXTREME regimen. 
•
To compare the OS of all study participants receiving nivolumab combined with ipilimumab to those receiving 
EXTREME regimen
Secondary Objectives:
•
To compare the OS of participants with PD-L1 CPS ≥ 1 who are receiving nivolumab combined with ipilimumab 
to those receiving EXTREME regimen 
•
To evaluate progression-free survival (PFS) based on BICR in all study participants and those with PD-L1 CPS 
≥ 20 who are receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
Revised Protocol No.: 05
Date: 19-Dec-2019
6
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
To evaluate objective response rate (ORR) based on BICR in all study participants and those with PD-L1 CPS 
≥20 who are receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate the duration of response (DOR) based on BICR in all study participants and those with PD-L1 CPS 
≥ 20 who are receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
Exploratory Objectives:
•
To evaluate OS of participants with tumor cell PDL-1 expression level < 1% and PD-L1 CPS < 20 who are 
receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate the OS of participants with tumor inflammation score measured as gene expression profile (GEP) 
≥10 who are receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate the OS of participants with tumor mutation burden (TMB) ≥ 7 who are receiving nivolumab combined 
with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate clinical outcomes (OS, PFS, ORR, DOR) by select baseline and on-treatment biomarker expression 
levels in peripheral blood and tumor biopsy specimens.
•
To assess safety and tolerability of nivolumab in combination with ipilimumab and of EXTREME regimen, in all 
study participants
•
To characterize pharmacokinetics and immunogenicity of nivolumab in combination with ipilimumab as first line 
therapy in participants with recurrent or metastatic SCCHN
•
To evaluate time to symptom deterioration (TTSD) in each arm as assessed using the Functional Assessment of 
Cancer Therapy - Head and Neck (FACT-H&N) 10-item Symptom Index (FHNSI-10), in participants with PD-
L1 CPS ≥ 20 and also in all study participants
•
To assess the participant’s overall health status and health utility using the 3-level version of the EQ-5D (EQ-5D-
3L) visual analog scale (VAS) and utility index, respectively, in participants with PD-L1 CPS ≥ 20 and also in all 
study participants
•
To assess the participant’s cancer-related symptoms and quality of life using components of the FACT-H&N 
questionnaire in participants with PD-L1 CPS ≥ 20 and also in all study participants.
Study Design: 
This is a randomized, open-label, Phase 3 trial in participants ≥18 years old with untreated metastatic or recurrent 
SCCHN that is not amenable to curative therapy, evaluating nivolumab + ipilimumab versus the EXTREME regimen 
(Cetuximab + cisplatin/carboplatin + fluorouracil) as a first-line treatment. 
HPV p-16 status and tumor cell PD-L1 status (expressing or non-expressing/non-evaluable) test results will be needed 
prior to randomization. Participants will undergo screening evaluations to determine eligibility prior to randomization. 
The dose and treatment schedules for each arm are as follows:
•
Arm A: Nivolumab + Ipilimumab Arm:
−
Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, 
unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.
•
Arm B: EXTREME regimen Arm: 
−
Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100 mg/m2) or 
carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 
4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly 
(or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the 
choice of cisplatin or carboplatin is at the discretion of the investigator.
Revised Protocol No.: 05
Date: 19-Dec-2019
7
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Approximately 930 participants will be randomized to the two treatment arms in a 1:1 ratio and stratified by the 
following factors: 
•
Tumor cell PD-L1 status (expressing [≥1%] vs non-expressing [< 1%] or non-evaluable). Up to 10% of 
randomized participants per cohort can be included into the study as “non-evaluable.” After this point, participants 
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 randomize the 
participant. 
•
HPV p-16 status (oropharyngeal HPV p-16 positive vs oropharyngeal HPV p-16 negative or non-oropharyngeal). 
Oropharyngeal CA sites defined in Appendix 5.
•
Prior chemotherapy (adjuvant/neoadjuvant/multimodal treatment) status (Yes/No)
Tumor progression or response will be assessed by investigator using RECIST 1.1 criteria. Treatment with study 
medication will continue until RECIST 1.1 defined progression, unacceptable toxicity, a maximum of 24 months since 
the first dose of nivolumab, or withdrawal of consent. 
In addition to investigator assessment of response and progression, there will be a blinded independent central review 
(BICR) of tumor scans and study sites will need to submit tumor scans for central radiology review.
A DMC will be established and meet regularly during the study to ensure that participant safety is carefully monitored 
and to provide oversight regarding safety and efficacy considerations in protocol CA209651.
The maximum duration of the study from start of randomization to final analysis of OS is projected to be 
approximately 51 months, assuming 26 months accrual duration. Additional 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 1 below
Figure 1: 
Study Design Schematic
Study Population: 
For entry into the study, the following criteria MUST be met:
Key Inclusion Criteria (See Protocol Section 3.3.2 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.
b)
Must have metastatic or recurrent disease that is not amenable to therapy with curative intent (surgery or 
radiation therapy with or without chemotherapy). Participants that refuse potentially curative salvage surgery 
for recurrent disease are ineligible. 
Revised Protocol No.: 05
Date: 19-Dec-2019
8
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
c)
No prior treatment with systemic anti-cancer therapy for recurrent or metastatic SCCHN, unless under all of 
the following conditions:
i)
Prior chemotherapy was given as adjuvant or neoadjuvant or as part of multimodal treatment for locally 
advanced disease 
ii)
These treatments must have been completed > 6 months prior to enrollment 
iii) There is no evidence of disease progression for at least 6 months after completion of such treatment. 
iv) Participants having progression after 2 cycles of induction chemotherapy are excluded.
d)
ECOG Performance Status of 0−1. (See Appendix 1). 
e)
Measurable disease by CT or MRI per RECIST 1.1 criteria 
f)
Documentation of HPV p-16 status is required for SCCHN tumor of the oropharynx. 
g)
Documentation of tumor cell PD-L1 status by IHC performed by the central lab prior to randomization.
Key Exclusion Criteria (See Protocol Section 3.3.1 for full list of criteria)
1.
Target Disease Exceptions
a)
Recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, 
squamous cell carcinoma that originated from the skin and salivary gland or non-squamous histologies 
(eg, mucosal melanoma).
b)
Participants with untreated CNS metastases. 
Participants 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, participants must be either off corticosteroids, or on a stable or decreasing dose 
of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization.
c)
Participants with carcinomatous meningitis.
2.
Medical History and Concurrent Diseases
a)
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or 
drug specifically targeting T-cell co-stimulation or checkpoint pathways.
b)
Prior treatment with cetuximab or EGFR inhibitors in any treatment setting
c)
Participants with previous malignancies (except non-melanoma skin cancers, and the following in situ 
cancers: bladder, gastric, esophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a 
complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required 
during the study period.
i)
A second primary squamous cell carcinoma of the head and neck is allowed if eligibility is based on a 
recurrent or a metastatic first primary squamous cell carcinoma of the head and neck.
d)
Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes 
mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or 
alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll.
e)
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled 
or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted 
in the absence of active autoimmune disease.
3.
Physical and Laboratory Test Findings
a)
Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
Revised Protocol No.: 05
Date: 19-Dec-2019
9
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
b)
Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).
c)
Inadequate hematologic, renal or hepatic function defined by any of the following screening laboratory 
values:
i)
WBC
< 2000/μL
ii)
Neutrophils
< 1500/μL
iii) Platelets
< 100 x 103/μL
iv) Hemoglobin
< 9.0 g/dL
v)
Serum creatinine
> 1.5 x ULN or creatinine clearance < 50 mL/min (using the Cockcroft 
Gault formula). Cisplatin should not be used if creatinine clearance is lower than 60 mL/min
vi) AST/ALT
> 3.0 x ULN (> 5 x ULN if liver metastases) 
vii) Total Bilirubin
> 1.5 x ULN (except participants with Gilbert Syndrome who must have 
a total bilirubin level ≥3.0 x ULN)
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209651
Medication 
Potency 
IP/Non-IP 
Nivolumab Injection
100 mg/vial
(10 mg/mL)
IP
Ipilimumab Injection
200 mg/vial (5 mg/mL)
IP
Carboplatin Solution for IV Injection
450 mg/vial
(10 mg/mL)
IP
Cisplatin Concentrate for solution for infusion
100 mg/vial (1 mg/mL)
IP
Cetuximab solution for infusion
500mg/vial
(5 mg/mL)
IP
Fluorouracil Injection
1 g/vial (50 mg/mL)
IP
Study Assessments: Overall survival is defined as the time from randomization to the date of death. Participants will 
be assessed for response by CT or MRI beginning 6 weeks (± 1 week) after first dose and continuing every 6 weeks 
(± 7 days) until week 48 and then every 12 weeks (±1 week) until progression. Tumor assessments must continue per 
protocol until RECIST 1.1 progression has occurred. Participants will be followed for survival every 3 months via in 
person or telephone contact after the participant has discontinued study drug treatment. All randomized participants 
will be followed for survival.
Statistical Considerations:
Sample Size:
The primary objectives of this study are to compare OS between treatment groups, randomized participants with PD-
L1 CPS ≥ 20 and in all randomized participants. OS will be compared at the 0.025 alpha level for each of the above 
two populations. 
Revised Protocol No.: 05
Date: 19-Dec-2019
10
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
The OS comparison in all randomized participants will require up to 741 deaths. This number of events ensures that 
a two-sided, alpha=0.025 group sequential test using the O’Brien and Fleming spending function and with an interim 
analysis after approximately 80% of events will have overall 97% power for a HR of 1.2 for the first 7 months and 
0.55 thereafter. 
The final analysis of OS in all randomized participants is projected to occur 51 months after the first patient was 
randomized. An interim analysis in this population will be performed when approximately 593 deaths occur, or all 
randomized participants have been followed up for at least 12 months, whichever is later. It is projected for 39 months 
after the first patient was randomized. 
At the same time as the OS analysis is done for all randomized participants, OS will also be compared between arms 
in the randomized participants with PD-L1 CPS ≥ 20 via a two-sided, alpha=0.025 group sequential test procedure 
incorporating the O’Brien and Fleming alpha spending function. The group sequential test would have an interim 
analysis and the final analysis of OS, at which approximately 298 and 372 deaths, respectively, are expected. With 
this many events, the test procedure would have an overall 99% power if the HR was 1.06 for the first 7 months and 
0.45 thereafter. See Section 8.1, Sample Size Determination, for additional details.
Endpoints:
Primary Endpoints:
•
OS in randomized participants with PD-L1 CPS ≥20 
•
OS in all randomized participants
OS is defined as the time between randomization and death. For participants without documentation of death, OS will 
be censored on the last date the participant was known to be alive.
Secondary Endpoints:
OS in randomized participants with PD-L1 CPS ≥1. OS is defined the same way as for the primary endpoints.
PFS is defined as the time from randomization to disease progression, using RECIST 1.1 criteria, or, if there is no 
documented progression, death. (The date of progression will be based on the BICR assessment of progression). 
Participants who neither progress nor die will be censored on the date of their last tumor assessment. Participants who 
receive subsequent anti-cancer therapy prior to documented progression, including tumor-directed radiotherapy and 
tumor-directed surgery, will have their PFS time censored on the date of their last tumor assessment prior to subsequent 
therapy.
The Objective Response Rate (ORR) is defined as the number of participants with a best overall response (BOR) of 
complete response (CR) or partial response (PR), divided by the number randomized in the population.
The BOR is defined as the best response, based on RECIST 1.1 criteria, recorded between randomization and either 
progression or subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), 
whichever occurs first. (The BOR will be based on BICR assessments). For participants without evidence of RECIST 
1.1 progression or subsequent anticancer therapy, all available tumor evaluations will contribute to the BOR 
assessment. 
Duration of objective response (DOR) is the time between the first documented response (CR or PR) and progression, 
per RECIST 1.1, or, if no progression is reported, death. The DOR of a participant who neither progresses nor dies 
will be censored as in the primary definition of PFS. DOR is calculated on the subset of participants whose best 
response was either CR or PR, according to BICR assessments.
Analyses:
Demographics and Baseline Characteristics:
Demographics and baseline characteristics will be summarized by treatment arm as randomized using descriptive 
statistics. These analyses will be done on the PD-L1 CPS ≥20 population and on the all randomized population
Efficacy Analyses:
Efficacy analyses will be performed by treatment group as randomized.
Revised Protocol No.: 05
Date: 19-Dec-2019
11
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
OS will be compared between arms via a two-sided, overall alpha=0.025, group sequential log-rank test for each of 
the two primary endpoints population. The significance levels may be updated through graphical approach where the 
family-wise error rate will be protected in the strong sense. 
The nominal significance levels for each look of the group sequential log-rank test will be determined by the alpha 
spending function with the O’Brien and Fleming boundary based on the actual number of events observed at the time 
of the analysis. These tests will be stratified by the stratification factors used in the randomization.
An estimate of the hazard ratio (HR) and a corresponding two sided 100*(1 - adjusted α)% confidence interval for the 
HR will be generated for each endpoint using a stratified Cox proportional hazards model with treatment arm as the 
sole covariate. The stratification factors will be the same as those used for testing. The level for the confidence interval 
for the OS hazard ratio will be based on the same nominal significance level for the group sequential log-rank test.
Survival distributions will be estimated, by arm, via the Kaplan-Meier (KM) product-limit method. Median survival 
times along with 95% confidence intervals for the medians, will also be presented. The confidence interval for the 
median will be constructed using a generalization of the Brookmeyer and Crowley method based on a log {-log} 
transformation of the survival function.
Safety Analyses:
The safety analysis will be restricted to treated participants. Descriptive statistics of safety will be presented using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, by 
treatment arm. Safety analyses will be performed on all treated participants.
Pharmacokinetic Analyses:
The nivolumab and ipilimumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop or refine a population PK model.
Biomarker Analyses:
Potential relationships between biomarker data and efficacy or safety endpoints may be investigated as part of an 
analysis plan aimed at identifying baseline biomarkers that may be used to prospectively identify participants likely 
to respond to nivolumab and ipilimumab and to identify participants who may be predisposed to having adverse 
reactions to treatment. These exploratory predictive biomarker analyses will be completed with biomarkers measured 
in blood and in tumor samples and will focus primarily on SNPs in select genes associated with immunity, on the 
expression of PD-1, PD-L1, and PD-L2 proteins in tumor specimens, and on tumor mutational burden (TMB) and 
gene expression profile (GEP).
Outcomes Research Analyses:
Exploratory analyses of EQ-5D and FACT-H&N (including FHNSI-10) data will be performed in randomized 
participants who have an assessment at baseline (Day 1, assessment prior to administration of drug on day of first 
dose) and at least 1 subsequent assessment while on treatment. Questionnaire completion rate, defined as the 
proportion of questionnaires actually received out of the expected number, will be calculated and summarized at each 
assessment point. Analyses of QOL will be performed on all randomized population.
Interim Analyses:
An independent data monitoring committee (DMC) will be responsible for monitoring safety and efficacy data at 
regular intervals. In addition, the DMC will review the data for the formal interim analysis. 
A formal interim analysis for superiority of OS will be performed after approximately 593 OS events (out of 
741 required) have occurred on all randomized participants, or all randomized participants have been followed up for 
at least 12 months, whichever is later. Both primary endpoints will be tested at interim using the group sequential test 
procedure with initial overall alpha=0.025 for each. The overall alpha will be updated following the graphical
procedure which is detailed in the SAP. The stopping boundaries for the interim and final analyses will be determined 
by the O’Brien and Fleming alpha spending function, based on the actual number of events observed. 
If interim comparison of OS in either all randomized participants or randomized participants with PD-L1 CPS ≥ 20 is 
significant, the DMC will inform the sponsor, as described in the DMC charter. If comparison of OS in the randomized 
participants with PD-L1 CPS ≥ 20 is significant, OS in randomized participants with PD-L1 CPS ≥ 1 will be 
Revised Protocol No.: 05
Date: 19-Dec-2019
12
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
subsequently tested using group sequential testing procedure. The overall alpha for this secondary endpoint will be 
determined following the graphical procedure which is detailed in the SAP. 
The DMC will have access to periodic un-blinded interim reports of efficacy and safety to allow a risk/benefit 
assessment. Details will be included in the DMC charter.
Revised Protocol No.: 05
Date: 19-Dec-2019
13
Approved
6.0
v
Approved
1.0
v


TABLE OF CONTENTS
TITLE PAGE................................................................................................................
DOCUMENT HISTORY..............................................................................................
OVERALL RATIONALE FOR REVISED PROTOCOL 05:.....................................
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05.........................
SYNOPSIS....................................................................................................................
TABLE OF CONTENTS..............................................................................................
1 INTRODUCTION AND STUDY RATIONALE .....................................................
1.1 Study Rationale.................................................................................................
1.2 Rationale for revised protocol 04:.....................................................................
1.2.1 The Role of Human Papillomavirus (HPV) .............................................
1.2.2 Immunotherapy in SCCHN and role of PD-L1........................................
1.2.3 Rationale for Combination of Nivolumab and Ipilimumab .....................
1.2.4 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab....
1.2.5 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease....................................................................................
1.2.6 Rationale for 24 Months Maximum Treatment Duration ........................
1.3 Research Hypotheses ........................................................................................
1.4 Objectives(s) .....................................................................................................
1.4.1 Primary Objectives ..................................................................................
1.4.2 Secondary Objectives...............................................................................
1.4.3 Exploratory Objectives ............................................................................
1.5 Product Development Background...................................................................
1.5.1 Mechanism of Action of Nivolumab.........................................................
1.5.2 Mechanism of Action of Ipilimumab........................................................
1.5.3 Nivolumab Combined With Ipilimumab...................................................
1.6 Overall Risk/Benefit Assessment .....................................................................
2 STUDY GOVERNANCE CONSIDERATIONS......................................................
2.1 Regulatory and Ethical considerations..............................................................
2.1.1 Good Clinical Practice ............................................................................
2.1.2 Institutional Review Board/Independent Ethics Committee ....................
2.1.3 Informed Consent Process.......................................................................
3 INVESTIGATIONAL PLAN....................................................................................
3.1 Study Design and Duration...............................................................................
3.2 Post Study Access to Therapy...........................................................................
3.3 Study Population...............................................................................................
3.3.1 Inclusion Criteria.....................................................................................
3.3.2 Exclusion Criteria....................................................................................
3.3.3 Women of Childbearing Potential ...........................................................
3.4 Concomitant Treatments...................................................................................
3.4.1 Prohibited and/or Restricted Treatments.................................................
3.4.2 Other Restrictions and Precautions.........................................................
3.4.3 Permitted Therapy ...................................................................................
3.5 Discontinuation of Subjects following any Treatment with Study Drug..........
3.6 Post Study Drug Study Follow up ....................................................................











































Clinical Protocol
BMS-936558
CA209651
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
14
Approved
6.0
v
Approved
1.0
v


3.6.1 Withdrawal of Consent ............................................................................
3.6.2 Lost to Follow-Up....................................................................................
4 STUDY DRUG..........................................................................................................
4.1 Investigational Product .....................................................................................
4.2 Non-investigational Product .............................................................................
4.3 Storage and Dispensing.....................................................................................
4.4 Method of Assigning Participant Identification................................................
4.5 Selection and Timing of Dose for Each Participant..........................................
4.5.1 Dosing......................................................................................................
4.5.1.1 Nivolumab plus Ipilimumab (Arm A)..............................................
4.5.1.2 EXTREME Regimen (Arm B)..........................................................
4.5.2 Dose Delays .............................................................................................
4.5.2.1 Nivolumab and Ipilimumab (Arm A)...............................................
4.5.2.2 EXTREME Regimen........................................................................
4.5.3 Dose Reductions.......................................................................................
4.5.3.1 Nivolumab or Ipilimumab...............................................................
4.5.3.2 EXTREME Regimen........................................................................
4.5.4 Criteria to Resume Dosing.......................................................................
4.5.4.1 Criteria to Resume Nivolumab Dosing (Arm A).............................
4.5.4.2 Criteria to Resume Ipilimumab Dosing (Arm A)............................
4.5.4.3 Criteria to Resume Chemotherapy Dosing (Arm B).......................
4.5.5 Treatment Discontinuation Criteria ........................................................
4.5.5.1 Nivolumab Dose Discontinuation (Arm A).....................................
4.5.5.2 Ipilimumab Dose Discontinuation (Arm A)....................................
4.5.5.3 EXTREME Regimen Dose Discontinuation (Arm B)......................
4.5.6 Treatment Beyond Disease Progression (Arm A only)............................
4.5.7 Management Algorithms for Immuno-Oncology Agents .........................
4.5.8 Treatment of Infusion Reactions..............................................................
4.5.8.1 Nivolumab or Ipilimumab Infusion Reactions................................
4.5.8.2 Treatment of Cetuximab Infusion Reactions...................................
4.6 Blinding/Unblinding .........................................................................................
4.7 Treatment Compliance......................................................................................
4.8 Destruction of Study Drug................................................................................
4.9 Return of Study Drug........................................................................................
4.10 Retained Samples for Bioavailability / Bioequivalence .................................
5 STUDY ASSESSMENTS AND PROCEDURES.....................................................
5.1 Flow Chart/Time and Events Schedule.............................................................
5.1.1 Retesting During Screening or Lead-in Period .......................................
5.2 Study Materials.................................................................................................
5.3 Safety Assessments...........................................................................................
5.3.1 ECOG Performance Status......................................................................
5.3.2 Pregnancy Testing ...................................................................................
5.3.3 Thyroid Function Testing.........................................................................
5.3.4 Electrocardiogram (ECG) .......................................................................
5.4 Efficacy Assessments........................................................................................
5.4.1 Primary Efficacy Assessment...................................................................














































Clinical Protocol
BMS-936558
CA209651
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
15
Approved
6.0
v
Approved
1.0
v


5.4.2 Secondary Efficacy Assessment ...............................................................
5.5 Pharmacokinetic Assessments ..........................................................................
5.6 Biomarker Assessments....................................................................................
5.6.1 Exploratory Serum Biomarkers ...............................................................
5.6.2 Circulating Tumor DNA in Plasma .........................................................
5.6.3 Tumor Tissue Specimens..........................................................................
5.6.4 Peripheral Blood Gene Expression .........................................................
5.6.5 T cell Repertoire Analysis (Whole Blood and Tumor Tissue Sample).....
5.6.6 Characterization of Oral Microbiome.....................................................
5.6.7 Whole Blood for Genomic Analyses ........................................................
5.6.8 HPV Assessment.......................................................................................
5.7 Outcomes Research Assessments .....................................................................
5.8 Additional Research..........................................................................................
6 ADVERSE EVENTS.................................................................................................
6.1 Serious Adverse Events ....................................................................................
6.1.1 Serious Adverse Event Collection and Reporting....................................
6.2 Nonserious Adverse Events..............................................................................
6.2.1 Nonserious Adverse Event Collection and Reporting..............................
6.3 Laboratory Test Result Abnormalities..............................................................
6.4 Pregnancy..........................................................................................................
6.5 Overdose ...........................................................................................................
6.6 Potential Drug Induced Liver Injury (DILI).....................................................
6.7 Other Safety Considerations .............................................................................
6.7.1 Adverse Events of Interest........................................................................
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
.................................................................................................................................
8 STATISTICAL CONSIDERATIONS.......................................................................
8.1 Sample Size Determination...............................................................................
8.2 Populations for Analyses ..................................................................................
8.3 Endpoints ..........................................................................................................
8.3.1 Primary Endpoints...................................................................................
8.3.2 Secondary Endpoints ...............................................................................
8.3.3 Exploratory Endpoint(s) ..........................................................................
8.4 Analyses............................................................................................................
8.4.1 Demographics and Baseline Characteristics...........................................
8.4.2 Efficacy Analyses .....................................................................................
8.4.2.1 Analysis Methods for Primary Endpoints.......................................
8.4.2.2 Analysis Methods for Secondary Endpoints ...................................
8.4.3 Safety Analyses.........................................................................................
8.4.4 Pharmacokinetic Analyses.......................................................................
8.4.5 Biomarker Analyses .................................................................................
8.4.6 Outcomes Research Analyses ..................................................................
8.4.7 Other Analyses.........................................................................................
8.5 Interim Analyses...............................................................................................
9 STUDY MANAGEMENT ........................................................................................
9.1 Compliance .......................................................................................................













































Clinical Protocol
BMS-936558
CA209651
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
16
Approved
6.0
v
Approved
1.0
v


9.1.1 Compliance with the Protocol and Protocol Revisions...........................
9.1.2 Financial Disclosure................................................................................
9.1.3 Monitoring ...............................................................................................
9.1.3.1 Source Documentation....................................................................
9.1.4 Study Treatment Records.........................................................................
9.1.5 Investigational Site Training....................................................................
9.2 Records .............................................................................................................
9.2.1 Records Retention....................................................................................
9.2.2 Study Drug Records.................................................................................
9.2.3 Case Report Forms ..................................................................................
9.2.4 Clinical Study Report and Publications...................................................
9.2.4.1 Scientific Publications ....................................................................
10 LIST OF ABBREVIATIONS..................................................................................
11 REFERENCES ........................................................................................................
APPENDIX 1 ECOG PERFORMANCE STATUS .....................................................
APPENDIX 2 MANAGEMENT ALGORITHMS.......................................................
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........




















Clinical Protocol
BMS-936558
CA209651
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
17
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
1
INTRODUCTION AND STUDY RATIONALE
CA209651 is a randomized, open-label, global Phase 3 trial of nivolumab (also known as 
BMS-936558) plus ipilimumab versus EXTREME regimen (cetuximab + cisplatin/carboplatin + 
fluorouracil) as first-line therapy in recurrent or metastatic head and neck squamous cell carcinoma 
(SCCHN). This study will determine if nivolumab plus ipilimumab improves overall survival (OS)
over standard of care chemotherapy in all study participants and biomarker selected patient 
population. Additional objectives include further characterization of the efficacy, adverse event 
profile, pharmacokinetics, patient-reported outcomes, and potential predictive biomarkers of 
nivolumab plus ipilimumab in participants with SCCHN.
1.1
Study Rationale
Head and neck cancers are among the most common cancers worldwide, accounting for more than 
550,000 cases and around 300,000 deaths each year,1 and these trends are increasing. In the United 
States, ~45,780 new cases of oral cavity and pharynx cancer and ~8,650 people were expected to
die of this disease in 2015.2 About ~90% of all head and neck cancer cancers are squamous cell 
carcinomas. Most SCCHNs arise from the epithelial lining of the oral cavity, oropharynx, larynx 
and hypopharynx. The most important risk factors identified in SCCHNs, include tobacco and 
alcohol use, and, in a subgroup of SCCHNs (particularly oropharynx tumors), human papilloma 
as a strong independent prognostic factor, with HPV positive-infected tumors associated with more 
favorable clinical outcomes.3
The treatment approach and prognosis for patients with SCCHN is mostly determined by the tumor 
stage at presentation. About one-third of patients presents with early stage disease, whereas the 
majority present with advanced disease with lymph node metastasis. With standard of care 
treatment, the 5-year survival for localized oral cavity and pharynx cancer is 83%, but survival
drops to 37.7% for metastatic disease.2 Approximately half of the treated population returns with 
recurrent or refractory disease, and for these patients, the 1-year survival rate ranges from 5% to 
33% with a median overall survival (OS) of 6 to 9 months. Recurrent disease that is not amenable 
to curative-intent radiation or surgery have the same treatment approach as metastatic disease, and 
participation in a clinical trial is a recommended treatment option for these patients.4 A Phase 3 
randomized trial in first-line recurrent or metastatic (1L R/M) SCCHN showed that cetuximab plus 
platinum-fluorouracil 
chemotherapy 
(EXTREME
regimen) 
improved 
survival 
over 
platinum-fluorouracil alone as first-line treatment with a median OS of 10.1 months versus 
7.4 months (Hazard Ratio [HR] = 0.80, 95% CI 0.64-0.99, p = 0.04). As a result, the EXTREME
regimen has been adapted as a standard treatment approach in this population. While the addition 
of cetuximab to platinum-fluorouracil chemotherapy improved response rates and disease control 
rates, the duration of response did not differ significantly between treatment regimens. Since 
the introduction of the EXTREME regimen in 2008,4 no marked improvement in survival has been 
achieved, with patients still frequently developing recurrences and distant metastasis. After 
progression, the limited treatment options available are associated with substantial morbidity and 
mortality. Thus, new treatment approaches need to be explored as the first-line treatment in this 
population.5
Revised Protocol No.: 05
Date: 19-Dec-2019
18
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
1.2
Rationale for revised protocol 04:
Emerging data from multiple studies in recent years demonstrated long term OS benefit with PD-1 
inhibitor (nivolumab and pembrolizumab) therapy compared to standard of care chemotherapy in 
R/M SCCHN population. 6’7’8’9 These studies while suggesting OS benefit in all study subjects 
also showed a trend towards better efficacy in participants who express Programmed 
death-ligand 1 (PD-L1) in either their tumor or immune cells. However, PFS did not capture the 
benefit of PD-1 therapy versus standard of care therapy in both biomarker selected and unselected 
population.
Benefit of PD-1 inhibitors as a second-line therapy (2L) for R/M SCCHN population:
In the two year survival update of CheckMate-141,6 Phase 3 trial evaluating nivolumab as a second 
line therapy (2L) in R/M SCCHN, single-agent nivolumab showed significant OS benefit over 
investigator’s choice chemotherapy (IC) in all study participants (HR = 0.68, 95% CI 0.54 to 0.86; 
p = 0.01), with a relatively better efficacy noted in participants who expressed tumor cell PD-L1
≥1% (HR = 0.55, 95% CI 0.39–0.78). In a sub-group analysis of this study, participants who had 
both tumor cell PD-L1 ≥ 1% and a high tumor-associated immune cell PD-L1 (TAIC) expression
demonstrated a relatively better OS benefit (HR = 0.43, 95% CI 0.28, 0.67). However, significant 
PFS benefit for nivolumab was not demonstrated in the intent-to-treat population (HR=0.87, 95% 
CI 0.68–1.11) or in any of the biomarker selected sub-groups.
Similarly, in another Phase 3 trial in the same setting (KeyNote-040),7 pembrolizumab showed OS 
benefit over IC in all study participants (HR = 0·80, 0·65–0·98), with a significant OS benefit in 
the sub-population who expressed PD-L1, on both tumor and immune cells, measured as PD-L1
combined positive score (PD-L1 CPS) ≥ 1 (HR = 0·74, 95% CI 0·58–0·93). In this study as well,
PFS benefit was not demonstrated for pembrolizumab arm versus standard of care regimen 
(HR = 0·96, 95% CI 0·79–1·16). Thus both of these studies in 2L R/M SCCHN demonstrate long 
term OS benefit of PD-1 inhibitors in SCCHN participants, irrespective of biomarker expression. 
Additionally, these studies also establish that PD-1 inhibitors may provide a greater efficacy 
benefit in the sub-population of SCCHN participants who express PD-L1 in both tumor and 
immune cells.
Benefit of PD-1 inhibitors as a first-line therapy (1L) for R/M SCCHN population:
Other recent trials in SCCHN are evaluating PD-1 inhibitors as a first-line therapy (1L) for R/M
SCCHN population. In a Phase 3 study of 1L R/M SCCHN (KeyNote-048), efficacy of 
pembrolizumab as a single agent or in combination with chemotherapy (cisplatin+5FU) was 
compared to EXTREME regimen in both PD-L1 CPS high expressers (cut-offs of ≥ 20 and ≥ 1) 
and in all study participants.8,9 This study demonstrated significant improvement in OS compared 
to EXTREME regimen for pembrolizumab monotherapy (HR = 0.61, 95% CI 0.45-0.83, 
p = 0.0007) in participants whose tumors expressed PD-L1 CPS ≥ 20. This data further confirms 
that selection based on PD-L1 CPS, a measure of both tumor and immune cell PD-L1 expression,
may offer efficacy benefit for single agent PD-1 inhibitor in this SCCHN population. However, 
this study also demonstrated the lack of PFS benefit for PD-1 inhibitors versus comparator. 
Revised Protocol No.: 05
Date: 19-Dec-2019
19
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Pembrolizumab demonstrated a numerically lower median PFS (3.4 months) versus EXTREME 
regimen (5.0 months) in PD-L1 CPS ≥ 20 sub-group (HR = 0.99, 95% CI 0.75-1.29).
Additionally, in the analysis of all study participants (irrespective of PD-L1 CPS) in KeyNote-048, 
only pembrolizumab +
chemotherapy
(P+C) arm demonstrated statistically significant 
improvement in the OS (HR = 0.77, 95% CI 0.63-0.93, p = 0.0034) compared to EXTREME
regimen. This suggests that combination therapy with PD-1 inhibitors may be needed for optimal 
efficacy benefit in an unselected patient population. However, in KeyNote-048 P+C demonstrated 
only a modest median OS improvement in this population (13 months for P+C vs 10.7 months for 
EXTREME regimen). Additionally, the safety profile of P+C was not better than the EXTREME 
regimen with grade 3-4 treatment related adverse events reported in 71% of participants in P+C
arm and 69% of participants in EXTREME regimen arm. This population does not currently have 
a treatment option that provides a good benefit-risk balance. Therefore, new combination treatment 
approaches need to be explored to not only improve the survival benefit in participants with high 
PD-L1 CPS but also provide safe and efficacious treatment options for participants irrespective of 
PD-L1 expression. 
Benefit of combining ipilimumab to nivolumab:
Addition of ipilimumab (CTLA-4 inhibitor) to nivolumab has demonstrated efficacy benefit over 
single agent nivolumab in multiple disease indications including melanoma, non-small cell lung 
cancer and renal cell carcinoma. This efficacy benefit was not restricted to patients with tumor cell
PD-L1 alone.
 Thus the summary of 
available evidence across indications suggests that addition of ipilimumab to nivolumab may offer 
an opportunity to improve the OS in R/M SCCHN participants irrespective of PD-L1 expression 
status, with a relatively better efficacy benefit in participants with high PD-L1 CPS. 
Summary of the rationale for the key end-point changes:
Based on the above evolving data in SCCHN in recent years suggesting PD-L1 CPS as a more 
appropriate PD-L1 measure for selecting participants who derive the best benefit for 
immunotherapy and potential for nivolumab + ipilimumab to benefit a broader SCCHN patient 
population than tumor cell PD-L1 expressers alone.
The primary end-points of the current study (CheckMate 651) will be revised to compare:
•
OS of participants with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with 
ipilimumab to those receiving EXTREME regimen (changed from tumor cell PD-L1 ≥ 1%).
•
OS of all study participants (irrespective of PD-L1 expression) who are receiving nivolumab 
combined with ipilimumab to those receiving EXTREME regimen.
Additionally, OS for nivolumab + ipilimumab versus EXTREME regimen in participants with 
PD-L1 CPS ≥1 will be added as a key secondary end-point. The primary end-point of PFS for 
Revised Protocol No.: 05
Date: 19-Dec-2019
20
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
nivolumab + ipilimumab versus EXTREME regimen will be removed as evolving data suggest 
that PFS is not an appropriate end-point for immunotherapy in SCCHN.
1.2.1
The Role of Human Papillomavirus (HPV) 
HPV-associated head and neck cancer, largely presenting in the oropharynx has been increasing 
in incidence in the past few decades.10,11 In the US, two-thirds of patients with oropharynx cancer 
have HPV-associated tumors. In 2010, approximately 4,200 squamous cancers of the oropharynx 
(OPC) caused by tobacco and alcohol and 8,400 new HPV-associated oropharynx cancer will 
present for treatment.12 HPV status is an independent prognostic factor for OS and progression-
free survival (PFS) among patients with squamous cell OPC.13 In this study (CheckMate 651), 
64% of OPC patients had HPV-positive tumors, as measured in-situ hybridization for the HPV 
subtype 16. The presence of HPV DNA correlated well with p-16 expression (kappa = 0.80; 95% 
CI, 0.73 to 0.87). Patients with HPV-positive tumors had significantly increased OS as well as PFS 
compared to patients with HPV-negative tumors. Furthermore, after adjusting for demographics, 
T stage, N stage, smoking, patients with HPV-positive OPC had a 58% reduction in the risk of 
death and a 51% reduction in risk of progression or death. Patients with HPV-negative tumors had 
a 25.1% reduction in OS at 3 years (57.1% vs 82.4%) when compared to patients with HPV-
positive tumors.11 Local-regional relapse at 3 years was 21% higher in patients with HPV-negative 
tumors: 35.1% (95% CI: 26.4 - 43.8) versus 13.6% (95% CI: 8.9 - 18.3) for HPV-positive tumors 
(P < 0.001). These poor outcomes for HPV-negative patients occur despite the gradual trend 
toward increasing intensification of treatment with altered fractionation schema,14 concurrent 
chemoradiation,15,16 multi-drug induction chemotherapy,17 and targeted molecular therapies.18
For patients with HPV-negative tumors altering the method of radiation delivery and the dosing 
and/or types of concurrent chemotherapy is not sufficient to improve oncologic outcomes. 
Because HPV-associated head and neck cancers more frequently present in a younger population 
and seem particularly responsive to treatment with a better overall survival,19 attention has focused 
on the subpopulation of > 10 pack-year smoking and N2-N3, whose prognosis is worse 
(60% - 70% 2 year PFS) as well as HPV-negative head and neck cancer patients, whose clinical 
outcome has not improved despite intensification of standard chemotherapeutic agents and 
combinations. Thus, novel therapeutic approaches, such as immune modulation and blockade of 
suppressive immune cells and signals, are needed in clinical evaluation.
1.2.2
Immunotherapy in SCCHN and role of PD-L1
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer 
types, including melanoma, hormone-refractory renal cell carcinoma, and non-small cell lung 
cancer.20 Tumors may modulate and evade the host immune response through a number of 
mechanisms, including down regulation of tumor-specific antigen expression and presentation, 
secretion of anti-inflammatory cytokines, and upregulation of inhibitory ligands. In SCCHN,
down-regulation of T-cell function is thought to be mediated by multiple mechanisms: i.) Reduced 
expression of co-stimulating molecules of the B7-CD28 family21; ii.) Increased expression of 
PD-L1 in tumor cells and tumor associated fibroblasts; and, iii.) Loss of HLA-class I and selective 
Revised Protocol No.: 05
Date: 19-Dec-2019
21
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
down-regulation 
of 
HLA-A,B,C 
locus 
expression 
resulting 
in 
defective 
antigen 
presentation.21,22,23 In a subset of HPV-infected SCCHN, data shows that antigen-processing 
machinery components are downregulated compared to the adjacent normal squamous epithelium 
with incomplete activation of tumor specific T cells or suboptimal target recognition enabling 
tumor progression.24 T cell checkpoint regulators such as CTLA-4 and programmed death-1 
(PD-1, CD279) are cell surface molecules that, when engaged by their cognate ligands, induce 
signaling cascades down-regulating T cell activation and proliferation.
PD-L1 expression has been associated with poor prognoses in certain tumor types such as renal, 
esophageal, gastric, ovarian, pancreatic, and lung cancer.25,26,27,28,29,30 PD-1 engagement on 
T-cells by PD-L1-positive APC or PD-L1-positive tumor cells in the tumor microenvironment 
may limit effective immune responses. Conversely, PD-L1 expression may be a positive 
prognostic factor as it may indicate infiltration of tumor-specific T cells that secrete IFN-γ, which 
upregulates PD-L1 expression. Consistent with this hypothesis is the co-localization of lymphoid 
cell infiltrates and PD-L1 staining observed in human melanoma lesions.31 PD-L1 expression in 
SCCHN has been reported; preliminary results from a Phase 1 trial in patients with 32 recurrent or 
metastatic disease observed that 77.9% of patients tested (N = 104) expressed PD-L1, defined as 
≥1% of stained cells in the tumor microenvironment.
PD-L1 CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, 
macrophages) divided by the total number of viable tumor cells, multiplied by 100.33 PD-L1 CPS 
is a composite score that incorporates both tumor and tumor-associated immune cell (TAIC) PD-
L1 expression, whereas tumor proportion score (TPS) or tumor cell PD-L1 only reflects the 
percentage of tumor cells that are positive for PD-L1 expression. Emerging evidence suggests that 
PD-L1 CPS as the biomarker that could be a good predictor of response with check-point 
inhibitors.
The role of the PD-1 blockade in squamous non-small cell carcinoma of the lung has been
established in CA209017 study,34 where nivolumab monotherapy in the second-line treatment 
setting demonstrated clinically meaningful survival benefit regardless of PD-L1 expression
compared to standard of care docetaxel. In a similar histology, for squamous cell carcinoma of the 
head and neck primary, the role of PD-1 blockade is evolving. 
CheckMate 141 study (CA209141), is a randomized, open-label, Phase 3 trial that compared 
nivolumab, a fully human anti-programmed death 1 (PD-1) monoclonal antibody, to investigator’s 
choice (IC) of systemic therapy in patients with recurrent or metastatic SCCHN who progressed 
from a platinum-containing therapy. At the primary analysis, the median OS was 7.5 months (95% 
confidence interval [CI], 5.5 to 9.1) with nivolumab versus 5.1 months (95% CI, 4.0 to 6.0) with 
IC. There is a 30% reduction in the risk of death for patients on the nivolumab arm (hazard ratio 
0.70; 97.73% CI, 0.51 to 0.96; P = 0.0101) over IC. The overall response rate (ORR) was 13.3% 
with nivolumab versus 5.8% with IC. In addition, the overall safety profile of nivolumab was 
favorable compared to IC.35 Clinical benefit seen in this chemotherapy pre-treated SCCHN
suggests the potential clinical activity of nivolumab in earlier treatment setting.
Revised Protocol No.: 05
Date: 19-Dec-2019
22
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
In the long-term (2-year) follow-up of the CheckMate 141 study (CA209141), nivolumab showed 
a consistent long term benefit in OS compared to IC systemic therapy (HR = 0.68 [95% CI: 0.54, 
0.86]) in the overall study-population. Furthermore, nivolumab demonstrated 45% reduction in 
risk of death versus IC in patients whose tumors expressed tumor cell PD-L1 ≥1% (HR = 0.55 
[95% CI: 0.39, 0.78]). In a sub-group analysis of this study, participants who had both tumor cell 
PD-L1≥ 1% and a high tumor-associated immune cell PD-L1 (TAIC) expression demonstrated a 
relatively better OS benefit (HR: 0.43, 95% CI 0.28, 0.67) with median OS of 9 months. In 
participants who only showed high expression of TAICs a 33% reduction in risk of death was 
noted (HR = 0.67, 95% CI 0.38, 1.18), with a median OS of 11.73 months. This recent data, while 
confirming the clinical benefit of check-point inhibitors in the over-all SCCHN population 
(irrespective of baseline biomarker status), also demonstrates a relatively better efficacy in 
participants with high PD-L1 CPS. 36.
A recent Phase 3 study (KeyNote-048) evaluated immunotherapy either as a single agent 
(pembrolizumab) or in combination with chemotherapy (pembrolizumab+platinum+5FU) in 1L 
R/M SCCHN. The study demonstrated that the participants expressing high PD-L1 CPS
≥20 derive a significant survival benefit with immunotherapy compared to treatment with 
EXTREME regimen (HR = 0.61, 95% CI 0.45-0.83, p = 0.0007). This sub-group (PD-L1 CPS
≥20) covers approximately 40-45% of the 1L recurrent or metastatic SCCHN population. The 
study also evaluated pembrolizumab monotherapy in participants who expressed PD-L1 CPS
≥1 (approximately 85% of the study population) and pembrolizumab + chemotherapy in all study 
participants. The results showed a modest 2 months improvement in median OS for 
pembrolizumab monotherapy compared to EXTREME regimen in PD-L1 CPS ≥1 sub-group 
(HR= 0.78, 95% CI 0.64-0.96, p = 0.0086) and a 2.3 months improvement in median OS for 
pembrolizumab + chemotherapy compared to EXTREME regimen in all-comes population 
(HR = 0.77, 95% CI 0.63-0.93, p = 0.0034). The pembrolizumab + chemotherapy regimen did not 
offer significant benefit over EXTREME regimen for duration of tumor response (median 
6.7 months for P+C versus 4.3 months with EXTREME regimen) or in terms of overall safety 
profile. This recent data, while supporting patient selection based on PD-L1 CPS level for 
treatment with immunotherapy, also suggests that neither pembrolizumab monotherapy or 
pembrolizumab + chemotherapy are optimal treatment options unselected 1L R/M SCCHN patient 
population or those with low PD-L1 CPS levels.
Similar encouraging data on PD-L1 CPS selection for PD-1 inhibitors have been recently reported 
in other indications as well. In KeyNote-059 Cohort 1, patients with advanced gastric cancer (GC)
who had received ≥2 lines of prior chemotherapy were treated with pembrolizumab monotherapy 
(n = 257). Pembrolizumab showed promising clinical activity with antitumor response 
significantly associated with PD-L1 CPS (P = 0.002) but not TPS (P = 0.224) at PD-L1 
CPS/TPS ≥1. The odds ratio between the PD-L1 positive and negative populations had increased 
from 1.4 for TPS ≥1 to 2.8 for PD-L1 CPS ≥ 1, indicating the better predictive value of PD-L1 
CPS compared to TPS.
In CA209-032 GC cohorts, PD-L1 CPS has been associated with longer survival. The mOS for 
patients with PD-L1 CPS ≥ 5 was 7.7 months compared with 5.4 months for PD-L1 CPS < 5 when 
Revised Protocol No.: 05
Date: 19-Dec-2019
23
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
all treatment regimens were combined. These data suggested PD-L1 CPS is a better predictor of 
treatment effects of immunotherapy in advanced or metastatic GC/GEJ.
Based on accumulating clinical data, PD-L1 CPS seems to better predict response than TPS and 
able to better select patients for treatment with checkpoint inhibitors.
Additionally, recent evolving data from multiple Phase 3 studies in SCCHN (Checkmate 141, 
KeyNote-040 and KeyNote-048) suggest that PFS did not capture the benefit of immunotherapy
therapy versus standard of care therapy in both biomarker selected and unselected population. In 
1L R/M SCCHN, pembrolizumab showed a median PFS of 3.4 months in participants with PD-L1 
CPS ≥20 sub-group and 3.2 months in participants with PD-L1 CPS ≥1 sub-group versus 5.0 
months with EXTREME regimen. This suggest that PFS is not an ideal end-point for 
immunotherapy.
Based on the review of available data, this study (CA209651) will be revised to compare the 
difference in OS between study arms in participants who express PD-L1 CPS ≥20 and in all study 
participants as the co-primary end-points. 
1.2.3
Rationale for Combination of Nivolumab and Ipilimumab
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-γ 
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer models. 
In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased 
the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and 
dual blockade increased tumor infiltration of T effector cells and decreased intratumoral 
T regulatory cells, as compared to either agent alone.19
Checkmate 141 showed that nivolumab monotherapy increased the length of time patients lived 
when compared with standard, single agent chemotherapy with a relatively better efficacy noted 
in tumor cell PD-L1 expressers. In similar trials in lung cancer patients that had recurred after 
treatment with platinum-based chemotherapy, nivolumab monotherapy also prolonged survival 
versus single agent chemotherapy, both in tumors with squamous subtype, and non-squamous 
subtype. These trials led to approval of nivolumab for previously treated lung cancer in the US, 
Europe, and other countries.
In the clinical setting, the combination of nivolumab and ipilimumab was evaluated in CA209004 
(MDX1106-04), a Phase 1b multiple ascending dose study in participants with treatment-naive 
and previously treated advanced melanoma. Results showed promising activity with higher, 
tolerable toxicity profile compared to ipilimumab alone. Based on this, CA209069, a randomized 
double-blind Phase 2 study of nivolumab in combination with ipilimumab versus ipilimumab 
monotherapy in participants with BRAF-wild type (WT) and mutant, with untreated unresectable 
or metastatic melanoma, was conducted. The regimens used were: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks 
versus ipilimumab 3 mg/kg every 3 weeks for 4 doses.20 In patients with BRAF-WT tumors treated 
Revised Protocol No.: 05
Date: 19-Dec-2019
24
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
with nivolumab and ipilimumab combination, there was improved ORR at 61% (44/72), with 22% 
(16/72) complete responses (CR), as compared to 11% (4/37) with 0 CRs in those treated with 
ipilimumab alone. The median PFS was not reached in the combination versus 4.4 months for 
ipilimumab alone (HR = 0.4). Improved clinical outcomes (PFS and ORR) with nivolumab and 
ipilimumab combination was confirmed by CA209067, a randomized Phase 3 study. In patients 
with previously untreated, unresectable or metastatic melanoma (n =945), the median PFS was 
11.5 months (95% CI, 8.9 to 16.7) in the nivolumab plus ipilimumab group, 6.9 months 
(95% confidence interval [CI], 4.3 to 9.5) in the nivolumab group, and 2.9 months (95% CI, 2.8 to 
3.4) in the ipilimumab group. Significantly longer PFS was observed in the nivolumab plus
ipilimumab group than in the ipilimumab group (hazard ratio for death or disease progression, 
0.42; 99.5% CI, 0.31 to 0.57; P<0.001) and in the nivolumab group than in the ipilimumab group 
(HR = 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). The hazard ratio for the comparison between the 
nivolumab plus ipilimumab group and the nivolumab group was 0.74 (95% CI, 0.60 to 0.92).37
Clinical activity of nivolumab and ipilimumab combination was further evaluated in patients with 
stage IIB-IV NSCLC as first-line treatment in CA209012 study.38 This was a large Phase 1, 
multi-arm safety study of nivolumab monotherapy and nivolumab in combination with various 
systemic anticancer therapies like ipilimumab, platinum-based chemotherapies and epidermal 
growth factor receptor (EGFR) tyrosine kinase inhibitor. Early combination cohorts evaluated 
2 dosing schedules that were studied in the CA209004 melanoma study: nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg (arms G and H, n = 24) and nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arms 
I and J, n = 25). Both regimens were given every 3 weeks 4 doses, followed by maintenance 
nivolumab 3 mg/kg q 2 weeks. Unlike in melanoma, these regimens resulted in significant toxicity 
in the NSCLC population, with 39% of patients discontinuing treatment due to a treatment-related 
adverse events. Thus, additional combination cohorts were initiated (arms N, O, P, Q), using lower 
doses of both nivolumab and ipilimumab, or the approved dose of nivolumab with less frequent 
dosing of ipilimumab. These new regimens were better tolerated, and the safety profile was 
comparable to what has been observed in the nivolumab monotherapy cohort (arm F) in CA209012
study (Table 1.2.3-1). 
Table 1.2.3-1:
Treatment-related adverse events from selected cohorts in 
CA209012 (NSCLC)
Arma
No. 
Participants
/ arm
Follow-up 
time 
(median, 
wks)
No. 
Participants
still on 
treatment
No. 
Participants
with drug-
related AEs
No. 
Participants
with grade 3-
4 drug-
related AEs
No. Participants
d/c due to drug-
related AEs 
(all grades)
Nb
31
72
6 (19%)
24 (77%)
9 (29%)
4 (13%)
Ob
40
27
14 (35%)
29 (73%)
14 (35%)
3 (8%)
Pb
38
37
20 (53%)
28 (74%)
11 (29%)
2 (5%)
Qb
39
34
15 (39%)
27 (69%)
11 (28%)
4 (10%)
Revised Protocol No.: 05
Date: 19-Dec-2019
25
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 1.2.3-1:
Treatment-related adverse events from selected cohorts in 
CA209012 (NSCLC)
Arma
No. 
Participants
/ arm
Follow-up 
time 
(median, 
wks)
No. 
Participants
still on 
treatment
No. 
Participants
with drug-
related AEs
No. 
Participants
with grade 3-
4 drug-
related AEs
No. Participants
d/c due to drug-
related AEs 
(all grades)
Fc
52
62
5 (10%)
37 (71%)
10 (19%)
5 (10%)
a N:nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x 4, followed by nivolumab 3 mg/kg every 2 weeks; 
O: nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; P: nivolumab 3 mg/kg every 2 weeks 
plus ipilimumab every 12 weeks; Q: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; 
F: nivolumab 3 mg/kg every 2 weeks
b based on August 2015 database lock
c based on March 2015 database lock
Table 1.2.3-2:
Efficacy of First-Line Treatment of Nivolumab/Ipilimumab 
Combination in CA209012 (NSCLC)
Nivo 1 + Ipi 1
q3w→Nivo 3
(Arm N; n = 31)
Nivo 1 q2w + Ipi 
1 q6w
(Arm O; n = 40)
Nivo 3 q2w + Ipi 1
q12w
(Arm P; n = 38)
Nivo 3 q2w+ Ipi 1
q6w
(Arm Q;n = 39)
Confirmed ORR, % 
(95% CI)
13 (4, 30)
25 (13, 41)
39 (24, 57)
31 (17, 48)
PFS rate at 24 wks 
(95% CI)
55 (36, 73)
58 (41, 73)
74 (57, 87)
51 (35, 68)
mPFS, mos
(95% CI)
10.6 (2.1, 16.3)
4.9 (2.8, )
8.0 (4.2, )
8.3 (2.6, )
Median length of 
follow-up, months
16.6
6.2
8.4
7.7
Table 1.2.3-3:
Efficacy by Tumor Cell PD-L1 Expression (( ≥1%) in CA209012 
(NSCLC)
Nivo 1 + Ipi 1
q3w→Nivo 3
(Arm N n = 12)
Nivo 1 q2w + Ipi 1
q6w
(Arm O; n = 21)
Nivo 3 q2w + Ipi 1 
q12w
(Arm P; n = 21)
Nivo 3 q2w + Ipi 1 
q6w
(Arm Q; n = 23)
ORR, %
8
24
48
48
mPFS, wks
(95% CI)
11.5
(7.1, )
21.1
(11.4, )
34.6
(15.9, 35.3)
NR
(15.4, )
PFS rate at 24 wks, 
% (95% CI)
42
(15,67)
40
(18, 61)
74
(48,88)
65
(42, 81)
Revised Protocol No.: 05
Date: 19-Dec-2019
26
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Clinical activity was observed in all combination cohorts (Table 1.2.3-2), but numerically higher 
response rates were observed in cohorts evaluating the approved dose of nivolumab 3 mg/kg in 
combination with ipilimumab, with confirmed response rates ≥30% (cohorts P and Q). When 
clinical activity was analyzed by tumor cell PD-L1 expression, there appears to be higher efficacy 
in participants with PD-L1 expressing tumors however interpretation is limited by the small 
number of patients. Those with tumor cell PD-L1 ≥1% expressing tumors treated with nivolumab 
and ipilimumab combination in cohorts P and Q had response rates of 48%. PFS appeared to be 
also higher in these subsets; of note, in cohort Q, PFS was not yet reached (Table 1.2.3-3). 
Although follow-up is still limited (7 to 8 months), the PFS and ORRs observed in these cohorts 
are highly encouraging. With comparable efficacy and safety data from cohorts P and Q, the 
nivolumab plus ipilimumab every 6 week dosing schedule (cohort Q) is the selected regimen 
moving forward.39 Aside from utilizing the approved nivolumab dose in NSCLC, it would also 
provide the highest dose and frequency of ipilimumab feasible in a combination regimen.
The combination of ipilimumab with nivolumab showed increased activity versus nivolumab alone 
in multiple tumor types, including melanoma, multiple types of lung cancer, gastric cancer, and 
renal cancer as described below. This efficacy benefit is not restricted to tumor cell PD-L1
expressers alone. The combination is currently approved for the treatment of advanced or 
metastatic melanoma in the US and Europe. 
Given the similarity in patient profiles of NSCLC and SCCHN, nivolumab 3 mg/kg every 2 weeks 
and ipilimumab 1 mg/kg every 6 weeks 
 
 and will also be the treatment regimen for the experimental arm of the Phase 3 CA209651 
study.
 
 
Thus the 
summary of available evidence across indications suggests that addition of ipilimumab to 
nivolumab may offer an opportunity to improve the efficacy OS in R/M SCCHN participants
irrespective PD-L1 expression, with a relatively better efficacy benefit in participants with high 
PD-L1 CPS.
Overall, as discussed previously, based on the evolving data from SCCHN suggesting a relatively 
better efficacy for immunotherapy in PD-L1 CPS high expressers and potential for 
Nivolumab + Ipilimumab to benefit participants irrespective of PD-L1 CPS status, the CA209651 
study will evaluate the co-primary end-points of OS of the combination of nivolumab with 
ipilimumab versus EXTREME regimen in participants with PD-L1 CPS ≥20 and in all study 
participants.
1.2.4
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on patients and treatment centres. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes duration in 
participants will diminish the burden provided no change in safety profile. Previous clinical studies 
of nivolumab monotherapy and ipilimumab monotherapy and the combination of nivolumab and 
ipilimumab have used a 60-minute infusion duration for nivolumab and 90-minute infusion 
Revised Protocol No.: 05
Date: 19-Dec-2019
27
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration.
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg safely 
over long treatment duration. In Study CA209010 (a Phase 2, randomized, double blinded, 
dose-ranging study of nivolumab in participants with advanced/metastatic clear cell RCC), a dose 
association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1 - 2 and were 
manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided 
at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 
10 mg/kg nivolumab dose infused over a 60-minute duration.
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In the CA184022 
study, where ipilimumab was administered up to a dose of 10 mg/kg, on-study drug related 
hypersensitivity events (Grade 1 - 2) were reported in 1 (1.4%) participant in the 0.3 mg/kg and in 
2 (2.8%) participants in the 10 mg/kg group. There were no drug-related hypersensitivity events 
reported in the 3 mg/kg group. Across the 3 treatment groups, no Grade 3 - 4 drug-related 
hypersensitivity events were reported, and there were no reports of infusion reactions. Ipilimumab 
10 mg/kg monotherapy has also been safely administered as 90 minute infusion in large Phase 3 
studies in prostate cancer (CA184043) and as adjuvant therapy for stage 3 melanoma (CA184029), 
with infusion reactions occurring in participants. Administering 1 mg/kg of ipilimumab represents 
one-tenth of the 10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across nivolumab or ipilimumab clinical studies or the combination of nivolumab and ipilimumab. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusion of nivolumab, ipilimumab or combination.
1.2.5
Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease 
Accumulating clinical evidence indicates some participants treated with immune system 
stimulating agents may develop progression of disease (by conventional response criteria) before 
demonstrating clinical objective responses and/or stable disease. This phenomenon was observed 
in approximately 10% of participants in the Phase 1 study of nivolumab and also with ipilimumab 
monotherapy40 Two hypotheses have been put forth to explain this phenomenon. First, enhanced 
inflammation within tumors could lead to an increase in tumor size which would appear as 
enlarged index lesions and as newly visible small non-index lesions. Over time, both the malignant 
and inflammatory portions of the mass may then decrease leading to overt signs of clinical 
improvement. Alternatively, in some individuals, the kinetics of tumor growth may initially 
outpace anti-tumor immune activity. With sufficient time, the anti-tumor activity will dominate 
and become clinically apparent. Therefore participants will be allowed to continue study therapy 
after initial investigator-assessed RECIST 1.1 defined progression if they are assessed to be 
Revised Protocol No.: 05
Date: 19-Dec-2019
28
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
deriving clinical benefit and tolerating study drug. Such participants must discontinue study 
therapy upon evidence of further progression as defined in section 4.5.5.
1.2.6
Rationale for 24 Months Maximum Treatment Duration 
The optimal duration of treatment by checkpoint blockade inhibitors in oncology is currently 
unknown. However, given their mechanism of action continuous treatment may not be required as 
opposed to targeted agents or most of cytotoxic therapies. 
With almost a decade of experience using CTLA-4 and PD-1/PD-L1 inhibitors, accumulating 
evidence from different clinical trials in different tumor types indicates that most of the responses 
are generally occurring early, with a median time to response of 2 to 4 months including in patients 
with NSCLC, and most of the responses are likely to be durable as compared to conventional 
therapies.41’42’43
Limited duration of therapy was explored in few trials, for instance, ipilimumab the first 
checkpoint blockade inhibitor targeting CTLA-4 was initially approved in metastatic melanoma in 
participants who failed standard of care chemotherapy. This approval was based on overall 
survival improvement after a limited duration of ipilimumab therapy, including only 4 induction 
doses for a duration of treatment of 12 weeks, with a sustained plateau in survival starting at around 
year two.44 Moreover, in Checkmate 003 a dose-escalation cohort expansion trial evaluating the 
safety and clinical activity of nivolumab in patients with advanced solid tumors implemented 
stopping nivolumab monotherapy at 96 weeks (~ 2 years). At 2 years, 16 NSCLC participants who 
were on still on therapy discontinued nivolumab per protocol, of these, 75% of patients (n = 12) 
were alive > 5 years and did not receive further therapy after stopping nivolumab and remained 
progression free.45
Moreover, long-term follow up data from study KeyNote-006 a phase 3 Melanoma study 
demonstrates that pembrolizumab provides durable efficacy after stopping the protocol-specified 
duration of treatment at 2 years. The median follow-up was of 33.9 months, among the 104 (19%) 
participants who completed pembrolizumab, median exposure was 24.0 months. After additional 
median follow-up of 9.0 months after completion of pembrolizumab, 102 (98%) pts were alive 
and responses were durable in pts who completed pembrolizumab.46
In addition, data from different series are showing that patients receiving immunotherapy-based 
treatment may discontinue treatment due to safety events. In a recent analysis in a melanoma study 
the majority of patients who discontinue nivolumab and/or ipilimumab for toxicity maintain 
disease control in the absence of further treatment.47
CheckMate 153 is the first randomized study to evaluate treatment duration with a PD-1/PD-L1 
inhibitor. In this study, progression free survival appears to be durable with a plateau at 2 years 
from first dose including in pts who stopped nivolumab after 1 year, suggesting the risk of 
progression after 2 years of treatment is minimal, even in the absence of further treatment, which 
is consistent with existing data with PD-1/PD-L1 datasets. In addition, 34 out of 87 patients with 
clinical benefit who stopped therapy at 1 year were retreated upon progression as per protocol, in 
this group, nivolumab retreatment did not appear to re-induce responses and in the majority of the 
Revised Protocol No.: 05
Date: 19-Dec-2019
29
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
cases, the tumor continues to progress suggesting that treatment change, using preferentially an 
agent or approach with a different MOA.48
Collectively, these data suggest that there is likely no benefit from treatment beyond two years in 
advanced tumors. However, even though immunotherapy is well tolerated, patients will be exposed 
to the risk of additional toxicity with longer-term treatment. Therefore, in CA209-651 treatment 
with nivolumab +/- ipilimumab will be given for up to 2 years from start of treatment.
1.3
Research Hypotheses 
•
Participants with PD-L1 CPS ≥ 20 who receive nivolumab in combination with ipilimumab 
for first-line treatment of recurrent or metastatic SCCHN will have longer OS than comparable 
participants who receive the EXTREME regimen 
•
Participants who receive nivolumab in combination with ipilimumab for first-line treatment of 
recurrent or metastatic SCCHN will have longer OS than comparable participants who receive 
the EXTREME regimen
1.4
Objectives(s)
1.4.1
Primary Objectives
•
To compare the OS of participants with PD-L1 CPS ≥ 20 who are receiving nivolumab 
combined with ipilimumab to those receiving EXTREME regimen.
•
To compare the OS of all study participants who are receiving nivolumab combined with 
ipilimumab to those receiving EXTREME regimen
1.4.2
Secondary Objectives
•
To compare the OS of participants with PD-L1 CPS ≥ 1 who are receiving nivolumab 
combined with ipilimumab to those receiving EXTREME regimen
•
To evaluate progression-free survival (PFS) based on BICR in all study participants and those
with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen.
•
To evaluate objective response rate (ORR) based on BICR in all study participants and those
with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen. 
•
To evaluate the duration of response (DOR) based on BICR in all study participants and those 
with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen. 
1.4.3
Exploratory Objectives 
•
To evaluate OS of participants with tumor cell PD-L1 < 1% and PD-L1 CPS < 20 who are 
receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
Revised Protocol No.: 05
Date: 19-Dec-2019
30
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
To evaluate the OS of participants with tumor inflammation score measured as gene expression 
profile (GEP) ≥ 10 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen. 
•
To evaluate the OS of participants with tumor mutation burden (TMB) ≥ 7 who are receiving 
nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate clinical outcomes (OS, PFS, ORR, DOR) by select baseline and on-treatment 
biomarker expression levels in peripheral blood and tumor biopsy specimens.
•
To assess safety and tolerability of nivolumab in combination with ipilimumab and of 
EXTREME regimen, in all study participants
•
To characterize pharmacokinetics and immunogenicity of nivolumab in combination with 
ipilimumab as first line therapy in participants with recurrent or metastatic SCCHN
•
To evaluate time to symptom deterioration (TTSD) in each arm as assessed using the 
Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) 10-item Symptom 
Index (FHNSI-10), in participants with PD-L1 CPS ≥ 20 and also in all study participants
•
To assess the participant’s overall health status and health utility using the 3-level version of 
the EQ-5D (EQ-5D-3L) visual analog scale (VAS) and utility index, respectively, in 
participants with PD-L1 CPS ≥ 20 and also in all study participants
•
To assess the participant’s cancer-related symptoms and quality of life using components of 
the FACT-H&N questionnaire, in participants with PD-L1 CPS ≥ 20 and also in all study 
participants.
1.5
Product Development Background
Nivolumab (Opdivo) is in clinical development for the treatment of patients with melanoma, 
non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck carcinoma and 
other tumors (eg, gastric cancer, glioblastoma multiforme, Hodgkins lymphoma, small cell lung 
cancer). Opdivo as monotherapy has been approved in the US in multiple indications, including, 
unresectable or metastatic melanoma and disease progression following ipilimumab and a BRAF 
inhibitor, if BRAF V600 mutation positive; previously untreated patients with BRAF wild-type 
unresectable or metastatic melanoma; NSCLC with progression on or after platinum-based 
chemotherapy; and advanced renal cell carcinoma who have received prior anti-angiogenic 
therapy. The combination of nivolumab and ipilimumab has also been approved in the US for the 
treatment of previously untreated metastatic melanoma.
Patients with recurrent or metastatic SCCHN have poor prognosis and experience limited survival 
benefit with standard of care therapies. In patients with recurrent or metastatic SCCHN who 
progress with platinum chemotherapy, nivolumab demonstrated prolonged survival benefit over 
standard of care in the Checkmate 141 study and is poised to become the standard of care in this 
population. To further improve clinical outcomes in patients with recurrent or metastatic SCCHN
in the first-line treatment setting, nivolumab in combination with ipilimumab is being explored in 
the CA209651 clinical study.
Revised Protocol No.: 05
Date: 19-Dec-2019
31
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
1.5.1
Mechanism of Action of Nivolumab
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD 1) cluster 
of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes49. Binding of PD-1 to its ligands, 
programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration.
1.5.2
Mechanism of Action of Ipilimumab
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses. Ipilimumab is a fully human 
monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human 
and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the 
interaction of CTLA-4 with B7 molecules on APCs, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA 4/B7 interaction50,51. 
1.5.3
Nivolumab Combined With Ipilimumab
The combination of nivolumab and ipilimumab has been studied in various tumor types such as 
melanoma and recently, as first line therapy in participants with previously untreated stage IV or 
recurrent NSCLC at different dose and schedules in study CA209012. As of 17 March 2015, 
80 patients have been treated with this combination in the original cohorts (arms G, H, I, J, N). 
Additional combination dosing schedules were developed using lower doses of both nivolumab 
and ipilimumab (1 mg/kg), or using the approved dose of nivolumab (3 mg/kg) with more extended 
dosing of ipilimumab 1 mg/kg (q6w and q12w). An additional 117 patients have been treated in 
these newer cohorts, and compared to other cohorts, shows acceptable safety profile with lower 
treatment related AEs (all grade and Grade 3-4) as well as lower treatment related AEs leading to 
discontinuation (Table 1.5.3-1). Based on the efficacy and safety data, nivolumab plus ipilimumab 
every 6 week dosing schedule was determined to be optimal combination regimen in NSCLC. 
Additional clinical data and rationale for the combination regimen is discussed in Section 1.2.3.
Table 1.5.3-1:
First-Line Nivolumab + Ipilimumab Safety Summary
Treatment-Related AEs, %
Treatment-Related AEs leading to 
discontinuation, %
Nivo 1 Q2W + Ipi 1 Q6W (n = 40)
Any Grade
73
8
Grade 3-4
35
8
Revised Protocol No.: 05
Date: 19-Dec-2019
32
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 1.5.3-1:
First-Line Nivolumab + Ipilimumab Safety Summary
Treatment-Related AEs, %
Treatment-Related AEs leading to 
discontinuation, %
Nivo 3 Q2W + Ipi 1 Q12W (n = 38)
Any Grade
74
5
Grade 3-4
29
3
Nivo 3 Q2W + Ipi 1 Q6W (n = 39)
Any Grade
69
10
Grade 3-4
28
10
1.6
Overall Risk/Benefit Assessment
Patients with recurrent, unresectable or metastatic SCCHN represent an important unmet need. 
There is robust clinical data available to suggest the potential to improve clinical outcomes in 
SCCHN:
•
CheckMate 141 study (CA209141), is a randomized, open label, Phase 3 trial that compared 
nivolumab, a fully human anti-programmed death 1 (PD 1) monoclonal antibody, to 
investigator’s choice (IC) of systemic therapy in patients with recurrent or metastatic SCCHN 
who progressed from a platinum-containing therapy. At the primary analysis, the median OS 
was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) with nivolumab versus 5.1 months 
(95% CI, 4.0 to 6.0) with IC. There is a 30% reduction in the risk of death for patients on the 
nivolumab arm (hazard ratio 0.70; 97.73% CI, 0.51 to 0.96; P = 0.0101) over IC. The overall 
response rate (ORR) was 13.3% with nivolumab versus 5.8% with IC. The long-term follow-
up data from the study confirms the prolonged survival benefit in the overall study population, 
while suggesting a relatively better OS in subjects who express PD-L1 on both tumor and 
immune cells. In addition, the overall safety profile and patient reported outcomes of 
nivolumab was favorable compared to IC. Clinical benefit seen in this chemotherapy pre-
treated SCCHN suggests the potential clinical activity of nivolumab in earlier treatment setting.
•
A recent Phase 3 study (KeyNote-048) in 1L R/M SCCHN evaluated immunotherapy either as 
a single agent (pembrolizumab) or in combination with chemotherapy (pembrolizumab 
+platinum+5FU) in 1L R/M SCCHN. The study demonstrated that the participants expressing 
high PD-L1 CPS ≥ 20 derive a significant survival benefit with immunotherapy compared to 
treatment with EXTREME regimen (HR = 0.61, 95% CI 0.45-0.83, p = 0.0007). This study 
also demonstrated that immunotherapy had a favorable safety profile vs EXTREME. There 
was a lower incidence of any-grade, grade 3-4, and grade 5 treatment-related AEs, and lower 
incidence of treatment-related AEs leading to discontinuation.
Revised Protocol No.: 05
Date: 19-Dec-2019
33
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
CheckMate 012 study (CA209112) is a multi-arm large phase 1 safety study of nivolumab as 
a single agent or in combination with various systemic anticancer therapies including 
ipilimumab in patients with stage IIIB-IV NSCLC as first-line treatment. Clinical activity was 
observed in all combination cohorts with numerically higher response rates observed in cohorts 
evaluating nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, with confirmed response rates ≥30% 
and median PFS ~8 months. 
Given the similarity in patient profiles of NSCLC and SCCHN, nivolumab 3 mg/kg every 2 weeks 
and ipilimumab 1 mg/kg every 6 weeks (will be the treatment regimen for the experimental arm 
of this study.
The safety profile of nivolumab and ipilimumab is well characterized from a large safety database 
at different dose and schedules as monotherapy or in combination.52,53 Consistent with the 
mechanism of action of nivolumab and ipilimumab, the most frequently reported drug-related 
adverse events observed in clinical trials are those associated with activation of the immune 
system. The most common types of immune-mediated adverse events include endocrinopathies, 
diarrhea/colitis, hepatitis, pneumonitis, nephritis and rash. In the combination regimen, the 
frequency and intensity of these events may vary and depend on the specific dose and schedule 
used. In the combination dosing schedule selected for this study (nivolumab 3 mg/kg Q2W plus 
ipilimumab 1 mg/kg Q6W), immune-mediated adverse events were mostly low grade and 
manageable with prompt use of corticosteroids. 
Nivolumab was evaluated in 240 patients with recurrent or metastatic platinum refractory SCCHN 
in CA209141 study and demonstrated a favorable safety profile with nivolumab monotherapy as 
compared to standard of care chemotherapy. Nivolumab in combination with ipilimumab will be 
evaluated in the SCCHN population for the first time.
To assure an ongoing favorable risk/benefit assessment for participants enrolled onto CA209651, 
the following safety measures will be employed throughout the conduct of the study:
•
Institution of a Data Monitoring Committee (DMC) to provide independent oversight of safety, 
study conduct and efficacy of nivolumab plus ipilimumab combination versus standard of care 
chemotherapy (EXTREME regimen).
•
Rigorous safety monitoring by BMS to ensure participants’ safety including regular and 
systematic review of safety data, close follow-up of reported safety events, intensive site and 
study investigator training/education on the implementation of the nivolumab and ipilimumab 
toxicity management algorithms as well as regular safety conference calls with study 
investigators.
•
Open-label drug administration of study drugs to allow for prompt and accurate assessment of 
the unique toxicities associated with study treatments
In conclusion, the overall risk-benefit of nivolumab and ipilimumab as first-line treatment in 
recurrent or metastatic SCCHN is deemed acceptable.
Revised Protocol No.: 05
Date: 19-Dec-2019
34
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented and was randomized to participate in the clinical research study
2.1
Regulatory and Ethical considerations
2.1.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the international ethical 
guidelines including the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines Good Clinical Practice (GCP), in 
accordance with ethical principles underlying European Union Directive 2001/20/EC and the 
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/participant’s informed consent will receive approval/favorable opinion by 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities 
according to applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, the safety or mental 
integrity of one or more of the subjects /participants; (2) the scientific value of the study (eg, 
reliability and robustness of generated data). Items (1) or (2) can be associated with either GCP 
Regulation(s) or Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.1.2
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.
Revised Protocol No.: 05
Date: 19-Dec-2019
35
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
2.1.3
Informed Consent Process
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
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 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
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 
Revised Protocol No.: 05
Date: 19-Dec-2019
36
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
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 to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
Protocol CA209651 is a randomized open-label, Phase 3 trial in subjects ≥18 years old with 
untreated metastatic or recurrent SCCHN that is not amenable to curative therapy, evaluating 
nivolumab + ipilimumab versus the EXTREME regimen (cetuximab + cisplatin/carboplatin + 
fluorouracil) as a first-line treatment. 
HPV p-16 status and tumor cell PD-L1 status (expressing or non-expressing/non-evaluable) test 
results will be needed prior to randomization. Subjects will undergo screening evaluations to 
determine eligibility prior to randomization. 
The dose and treatment schedules for each arm are as follows:
•
Arm A: Nivolumab + Ipilimumab Arm:
−
Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until 
progression, unacceptable toxicity, or a maximum of 24 months from first study treatment.
•
Arm B: EXTREME regimen Arm:
−
Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin 
(100 mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and 
fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles
followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local 
prescribing information) until disease progression or unacceptable toxicity; the choice of 
cisplatin or carboplatin is at the discretion of the investigator.
Approximately 930 subjects will be randomized to the two treatment arms in a 1:1 ratio and 
stratified by the following factors: 
•
Tumor cell PD-L1 status (expressing [≥1%] vs non-expressing [< 1%] or non-evaluable). Up 
to 10% of randomized subjects per cohort can be included into the study as “non-evaluable.” 
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 randomize the subject.
•
HPV p-16 status (oropharyngeal HPV p-16 positive vs oropharyngeal HPV p-16 negative or 
non-oropharyngeal). Oropharyngeal CA sites defined in Appendix 5.
•
Prior chemotherapy (adjuvant/neoadjuvant/multimodal treatment) status (Yes/No)
Revised Protocol No.: 05
Date: 19-Dec-2019
37
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Tumor progression or response will be assessed by investigator using RECIST 1.1 criteria. 
Treatment with study medication will continue until RECIST 1.1 defined progression, 
unacceptable toxicity, a maximum of 24 months from the first study treatment, or withdrawal of 
consent. See Section 3.5 for full details of discontinuation of study drug treatment.
Dose reductions will be not be allowed for nivolumab or ipilimumab.
Treatment beyond initial investigator-assessed progression (either clinical or radiographical) is 
permitted for nivolumab and ipilimumab if the participant has an investigator-assessed clinical 
benefit and is tolerating study drug (see Section 4.5.6).
In addition to investigator assessment of response and progression, there will be a blinded 
independent central review (BICR) of tumor scans and study sites will need to submit tumor scans 
for central radiology review.
A DMC will be established and meet regularly during the study to ensure that participant safety is 
carefully monitored and to provide oversight regarding safety and efficacy considerations in 
protocol CA209651.
The maximum duration of the study from start of randomization to final analysis of OS is projected 
to be 51 months, assuming 26 months accrual duration. Additional 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 3.1-1.
Figure 3.1-1:
Study Design Schematic
Revised Protocol No.: 05
Date: 19-Dec-2019
38
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
This study will consist of 3 phases: screening, treatment, and follow-up.
Screening Phase
•
Begins by establishing the participant’s initial eligibility and signing of the informed consent 
(ICF).
•
Participant is enrolled using the Interactive Voice Response System (IVRS).
•
Tumor tissue (archival or recent tumor biopsy) must be submitted by the site to a Central Lab 
for determination of tumor cell PD-L1 status. For this study we will use PD-L1 stained with 
the DAKO 28-8 antibody. Additional tumor tissue may be required by Central Lab if initial 
testing is unevaluable.
•
HPV p-16 status must be available prior to randomization. If it is not available locally, then 
this will need to be tested by central lab, and the results need to be known prior to 
randomization. See Section 5.6.8.
Participants will be stratified on tumor cell PD-L1 status (expressing vs non-expressing or non-
evaluable. Up to 10% of randomized subjects can be included into the study as non-evaluable. 
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 randomize the subject).
•
Participants must have the result of tumor cell PD-L1 IHC testing from the Central Lab 
available (and HPV p-16 result if not available locally) in order to randomize into the study.
•
Participant is assessed for study eligibility.
•
All screening assessments and procedures must be performed prior to randomization.
Treatment Phase
•
The treatment begins with the contact to the IVRS to randomize the patient.
•
Treatment to begin within 3 days of randomization.
Arm A: Nivolumab + Ipilimumab Combo (1 Cycle = 6 Weeks):
•
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).
•
On the day of infusion, nivolumab is to be administered first. The second infusion will always 
be ipilimumab and will start at least 30 minutes after completion of the nivolumab infusion.
•
Nivolumab 3 mg/kg Q2W and ipilimumab 1 mg/kg Q6W will be continued until the 
progression of disease, discontinuation due to toxicity, withdrawal of consent, or a maximum 
of 24 months from the first study treatment, or study closure (see Section 3.5 for full list of 
treatment discontinuation reasons). Participants may discontinue only ipilimumab and 
continue treatment with nivolumab if certain circumstances are met (See Section 4.5.6,
Treatment Beyond Disease Progression (Arm A only).
•
Treatment beyond initial investigator-assessed RECIST 1.1-defined progression is permitted 
for Arm A if the participant has investigator-assessed clinical benefit and is tolerating 
treatment.
Revised Protocol No.: 05
Date: 19-Dec-2019
39
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Arm B: EXTREME regimen Arm (1 Cycle = 3 weeks):
•
Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin 
(100 mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil 
(1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by 
maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing 
information) until disease progression or unacceptable toxicity; the choice of cisplatin or 
carboplatin is at the discretion of the investigator.
•
Study assessments are to be collected as outlined in Table 5.1-2
•
Upon completion of dosing, participants will enter the Follow-up Phase.
Follow-up Phase
The post-treatment follow-up begins when the decision to discontinue a participant from all 
treatment is made.
•
Participants who discontinue treatment for reasons other than disease progression will continue 
to have tumor assessments (if clinically feasible) according to the schedule in Table 5.1-3 until 
progression.
Participants will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All adverse events will be documented for a minimum of 100 
days after the last dose of study medication.
After completion of the first 2 follow-up visits, participants will be followed every 3 months for 
survival. Survival Follow-up visits may be performed by phone contact or office visit. BMS may 
request that survival data be collected on all treated participants outside of the protocol-defined 
window. At that time of this request, each participant will be contacted to determine their survival 
status unless the participant had withdrawn consent for all contact.
3.2
Post Study Access to Therapy
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug for the maximum treatment duration as described in 
Section 1.2.6. Study drug will be provided via an extension of the study, a rollover study requiring 
approval by responsible health authority and ethics committee or through another mechanism at 
the discretion of BMS. BMS reserves the right to terminate access to BMS supplied study drug if 
any of the following occur: a) the marketing application is rejected by responsible health authority; 
b) the study is terminated due to safety concerns; c) the participant can obtain medication from a 
government sponsored or private health program; or d) therapeutic alternatives become available 
in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met:
Revised Protocol No.: 05
Date: 19-Dec-2019
40
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care.
b) Participants 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.
b) Must have metastatic or recurrent disease that is not amenable to therapy with curative 
intent (surgery or radiation therapy with or without chemotherapy). Participants that refuse 
potentially curative salvage surgery for recurrent disease are ineligible. 
c) No prior treatment with systemic anti-cancer therapy for SCCHN, unless under all of the 
following conditions:
i)
Prior chemotherapy was given as adjuvant or neoadjuvant chemotherapy, or part of 
multimodal (chemo, radiation) treatment for locally advanced disease 
ii) These treatments must have been completed > 6 months prior to enrollment
iii) There is no evidence of disease progression for at least 6 months after completion of 
systemic treatment. 
iv) Participants having progression after 2 cycles of induction chemotherapy are excluded.
d) ECOG Performance Status of 0−1. (See Appendix 1). 
e) Measurable disease by CT or MRI per RECIST 1.1 criteria (see Appendix 3); radiographic 
tumor assessment performed within 28 days prior to first dose.
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. See 
Section 5.6.8 for additional guidance. 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 tumor cell PD-L1 status by IHC performed by the central lab prior to
randomization.
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections (archival or recent), with an associated pathology report, must be submitted for 
biomarker evaluation prior to randomization as described in Section 5.6.3. Biopsy should 
be excisional, incisional, or core needle. Fine needle aspiration is insufficient. Biopsies of 
bone lesions that do not have a soft tissue component are unacceptable for submission.
Revised Protocol No.: 05
Date: 19-Dec-2019
41
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
h) As of Revised Protocol 02, this criterion has been altered and rewritten as criterion 
2.l. Prior palliative radiotherapy must have been completed at least 8 weeks prior to 
randomization if radiotherapy was to the head and neck region and 4 weeks prior to 
randomization if radiotherapy was to other regions.
i)
All toxicities attributed to prior systemic anti-cancer therapy or surgery other than alopecia 
and fatigue must have resolved or returned to baseline at least 2 weeks before 
randomization.
j)
Participants must have a life expectancy of at least 3 months. Any participants whose body 
weight decreased by > 10% between the screening visit and randomization must be 
excluded from the study. 
k) As of Revised Protocol 02, this criterion has been removed because it is already part 
of criterion c. Participants having progression after 2 cycles of induction chemotherapy 
are excluded.
l)
Prior radiotherapy must have been completed at least 2 weeks prior to randomization. All 
toxicities attributed to the radiotherapy must have resolved or returned to baseline prior to 
treatment. 
3. Age and Reproductive Status
a) Males and Females, ages ≥18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception from the time of 
enrollment for the duration of treatment plus 5 half-lives of nivolumab (half-life up to 
25 days) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatment 
completion (Arm A). 
i. WOCBP must also agree to follow instructions for method(s) of contraception from 
the time of enrollment for the duration of treatment with chemotherapy plus 5-half-
lives of chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days
post-treatment completion or a duration specified by the local labels of the 
chemotherapy drugs received, whichever is longer (Arm B).
Revised Protocol No.: 05
Date: 19-Dec-2019
42
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
e) Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 
5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 7 
months post treatment completion (for participants treated in Arm A).
i. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with chemotherapy plus 5 half-lives of chemotherapy plus 90 days (duration 
of sperm turnover) for a total of 90 days post-treatment completion or a 
duration specified by the local labels of the chemotherapy drugs received, 
whichever is longer (for participants treated in Arm B).
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in these sections.
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male participants 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, participants must agree to use one highly effective method of contraception as 
listed in Appendix 4.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of 
unknown primary, squamous cell carcinoma that originated from the skin and salivary 
gland or non-squamous histologies (eg, mucosal melanoma).
b) Participants with untreated CNS metastases. 
Participants 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, participants must 
be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone 
(or equivalent) for at least 2 weeks prior to randomization.
c) Participants with carcinomatous meningitis.
2. Medical History and Concurrent Diseases
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
b) Prior treatment with cetuximab or EGFR inhibitors in any treatment setting. 
c) Other active malignancy.
Revised Protocol No.: 05
Date: 19-Dec-2019
43
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
d) Participants with previous malignancies (except non-melanoma skin cancers, and the 
following 
in situ cancers: 
bladder, gastric, esophageal, colon, endometrial, 
cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 
2 years prior to study entry AND no additional therapy is required during the study period.
i)
A second primary squamous cell carcinoma of the head and neck is allowed if 
eligibility is based on a recurrent or a metastatic first primary squamous cell carcinoma 
of the head and neck.
e) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
f)
Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 
mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
g) As of Revised Protocol 02, this criterion is no longer applicable. Participants 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)
Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to randomization/treatment.
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).
c) Inadequate hematologic, renal or hepatic function defined by any of the following 
screening laboratory values:
i)
WBC
< 2000/μL
ii) Neutrophils
< 1500/μL
iii) Platelets
< 100 x 103/μL
iv) Hemoglobin
< 9.0 g/dL
v) As of Revised Protocol 02, this criterion has been revised as 3.c.vii.
Creatinine
> 1.5 x ULN or creatinine clearance < 60 mL/min (using the 
Cockcroft Gault formula). 
vi) AST/ALT
> 3.0 x ULN (> 5 x ULN if liver metastases) 
Revised Protocol No.: 05
Date: 19-Dec-2019
44
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
vii)Total Bilirubin
> 1.5 x ULN (except participants with Gilbert Syndrome 
who must have a total bilirubin level ≥3.0 x ULN)
viii)
Creatinine
> 1.5 x ULN or creatinine clearance < 50 mL/min 
(using the Cockcroft Gault formula). Cisplatin should not be used if creatinine 
clearance is lower than 60 mL/min
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to platinum-containing compounds or other study 
drug components
5. Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a participant. Strict 
conditions apply, and Bristol-Myers Squibb approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. Participants not meeting the inclusion/exclusion criteria must not be 
enrolled into the study. There can be no exceptions to this rule.
Participant Re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be re-consented.
3.3.3
Women of Childbearing Potential
A woman 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 FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
period below are suggested guidelines and the investigators should use their judgment in checking 
serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time during the washout period, 
the woman can be considered postmenopausal:
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Revised Protocol No.: 05
Date: 19-Dec-2019
45
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Other parenteral products may require washout periods as long as 6 months. If the serum FSH
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
•
Any live/attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.
•
Immunosuppressive agents.
•
Immunosuppressive doses of systemic corticosteroids (except as stated in section 3.4.2)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of cancer)
•
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 3.4.3), all other radiation therapy or surgery to any tumor lesion is not 
permitted during study treatment. Participants who require such non-palliative procedures must be 
discontinued from study treatment.
3.4.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses > 
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 participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants 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 participant because of an iodinated contrast allergy, then a contrast 
enhanced MRI of the neck, chest, abdomen and pelvis will be performed. 
Revised Protocol No.: 05
Date: 19-Dec-2019
46
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate [eGFR] < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this participant population. In addition, safety screening for 
contraindications to MRI scanning should be performed according to the MR center’s standards 
prior to each MRI procedure. The ultimate decision to perform MRI in an individual participant in 
this study rests with the site radiologist, the investigator and the standard set by the local Ethics 
Committee.
3.4.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Regular concomitant use of bisphosphonates and RANK-L inhibitors for prevention or reduction 
of skeletal-related events in participants with 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 treatment.
Prior radiotherapy must have been completed at least 2 weeks prior to randomization. On study 
palliative radiotherapy is only allowed for treatment of painful bone lesions. Palliative surgical 
resection of tumor sites is not permitted. Participants 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 4 weeks 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 participants must either discontinue study drug treatment 
or they must meet criteria to continue treatment beyond progression (Section 4.5.6) 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/ipilimumab should be withheld for at least 1 week 
before, during, and 1 week after radiation. Participants should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and AEs should resolve to Grade ≤1 or 
baseline prior to resuming study treatment.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Participants MUST discontinue investigational product (study treatment) for any of the following 
reasons:
•
Participant’s request to stop study treatment
Revised Protocol No.: 05
Date: 19-Dec-2019
47
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply, and BMS approval is required.)
•
Pregnancy*
•
Additional protocol-specified reasons for discontinuation (See Section 4.5.5)
•
A maximum of 24 months from the first study treatment (Arm A only)
*In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur, if local regulations allow.
All participants 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 participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the participant’s completion of the study, the reason for the 
discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Participants 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 5.1 until death or the conclusion 
of the study.
Follow-Up Visit 1 is 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 35 days from last dose. Follow-Up Visit 
2 is to occur 90 days from Follow-Up Visit 1 (± 7 days). Survival Follow-Up Visits to occur 
approximately every 3 months 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 participants outside of the protocol defined 
window (Table 5.1-3). At the time of this request, each participant will be contacted to determine 
their survival status unless the participant has withdrawn consent for all contact.
Revised Protocol No.: 05
Date: 19-Dec-2019
48
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
3.6.1
Withdrawal of Consent
Participants 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 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. Participants should notify the 
investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study 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 participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant as noted above. Lost to 
follow-up is defined by the inability to reach the participant after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by participant to one registered mail letter. 
All attempts should be documented in the participant’s medical records. If it is determined that the 
participant has died, the site will use permissible local methods to obtain 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 participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining participant’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all attempts, 
the subject remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the participant’s medical records.
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:
Revised Protocol No.: 05
Date: 19-Dec-2019
49
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 4-1:
Study Drugs for CA209651
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
Nivolumab Injectiona
100 mg/vial
(10 mg/mL)
IP
Open Label
10 mL vial containing a clear to 
opalescent, colorless to pale yellow 
liquid; may contain particulates; 5 
vials/carton
Store 2 to 8°C. Store in 
original package. Do not 
freeze. Protect from light.
Ipilimumab Injection
200 mg/vial (5 mg/mL)
IP
Open Label
40 mL vial containing a clear, 
colorless liquid; may contain 
particulates; 4 vials/carton
Store 2 to 8°C. Store in 
original package. Do not 
freeze. Protect from light.
Carboplatin Solution for 
IV Injectionb
450 mg/vial
(10 mg/mL)
IP
Open Label
45 mL vial containing a sterile, 
colorless to slightly yellow aqueous 
solution; 4 vials/carton
Store at or below 25°C. 
Protect from light.
Cisplatin Concentrate for 
solution for infusionb
100 mg/vial (1 mg/mL)
IP
Open Label
100 mL vial containing a clear, 
colorless solution; 4 vials/carton
Do not store above 25°C.
Do not refrigerate or freeze.
Keep the vial in the outer 
carton.
Cetuximab solution for 
infusionb
500 mg/vial
(5 mg/mL)
IP
Open Label
100 mL vial, colorless solution; 1 
vial/carton.
Store in a refrigerator 
(2°C – 8°C).
Fluorouracil Injectionb
1 g/vial (50 mg/mL)
IP
Open Label
1 g/20mL/ 1 vial/carton;
Clear, colorless to slightly yellow 
solution.
Do not store above 25°C.
Do not refrigerate or freeze.
Keep the vial in the outer 
carton.
a May be labeled as either “BMS-936558-01” or “Nivolumab.”
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC).
Revised Protocol No.: 05
Date: 19-Dec-2019
50
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
•
Carboplatin
•
Cetuximab
•
Cisplatin
•
Fluorouracil
•
Ipilimumab
•
Nivolumab
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the sponsor and should be purchased locally if permitted by local regulations.
For nivolumab and ipilimumab, please refer to the current version of the Investigator Brochures 
and/or pharmacy reference sheets for complete storage, handling, dispensing, and infusion 
information.
Revised Protocol No.: 05
Date: 19-Dec-2019
51
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
4.4
Method of Assigning Participant Identification
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study by IVRS to obtain the participant number. Every 
participant that signs the informed consent form must be assigned a participant number in IVRS. 
Specific instructions for using IVRS will be provided to the investigational site in a separate 
document. The investigator or designee will register the participant for enrollment by following 
the enrollment procedures established by BMS. The following information is required for 
enrollment:
•
Date that informed consent was obtained
•
Date of birth
•
Gender at birth
Once enrolled in IVRS, enrolled participants that have met all eligibility criteria will be ready to 
be randomized through IVRS. Tumor cell PD-L1 expression data and HPV p-16 will be transferred 
directly from analyzing lab to IVRS (or the local HPV p-16 result, if available, can be entered by 
site directly into IVRS for the oropharyngeal cancer patients during the randomization call). The 
following information is required for participant randomization:
•
Participant number
•
Date of birth
•
HPV p-16 status (oropharyngeal HPV p-16 positive vs oropharyngeal HPV p-16 negative or 
non-oropharyngeal) - Oropharyngeal CA sites defined in Appendix 5
•
Tumor cell PD-L1 expression status: (≥1% vs < 1% or not evaluable)
•
Prior chemotherapy (adjuvant/neoadjuvant/multimodal) status (Yes vs No)
Participants meeting all eligibility criteria will be stratified by tumor cell PD-L1 status (expressing
[≥1%, non-expressing [< 1%] or non-evaluable), HPV p-16 status (oropharyngeal HPV p-16 
positive versus oropharyngeal HPV p-16 negative or non-oropharyngeal) and prior chemotherapy 
status (Yes or No). 
The exact procedures for using the IVRS will be detailed in the IVRS manual.
4.5
Selection and Timing of Dose for Each Participant
The dosing schedule is detailed below in Table 4.5-1.
All participants will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay, reduction, retreatment, or discontinuation) will be based on specific 
laboratory and adverse event criteria, as described in Sections 4.5.2, 4.5.3, 4.5.4, and 4.5.5. 
Revised Protocol No.: 05
Date: 19-Dec-2019
52
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 4.5-1:
Dosing Schedule (Arm A 1 Cycle = 6 weeks, Arm B 1 Cycle = 3 weeks)
Week 1
± 3 Daysd
Week 2
± 3 Daysd
Week 3
± 3 Daysd
Week 4
± 3 Daysd
Week 5
± 3 Daysd
Week 6
± 3 Daysd
Arm A:a
Nivolumab 3 mg/kg 
Q2W
+ Ipilimumab 1 mg/kg 
Q6Wb
Cycle 1, Day 1
Nivolumab
+
Ipilimumab
Cycle 1, Day 15
Nivolumab
Cycle 1 Day 29
Nivolumab
Arm B: a
EXTREME Regimen
Cetuximab 
400 mg/m2 initial dose 
then 250 mg/m2 weekly
+
Cis or Carbo
+
5-FU 
Every 3 weeks for up to 
6 Cycles followed by 
250 mg/m2 Cetuximab 
weeklyc 1 hour infusions
Cycle 1, Day 1
Cetuximab
2 hr infusion
+
Cis or Carbo
1 hr infusion
+
5-FU (for 4 days, 
Day 1, 2, 3, 4)
Cycle 1,Day 8
Cetuximab
1 hr infusion
Cycle 1, Day 15
Cetuximab
1 hr infusion
Cycle 2, Day 1
Cetuximab
1 hr infusion
+ 
Cis or Carbo
1 hr infusion
+
5-FU (for 4 days, 
Day 1, 2, 3, 4)
Cycle 2, Day 8
Cetuximab
1 hr infusion
Cycle 2, Day 15
Cetuximab
1 hr infusion
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 
Arm B: Cetuximab is administered first followed by Cisplatin 100 mg/m2 or Carboplatin (AUC 5) starting at least 1 hour after the completion of the Cetuximab 
infusion. 5-FU dose is 1000 mg/m2 day 1 to day 4 (rounding of dosing for 5-FU is permitted per institutional standards).
b Continues until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent, 24 months maximum from the first study treatment, or 
study closure
c Cetuximab maintenance may be administered every 2 weeks, per local prescribing information.
d   ± 3 Days window applies to Arm A only
Revised Protocol No.: 05
Date: 19-Dec-2019
53
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
4.5.1
Dosing 
4.5.1.1
Nivolumab plus Ipilimumab (Arm A)
Participants randomized to Arm A will receive treatment with nivolumab 3 mg/kg every 2 weeks 
as a 30-minute infusion and ipilimumab 1 mg/kg every 6 weeks as a 30-minute infusion, starting 
on Day 1, until progression, unacceptable toxicity, withdrawal of consent, the study ends, or a 
maximum of 24 months from the first study treatment, whichever occurs first.
When nivolumab and ipilimumab are to be administered on the same day, separate infusion bags 
and filters must be used for each infusion. Nivolumab is to be administered first. The second 
infusion will always be ipilimumab and will start no sooner than 30 minutes after completion of 
the nivolumab infusion. Participants who require small volumes may infuse over < 30 minutes but 
no less than 20 minutes. The second infusion will always be the ipilimumab study treatment and 
will start after the infusion line has been flushed, filters changed and participant has been observed 
to ensure no infusion reaction has occurred.
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution. 
Dosing calculations should be based on the body weight. If the participant’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the prior dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. There will be no dose 
modifications allowed for both nivolumab and ipilimumab.
Participants may be dosed with nivolumab no less than 12 days from the previous dose. There are 
no premedications recommended for the first dose of study drug.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 4.5.8
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is to be administered as an IV infusion through 
a 0.2-micron to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. When the dose is based on 
patient weight (ie, mg/kg), nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein 
concentrations as low as 0.35 mg/mL. When the dose is fixed (eg, 240 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 120 
mL. Nivolumab infusion must be promptly followed by flush of diluent to clear the line. 
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or pharmacy reference sheet. Care must be taken to assure sterility of 
the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Revised Protocol No.: 05
Date: 19-Dec-2019
54
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Ipilimumab injection can be used for IV administration without dilution after transferring to a 
PVC, non-PVC/non-DEHP or glass container and is stable for 24 hours at 2-8°C or room 
temperature/room light (RT/RL). For ipilimumab storage instructions, refer to ipilimumab IB 
and/or pharmacy reference sheets.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Ipilimumab is to be administered as a 30 minute IV infusion and may be infused using a volumetric 
pump with a 0.2 to 1.2 micron low-protein binding in-line filter at the protocol-specified dose. The 
drug can be diluted with 0.9% normal saline or 5% Dextrose Injection to concentrations between 
1 mg/mL and 4 mg/mL. It is not to be administered as an IV push or bolus injections. Care must 
be taken to assure sterility of the prepared solutions, since the drug product does not contain any 
antimicrobial preservatives or bacteriostatic agents. At the end of the infusion, flush the line with 
a sufficient quantity of diluent.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending 
on how well the participant tolerates the treatment. For more details, see Section 4.5.2 (dose 
delays), 4.5.4 (resuming treatment), and 4.5.5 (discontinuation).
4.5.1.2
EXTREME Regimen (Arm B)
Participants randomized to Arm B will receive treatment with an initial dose of cetuximab 
400 mg/m2 (over 2 hours infusion) then weekly 250 mg/m2 (over 1 hour infusion) (or every 2 
weeks, per local prescribing information), cisplatin (100 mg/m2 IV on Day 1) or carboplatin (AUC 
5 IV on Day 1) and 5-FU (1000 mg/m2 continuous IV from Day 1 to Day 4) every 3 weeks per 
cycle for a maximum of 6 cycles. 
Cetuximab maintenance begins after 6 cycles of the cetuximab, cisplatin or carboplatin, and 5-FU 
are complete and is considered cetuximab alone at 250 mg/m2 weekly (1 hour infusion). 
Cetuximab maintenance can continue until progression, unacceptable toxicity, withdrawal of 
consent, or other reason (see Section 3.5 for complete list of reasons for discontinuing study 
medication). 
The dosing calculations should be based on the body weight. If the participant’s weight on the day 
of dosing differs by > 10% from the weight used to calculate the dose, the dose must be 
recalculated. Doses can be rounded per institutional standards. Participants may be dosed no less 
than 7 days between doses.
The dose of Carboplatin during chemotherapy will be calculated using the following formula
(Calvert equation):
•
Carboplatin total dose in mg = AUC x (glomerular filtration rate [GFR] +25)
NOTE: When calculating carboplatin dose, GFR should not exceed 125 mL/min. Thus, the 
maximum carboplatin dose for AUC of 5 will be 750 mg.
Revised Protocol No.: 05
Date: 19-Dec-2019
55
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Calculated creatinine clearance (CrCl) will be used to estimate the GFR. The modified Cockcroft-
Gault formula below should be used to calculate the creatinine clearance.
•
140 – age (years) x actual weight (kg) / 72 x Serum creatinine (mg/dL) (for females, multiply 
the result by 0.85)
The actual weight will be used for the calculation of Creatinine Clearance.
If one of the study drugs is discontinued, the other study drugs may be continued for the remainder 
of the cycles.
Premedications
For cetuximab: 
The recommended premedication is with an H1 antagonist (eg, 50mg Diphenhydramine) IV 
30-60 minutes prior to the first dose; for subsequent doses, premedication should be administered 
based upon clinical judgement and presence/severity of prior infusion reactions in accordance with 
local institutional standard practice.
For carboplatin or cisplatin:
The recommended premedication are dexamethasone (dosing according to local standard; an 
equivalent dose of another corticosteroids may be substituted) and a 5-HT3 receptor antagonist 
(type per investigator discretion and local standards of care) prior to each dose. Additional use of 
emetics premedication may be employed at the discretion of the investigator. Refer to the local 
product label for more detail.
For cisplatin: 
Hydration guidelines may be modified at the discretion of the treating physician provided adequate 
pre- and post-cisplatin hydration is achieved, and renal function remains adequate. One suggested 
regimen consists of administering cisplatin in 500 cc to 1000 cc of IV fluids following adequate 
hydration and the establishment of adequate urinary output. It is suggested the pre-cisplatin 
hydration consist of NS at 500 cc/hr x 1 liter and post-cisplatin hydration consist of 1/2 NS + 
10 meq KCl/liter + 1 gram magnesium sulfate/liter + 25 grams mannitol/liter at 500 cc/hr for at 
least one hour, followed by additional hydration at the discretion of the investigator.
It is suggested that patients receive antiemetic therapy, acute and delayed, including 
dexamethasone, 5-HT3 serotonin receptor antagonists. However, the specifics of the regimen are 
at the discretion of the treating physician, provided adequate control is achieved. One potential 
regimen consists of 20 mg of oral or IV dexamethasone and a high dose of oral or IV 5-HT3 
antagonist (such as 2 mg oral or 10 mg/kg IV granisetron, or 32 mg oral or IV ondansetron) on the 
day of cisplatin administration. Followed by additional anti-emetics consisting of oral 
dexamethasone and scheduled 5-HT3 serotonin receptor antagonists on days 2-5. For example, 
8 mg orally, twice daily for days 2 and 3, and then 4 mg orally, twice daily for days 4 and 5, 
especially if aprepitant is not given. 
Revised Protocol No.: 05
Date: 19-Dec-2019
56
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
All supportive measures consistent with optimal patient care should be used throughout the study. 
Recombinant erythropoietin or similar compound may be administered for symptomatic and/or 
progressive > Grade 2 anemia. Agents such as G-CSF may also be used at the investigators’ 
discretion.
The use of cisplatin or carboplatin is at the discretion on the investigator. Switch from cisplatin to 
carboplatin is allowed. If patients develop specific intolerable cisplatin-associated toxicities (see 
dose modifications, carboplatin substitution), such as neuropathy, renal impairment, ototoxicity, 
or nausea/vomiting, carboplatin at an AUC of 5 will be substituted for cisplatin.
Doses of cetuximab, cisplatin or carboplatin and 5-FU (EXTREME regimen) may be interrupted, 
delayed, reduced or discontinued depending on how well the participant tolerates the treatment. 
For more details, see Sections 4.5.2 (dose delays), 4.5.3 (dose reductions), 4.5.4 (resuming 
treatment), and 4.5.5 (discontinuation).
Participants should be carefully monitored for infusion reactions. If an acute infusion reaction is 
noted, participants should be managed according to Section 4.5.8.
4.5.2
Dose Delays
Recommendations for dose modifications for EXTREME regimen should be considered with local 
institutional standards.
4.5.2.1
Nivolumab and Ipilimumab (Arm A)
Dose delay criteria apply for all drug-related AEs. Treatment delay is up to 6 weeks for nivolumab 
and up to 12 weeks for ipilimumab from the last dose are allowable (any dose delays greater than 
these will require approval from the medical monitor). It is permissible in cases of a dose held due 
to AE to skip the dose in the cycle in order to bring the patient back on track with the next Cycle 
visit.
Tumor assessments for all participants should continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see section 4.5.5)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
•
Participants receiving ipilimumab in combination with nivolumab that have drug-related 
toxicities that meet the criteria for dose delay, should have both drugs (ipilimumab and 
nivolumab) delayed until retreatment criteria are met. (Exceptions apply to the retreatment 
criteria after dose delay of ipilimumab and nivolumab for Grade ≤ 3 amylase and lipase 
Revised Protocol No.: 05
Date: 19-Dec-2019
57
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis 
and that are attributed to ipilimumab alone.)
•
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently 
if clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
Rescheduling:
•
Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab dose 
is scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be 
synchronized with nivolumab dosing.
•
Ipilimumab 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 
and nivolumab, the dosing days of nivolumab and ipilimumab 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.
•
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then 
subsequent ipilimumab doses should be rescheduled to maintain the 6 week interval between 
consecutive ipilimumab doses. 
•
A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 4.5.5.2.
For both nivolumab and ipilimumab: A dose given more than 3 days after the intended dose date 
will be considered a dose delay. Longer delays may be allowed following discussion with the 
Study Director/Medical Monitor.
4.5.2.2
EXTREME Regimen
It is permissible in cases of a dose held due to AE to skip the dose in the cycle in order to bring 
the patient back on track with the next Cycle visit. Cetuximab, cisplatin, carboplatin, and 5-FU
should be delayed for the following:
•
Presence of febrile neutropenia or neutropenia < 1500 cells/mm3 for greater than one week 
despite the use of Growth factors
•
Any Grade ≥2 non-skin, drug-related adverse event, except for alopecia, fatigue or laboratory 
abnormalities
•
Any Grade 3 skin drug-related AE 
•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions:
−
Grade 3 lymphopenia does not require a dose delay
−
Delay if total bilirubin > 1 x ULN or if AST and/or ALT > 1.5 x ULN occurs concomitant 
with alkaline phosphatase > 2.5 x ULN 
•
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants skipping the dose of study medication. 
Subsequent dose reductions may be required as per Section 4.5.3.2. Participants may receive 
growth factors (including G-CSF and erythropoietin) at the discretion of the investigator.
Revised Protocol No.: 05
Date: 19-Dec-2019
58
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
A dose given more than 3 days after the intended dose date will be considered a dose delay. 
A maximum delay of 6 weeks between doses is allowed. Longer delays may be allowed following 
discussion with the Medical Monitor.
4.5.3
Dose Reductions
4.5.3.1
Nivolumab or Ipilimumab
There will be no dose reductions for nivolumab or ipilimumab.
4.5.3.2
EXTREME Regimen
This section includes information on dose modifications for cetuximab, cisplatin or carboplatin 
and 5-FU treatment related toxicities.
A maximum of 2 dose reductions per study drug are permitted; if additional reductions are 
required, that particular study drug must be discontinued. Once a dose has been decreased, it should 
remain reduced for all subsequent dosing unless dose is further reduced. No dose escalations will 
be allowed. If one of the study drugs is delayed due to drug related toxicities during a treatment 
cycle, the other study drugs in the regimen may be administered at the discretion of the 
investigator; when dosing is resumed, dose reduction should only be applied to the study drug that 
was withheld. 
Participants who discontinue one of the study drugs may, at the investigators discretion continue 
administration of the other study drugs in the regimen.
For Cetuximab: Dose modifications are permitted, as follows: 
Infusion Reactions:
•
Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC Grade 3 
infusion reactions.
•
Immediately and permanently discontinue cetuximab for serious infusion reactions, requiring 
medical intervention and/or hospitalization. 
•
See Section 4.5.8.2 for treatment of Cetuximab Infusion Reactions. 
Dermatologic Toxicity: Table 4.5.3.2-1 contains the recommended dose modifications for severe 
(CTCAE v4 Grade 3 or 4) acneiform rash.
Table 4.5.3.2-1:
Cetuximab Dose Modification Guidelines for Rash
Severe Acneiform 
Rash
Cetuximab
Outcome
Cetuximab Dose Modification
1st Occurrence
Delay infusion
1 to 2 weeks
Improvement
No Improvement
Continue at 250 mg/m2
Discontinue Cetuximab
2nd Occurrence
Delay infusion
1 to 2 weeks
Improvement
No Improvement
Continue at 200 mg/m2
Discontinue Cetuximab
3rd Occurrence
Delay infusion
Improvement
Continue at 150 mg/m2
Revised Protocol No.: 05
Date: 19-Dec-2019
59
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 4.5.3.2-1:
Cetuximab Dose Modification Guidelines for Rash
Severe Acneiform 
Rash
Cetuximab
Outcome
Cetuximab Dose Modification
1 to 2 weeks
No Improvement
Discontinue Cetuximab
4th Occurrence
Discontinue Cetuximab permanently
For Cisplatin, Carboplatin and 5-FU:
Recommendations for dose modifications for cisplatin, carboplatin and 5-FU should be considered 
with local institutional standards. The dose levels for 5-FU, cisplatin and carboplatin are listed in
Table 4.5.3.2-2:
Table 4.5.3.2-2:
Dose Levels for 5-FU, Cisplatin, and Carboplatin 
5-FU Dose
Cisplatin Dose
Carboplatin Dose
Starting Dose
1000 mg/m2
100 mg/m2
AUC 5.0
Dose Level -1
750 mg/m2
75 mg/m2
AUC 4.0
Dose Level -2
560 mg/m2
56 mg/m2
AUC 3.0
4.5.3.2.1
Recommended Dose Modifications for Hematologic Toxicity
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. Dose level adjustments are relative to that of the preceding administration, and are 
described in Table 4.5.3.2-3
Table 4.5.3.2-3:
5-FU, Cisplatin, and Carboplatin Dose Modifications for 
Hematologic Toxicitya
Drug Related Toxicity
5-FU
Cisplatin
Carboplatin
Neutrophils (ANC) < 500/mm3 lasting ≥5 days
Decrease by -1 
dose level
Decrease by -1 
dose level
Decrease by -1 
dose level
Febrile neutropenia (body temperature ≥38.5°C 
and ANC < 1,000/mm3)
Decrease by -1 
dose level
Decrease by -1 
dose level
Decrease by -1 
dose level
Platelets < 25,000/mm3
Decrease by -1 
dose level
Decrease by -1 
dose level
Decrease by -1 
dose level
Platelets < 50,000/mm3 with significant bleeding 
or requiring blood transfusion
Decrease by -1 
dose level
Decrease by -1 
dose level
Decrease by -1 
dose level
Grade 4 hemoglobin (< 6.5 g/100 mL)
Decrease by -1 
dose level
Decrease by -1 
dose level
Decrease by -1 
dose level
a If considered in the best interest of the participant, and consistent with local practice, investigators may decide to 
use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. 
Revised Protocol No.: 05
Date: 19-Dec-2019
60
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one 
of the cytotoxics
4.5.3.2.2
Recommended Dose Modifications for Non-hematologic Toxicity
Dose adjustments for non-hematologic toxicity during treatment are described in Table 4.5.3.2-4. 
All dose modifications should be made based on the worst grade toxicity per CTCAE v4.0. 
Table 4.5.3.2-4:
5-FU, Cisplatin, and Carboplatin Dose Modifications for Non-
hematologic Toxicitya
Drug Related Toxicity
5-FU
Cisplatin
Carboplatin
Nausea/vomiting ≥Grade 3 
despite optimal medical 
treatment
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Stomatitis ≥Grade 3
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Diarrhea ≥Grade 3 despite 
optimal medical treatment
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Neuropathy (sensory or motor), 
Grade 2 lasting > 7 days OR 
Grade 3 lasting < 7 days
No modification
Decrease to -2 dose 
level
No modification
Neuropathy Grade 4 (sensory 
or motor)
No modification
Discontinue
No modification
Nephrotoxicity (Creatinine 
Clearance 50-59mL/min or 
Grade 3 Creatinine)
No modification
Decrease to -2 dose 
level or according to 
local practice
No modification
Total bilirubin > 1.5 x ULN
50% of previous dose
No modification
No modification
Total bilirubin > 2.5 x ULN
25% of previous dose
No modification
No modification
Total bilirubin > 4.0 x ULN
Discontinue
No modification
No modification
Other Grade ≥3 toxicities 
(except fatigue and transient 
arthralgia and myalgia)
Decrease by -1 dose 
level
Decrease by -1 dose 
level
Decrease by -1 dose 
level
a If considered in the best interest of the participant, and consistent with local practice, investigators may decide to 
use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. 
Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one 
of the cytotoxics.
4.5.4
Criteria to Resume Dosing
4.5.4.1
Criteria to Resume Nivolumab Dosing (Arm A)
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
Revised Protocol No.: 05
Date: 19-Dec-2019
61
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants 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 
≤10 mg/day.
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor (or
designee). Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
4.5.4.2
Criteria to Resume Ipilimumab Dosing (Arm A)
Participants may resume treatment with nivolumab and ipilimumab when drug-related AE(s) 
resolve(s) to Grade 1 or baseline value, with the following exceptions: 
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants 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.
•
Participants 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.
•
Participants 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 
≤10 mg/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 which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 4.5.5.2.
•
Ipilimumab may not be resumed sooner than 6 weeks (± 3 days) after the prior ipilimumab 
dose.
•
In general, participants who meet criteria to resume ipilimumab will also have met criteria to 
resume nivolumab, so it should be feasible to synchronize dosing of both drugs when resuming 
Revised Protocol No.: 05
Date: 19-Dec-2019
62
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
ipilimumab. In order to facilitate this, the dosing days of nivolumab and ipilimumab may be
adjusted within the permitted ± 3 day window, as long as consecutive nivolumab doses are 
given at least 12 days apart.
•
One exception to note is when ipilimumab 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 and not related to nivolumab, nivolumab may be 
resumed when the amylase or lipase abnormality resolves to Grade < 3 but ipilimumab may 
only be resumed when the amylase or lipase abnormality resolves to Grade 1 or baseline. 
Investigator attribution of this toxicity to the ipilimumab dosing must be clearly noted in the 
participant’s medical chart. The BMS Medical Monitor should be consulted prior to resuming 
nivolumab in such participants.
4.5.4.3
Criteria to Resume Chemotherapy Dosing (Arm B)
Participants may resume treatment with study drug when the drug-related AE(s) resolved or
returned to baseline value, with the following exceptions below.
•
Participants may resume treatment in the presence of ANC ≥1500 / mm3 and Platelets ≥100 
x 103 /μL
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
•
Participants 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.
•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.5.5.3) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed.
•
For Cetuximab:
−
Pulmonary Toxicity: Permanently discontinue for confirmed interstitial lung disease. 
−
Skin Reaction: If a participant experiences a Grade 3 skin reaction, cetuximab therapy is 
to be withheld for up to 2 consecutive infusions; the dose level should not be changed. The 
investigator can also consider concomitant treatment with topical and/or oral antibiotics; 
topical corticosteroids are not recommended. If the toxicity resolves to Grade 2 or less 
within 2 weeks, treatment may resume. For repeat occurrences of a Grade 3 skin reaction, 
see Table 4.5.3.2-1 above. 
If the criteria to resume treatment are met, the participant should restart treatment at the next 
scheduled time-point per protocol. If treatment is delayed > 6 weeks, the participant must be 
permanently discontinued from study therapy, except as specified in Section 4.5.5.3.
Revised Protocol No.: 05
Date: 19-Dec-2019
63
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
4.5.5
Treatment Discontinuation Criteria
For all participants, 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 participants who discontinue study treatment or 
who have clinically progressed without radiographic progression, should continue as per protocol 
until radiographic progression per RECIST 1.1 is determined.
4.5.5.1
Nivolumab Dose Discontinuation (Arm A)
Treatment with nivolumab should be permanently discontinued for any of the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study 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
Revised Protocol No.: 05
Date: 19-Dec-2019
64
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued 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 6 weeks 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. 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 is discontinued. 
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to both or one study drug, the participant should discontinue both nivolumab 
and ipilimumab and be taken off the treatment phase of the study. Continuation of ipilimumab 
after discontinuation of nivolumab is not allowed on study.
4.5.5.2
Ipilimumab Dose Discontinuation (Arm A)
Ipilimumab should 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 to topical 
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);
Revised Protocol No.: 05
Date: 19-Dec-2019
65
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation:
−
AST or ALT > 8x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
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. 
−
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 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 participant 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.
•
Dosing delays resulting in no ipilimumab 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 participant 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 participant with continued 
ipilimumab dosing
The assessment for discontinuation of ipilimumab 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 but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to both or one study drug, the participant should discontinue both nivolumab 
and ipilimumab and be taken off the treatment phase of the study.
Revised Protocol No.: 05
Date: 19-Dec-2019
66
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
4.5.5.3
EXTREME Regimen Dose Discontinuation (Arm B)
Treatment should be permanently discontinued for the following:
•
Any drug-related Grade 4 toxicity including laboratory abnormalities the subject will be 
discontinued from the relevant study drug, with the following exceptions:
−
Isolated Grade 4 electrolyte abnormalities not associated with clinical sequelae and are 
adequately managed and corrected within 72 hours of onset.
−
Grade 4 neutropenia or lymphopenia ≤7 days 
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions:
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation, 
except for the following scenarios:
♦Grade 3 drug-related thrombocytopenia associated with bleeding 
♦Any of the following drug-related liver function test (LFT) abnormalities: 
o
AST or ALT > 8 x ULN
o
Total bilirubin > 5 x ULN
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
♦Calculated creatinine decreases to < 60 mL/min based on Cockcroft Gault formula on 
participants receiving cisplatin. Switch to carboplatin is allowed at the discretion of 
investigator for the remaining cycles. See re-treatment criteria section 4.5.4.3
•
Any dosing delay lasting > 6 weeks, with the following exceptions: 
−
If local standards allow dosing delays > 6 weeks for drug-related AEs, contact the BMS 
Medical Monitor prior to re-initiating treatment.
−
Dosing delays > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS Medical Monitor. Prior to reinitiating treatment in a participant with 
a dosing delay lasting > 6 weeks, the BMS Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued treatment.
Participants who discontinue one of the study drugs in Arm B may, at the investigators discretion,
continue administration of the other study drugs. For example, if 5-FU is discontinued, cetuximab 
and platinum agent may be continued at the intended dose and schedule.
4.5.6
Treatment Beyond Disease Progression (Arm A only)
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.
Participants will be permitted to continue on nivolumab combined with ipilimumab for treatment 
beyond initial RECIST 1.1 defined PD up to a total of 24 months total treatment duration from the 
start of study treatment as long as they meet the following criteria:
Revised Protocol No.: 05
Date: 19-Dec-2019
67
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Investigator-assessed clinical benefit and no rapid disease progression
•
Participant is tolerating study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional nivolumab and 
ipilimumab treatment, using an ICF describing any reasonably 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. A follow-up scan 
should be performed within six (6) weeks ± 1 week of original PD to determine whether there has 
been a decrease in the tumor size, or continued progression of disease. Subsequent scans should 
be performed every six (6) weeks ± 1 week until further progression is determined. In the event of 
unscheduled scans, efforts should be made to get subsequent scan back on the every six (6) weeks 
± 1 week until further progression is determined.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Time and Events Schedule in Table 5.1-2.
For the participants 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 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 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
4.5.7
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
Revised Protocol No.: 05
Date: 19-Dec-2019
68
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures, as 
well as in Appendix 2.
4.5.8
Treatment of Infusion Reactions
4.5.8.1
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 NCI CTCAE (Version 4.0) 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory 
drugs, 
narcotics, 
corticosteroids, 
bronchodilators, 
IV 
fluids]; 
prophylactic medications indicated for ≤24 hours)
•
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the 
participant
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant
closely. If symptoms recur, then no further nivolumab or ipilimumab will be administered at 
Revised Protocol No.: 05
Date: 19-Dec-2019
69
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
participant until resolution of symptoms. The amount of study drug infused must be recorded 
on the electronic case report form (eCRF).
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab or ipilimumab 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. Begin an IV infusion of normal 
saline and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab or 
ipilimumab will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant until 
recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.5.8.2
Treatment of Cetuximab Infusion Reactions
Treatment recommendations are provided below and may be modified based on local institutional 
standards, package inserts, and guidelines as appropriate.
Monitor participants for 1 hour following cetuximab infusions in a setting with resuscitation 
equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, 
intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of 
the event in participants requiring treatment for infusion reactions. Immediately and permanently 
discontinue cetuximab in participants with serious infusion reactions. 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not 
indicated):
Remain at bedside and monitor participant until recovery from symptoms. Decrease the cetuximab 
infusion rate by 50% and monitor closely for any worsening. The total infusion time for cetuximab 
should not exceed 4 hours.
Revised Protocol No.: 05
Date: 19-Dec-2019
70
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
≤24 hours):
Stop cetuximab infusion, administer bronchodilators, oxygen, etc. as medically indicated, and 
resume infusion at 50% of previous rate once allergic/hypersensitivity reaction has resolved or 
decreased to Grade 1 in severity, and monitor closely for any worsening. 
For Grade 3 or Grade 4 Symptoms (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; presser or ventilatory 
support indicated)
Immediately discontinue infusion of cetuximab and disconnect participant from tubing. Begin an 
IV infusion of normal saline, and treat the participant as follows. Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of 
a 1:10,000 solution and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Participants have to be withdrawn immediately from the treatment and 
must not receive any further cetuximab treatment. Participant should be monitored until the 
investigator is comfortable that the symptoms will not recur. Cetuximab will be permanently 
discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. Remain 
at bedside and monitor participant until recovery from symptoms. In the case of late-occurring 
hypersensitivity symptoms (eg, appearance of a localized or generalized pruritus within 1 week 
after treatment), symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids).
Once the cetuximab infusion rate has been decreased due to an allergic/hypersensitivity reaction, 
it will remain decreased for all subsequent infusions. If the participant has a second 
allergic/hypersensitivity reaction with the slower infusion rate, the infusion should be stopped and 
cetuximab treatment should be discontinued. If there is any question as to whether an observed 
reaction is an allergic/hypersensitivity reaction of Grade 1 - 4, the sponsor should be contacted 
immediately to discuss and grade the reaction.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Revised Protocol No.: 05
Date: 19-Dec-2019
71
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
Arrangements for the return of study drug will be made by the responsible Study Monitor.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not Applicable
Revised Protocol No.: 05
Date: 19-Dec-2019
72
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209651)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Original IC before start of screening procedures for protocol participation;
Study allows for re-enrollment of a participant that has discontinued the study as a pre-
treatment failure. If re-enrolled, the participant must be re-consented and assigned a new 
participant 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
Tumor sample prior to therapy is mandatory for PD-L1 testing (sample to be shipped to 
Central Lab) and for HPV p-16 testing for participants with oropharyngeal CA (sample 
either tested locally or shipped to Central Lab). 
If a recent tumor sample (obtained within 6 months 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 2 full block or a minimum of 25 slides, obtained from core 
biopsy, punch biopsy, excisional biopsy or surgical specimen). Contact the Study Director if 
sufficient tissue is not available. 
Screening/Baseline Tumor Assessment
X
Must be performed within 28 days prior to first dose.
CT with IV contrast of Neck, Chest, Abdomen, Pelvis (CAP) and all other known sites of 
disease should be imaged during the screening period.
Gadolinium contrast enhanced MRI of the neck and CAP may be obtained if CT iodinated 
contrast is contraindicated.
MRI of brain without and with Gadolinium is required for ALL participants in screening to 
rule out brain metastases. Note: MRI of the brain is preferred but CT scan is acceptable.
CT of the head (with and without contrast) to be performed if MRI is contraindicated or 
unavailable. 
TAs following RECIST 1.1 criteria.
Revised Protocol No.: 05
Date: 19-Dec-2019
73
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209651)
Procedure
Screening
Visit
Notes
Prior Medications
X
Dates and doses of platinum-based therapy plus prior medications subjects received to treat 
cancer.
ECOG Performance Status
X
During screening; within 28 days prior to the first dose. 
Safety Assessments
Vital Signs
X
Including BP, HR, and temperature. Obtain vital signs at the screening visit and within 72 
hours prior to first dose.
Physical Measurements/Physical 
Examination
X
Height and Weight. BSA. Within 28 days prior to first dose
12 lead ECG
12 Lead ECG Required at Screening, See Section 5.3.4
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Concomitant Medication Collection
X
Within 14 days prior to first dose
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 randomization and again within 72 hours 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.
Participants 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.
Revised Protocol No.: 05
Date: 19-Dec-2019
74
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209651)
Procedure
Screening
Visit
Notes
Biomarker Assessments
Tumor Biopsy sample: 
X
See Table 5.6-1 and above. 
Study Drug
Enrollment In IVRS
X
Revised Protocol No.: 05
Date: 19-Dec-2019
75
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (All Treatments) CA209651 (All Cohorts)
Procedure
During Treatment
Visit a,b
Notes
Safety Assessments
Targeted Physical Examination
X
Vital Signs
X
Including BP, HR, and temperature prior to dosing for all treatment Arms. 
Physical Measurements (including 
performance status)
X
Weight and ECOG status within 72 hours prior to each dose. The dosing calculations 
should be based on the body weight. If the participant’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
Laboratory Tests
X
Arm A: On-study local laboratory assessments should be done within 72 hours prior to 
each dose. For Arm B: Within 72 hours prior to dosing of Day 1 of each Cycle, and every 3 
weeks or more frequently as clinically indicated for weekly cetuximab dosing visits).
CBC w/differential, (albumin if clinically indicated), LFTs (ALT, AST, total bilirubin, 
alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, 
phosphate, glucose, amylase, lipase, TSH with reflexive Free T4, Free T3 (ONLY if TSH 
is abnormal).
(Thyroid Function Testing to be evaluated every 6 weeks).
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours prior to first dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule.
Concomitant Medications 
X
Efficacy Assessments
Tumor Assessment
X
• Tumor assessments should occur every 6 weeks (starting from first dose ± 1 week) for the 
first 48 weeks, then every 12 weeks (± 1 week) until disease progression or treatment is 
discontinued, whichever occurs later. If treatment beyond progression is approved, then 
scanning should continue every 6 weeks ± 1 week until further progression is determined.
• CT or MRI of the neck, chest, abdomen, pelvis and all known sites of disease. Use same 
imaging method as was used at screening/baseline.
Revised Protocol No.: 05
Date: 19-Dec-2019
76
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (All Treatments) CA209651 (All Cohorts)
Procedure
During Treatment
Visit a,b
Notes
• MRI of the brain (without AND with Gadolinium contrast) is required for participants 
with a history of brain metastasis. Note: MRI of the brain is preferred but CT scan is a
participant acceptable.
Surveillance scans should be performed approximately every 12 weeks, or sooner if
clinically indicated. (CT of the head without AND with contrast may be performed if MRI 
is contraindicated).
Outcomes Research Assessment 
FACT-H&N
X
Assessed following randomization but before treatment every 6 weeks (± 1 week)
regardless of dosing.
Can be collected over the phone at regularly scheduled time if needed.
EQ-5D-3L
X
Assessed following randomization but before treatment every 6 weeks (± 1 week)
regardless of dosing.
Can be collected over the phone at regularly scheduled time if needed.
Health care resource utilization questions
X
To be completed by the site in CRF
Pharmacokinetic Assessments
PK samples (Arm A Only)
X
See Table 5.5-1.
Immunogenicity blood samples
X
See Table 5.5-1.
Biomarker Assessments
See Table 5.6-1.
Serum sample: Soluble Biomarkers
X
See Table 5.6-1. 
Whole Blood sample: 
SNP (pre dose D1 only) & Gene 
expression
X
See Table 5.6-1
Plasma samples
X
See Table 5.6-1
Tumor Biopsy Sample: 
X
Tumor biopsy specimens will be obtained from consenting participants within all treatment 
arms at Week 7 and once disease progression has been documented (See Table 5.6-1). 
Biopsy should be excisional, incisional or core needle (fine needle aspiration is 
insufficient) and submitted to central lab see also Table 5.6-1
Revised Protocol No.: 05
Date: 19-Dec-2019
77
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-2:
On Treatment Procedural Outline (All Treatments) CA209651 (All Cohorts)
Procedure
During Treatment
Visit a,b
Notes
Saliva Sample: Oral microbiome
X
See Table 5.6-1
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Dispense Study Drug
X
Within 3 days from randomization, the participant must receive the first dose of study 
medication. 
a For Ipilimumab/Nivolumab Arm: Visits occur every 2 weeks
b For EXTREME regimen Arm: Visits occur every 3 weeks
Revised Protocol No.: 05
Date: 19-Dec-2019
78
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-3:
Follow-Up Period (all treatment groups)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-Up 
Visits b
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 period only 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, phosphate, glucose, amylase, lipase. TSH 
(+ reflex Free T4 and Free T3 collected ONLY if TSH is abnormal).
To be done at FU1, to be repeated at FU2, if study related toxicity 
persists.
Pregnancy Test (WOCBP only)
X
Serum or urine.
Efficacy Assessments
Tumor Assessment
X
X
Only for participants without progression.
- Tumor assessments should occur every 6 weeks (± 1 week) for the first 
48 weeks, then every 12 weeks (± 1 week) until disease progression or 
treatment is discontinued (whichever occurs later).
- CT or MRI of the neck, chest, abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at screening/baseline.
- MRI of the brain (without AND with Gadolinium contrast) is required 
for participants with a history of brain metastasis. Note: MRI of the 
brain is preferred but CT scan is acceptable.
Surveillance scans should be performed approximately every 12 weeks, 
or sooner if clinically indicated. (CT of the head without AND with 
contrast may be performed if MRI is contraindicated).
Outcomes Research Assessment 
FACT-H&N
X
Can be collected over the phone.
FHNSI-10
X
Can be collected over the phone.
Revised Protocol No.: 05
Date: 19-Dec-2019
79
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.1-3:
Follow-Up Period (all treatment groups)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-Up 
Visits b
Notes
EQ-5D-3L
X
X
Can be collected over the phone.
Health care resource utilization 
questions
X
To be completed by the site in CRF
Participant 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 visits 1 (FU1) and 2 (FU2) are in clinic visits. Follow-up visit 1 (FU1) = 30 days from the last dose ± 7 days or coincides with the date of 
discontinuation (± 7 days) if date of discontinuation is greater than 35 days after last dose, Follow-up visit 2 (FU2) = 90 days (± 7 days) from Follow-up Visit 1
b Survival Follow Up Visits may be conducted in clinic or via telephone contact: Every 3 Months (± 7 days) from FU2
Revised Protocol No.: 05
Date: 19-Dec-2019
80
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed, as it represents the participant’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 participants. 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 Interactive Voice Response System (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 randomization and 
are to include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, phosphate, LDH, glucose, amylase, 
lipase, Thyroid function tests includes TSH, free T4, and free 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.: 05
Date: 19-Dec-2019
81
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the Day 1 
of first dose and then every 4 weeks ± 1 week regardless of dosing cycle
For Arm A: local laboratory assessments should be done within 72 hours prior to each dose.
For Arm B: to be performed within 72 hours prior to dosing of Day 1 of each Cycle, every cycle 
(3 weeks) or more frequently as clinically indicated for weekly cetuximab dosing visits, including 
CBC w/differential, (Albumin if clinically indicated), LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, phosphate, glucose, 
amylase, lipase, TSH with reflexive Free T4, Free T3 (Thyroid Function Testing to be evaluated 
every 6 weeks). Free T4 and Free T3 assessment will be done only if TSH is abnormal
Participants will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Table 5.1-3),
toxicity assessments should be done in person. Once participants reach the survival follow-up 
phase either in person or documented telephone calls to assess the participant’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 required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
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 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 24 hours 
prior to Day 1 of first dose and then every 4 weeks (± 1 week) during the treatment period and first 
Revised Protocol No.: 05
Date: 19-Dec-2019
82
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
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 
cannot be obtained within the standard 24 hour window. This is participant to medical monitor 
approval.
5.3.3
Thyroid Function Testing
Local thyroid function testing will be performed as outlined in Section 5.1.
At Screening, thyroid function testing is 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 participants who have met the eligibility criteria are required to have a 12-lead ECG performed 
during 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 Time and Events tables in 
Section 5.1 and according to RECIST 1.1 Appendix 3.
Sites will be trained prior to scanning the first study participant. Image acquisition guidelines and 
submission process will be outlined in the study Imaging Manual to be provided by the radiology 
vendor. Images will be submitted to an imaging third-party radiology vendor for central review as 
they are performed on an ongoing basis.
Screening (baseline) tumor assessments are to be performed prior to first dose. In addition to the 
brain/head, neck, chest, abdomen, pelvis, all known sites of disease should be assessed at baseline. 
Subsequent assessments should include brain (only if brain metastases are detected at screening, 
or if clinically indicated during the course of the trial), 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 of the brain without and with Gadolinium contrast, including base of skull 
involvement, is preferred but CT scan is acceptable for all participants, in order to rule out active 
metastases. A CT of the head (with and without contrast) to be performed if MRI is contraindicated 
or unavailable. 
Radiographic tumor response will be assessed at Week 6 (± 1 week) from first dose date, then 
every 6 weeks (± 1 week) for the first 12 months (until week 48) and every 12 weeks (± 1 week) 
thereafter, until disease progression is documented or treatment is discontinued (whichever occurs 
later). Previously treated CNS metastases are not considered measurable lesions for purposes of 
RECIST determined response. MRI of the brain (without AND with Gadolinium contrast) is 
required for participants with a history of brain metastasis. Surveillance scans should be performed 
approximately every 12 weeks, or sooner if clinically indicated (CT of the head without AND with 
contrast may be performed if MRI is contraindicated). 
Revised Protocol No.: 05
Date: 19-Dec-2019
83
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
CT with PO and IV contrast or contrast-enhanced MRI are the preferred imaging modalities for 
assessing radiographic tumor response. If a participant 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 suffice. Should a participant have a contraindication for CT IV contrast, contrast-
enhanced MRI of the head, neck, chest, abdomen and pelvis may be obtained. Every attempt 
should be made to image each participant using the same image modality, acquisition protocol,
and same scanner for all imaging time points.
Use of CT component of a PET/CT scanner: Combined modality scanning such as with 
FDG-PET/CT is increasingly used in clinical care, and is a modality/technology that is in rapid 
evolution; therefore, the recommendations outlined here may change rather quickly with time. At 
present, low dose or attenuation correction CT portions of a combined 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 are the 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 participants 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 off-treatment disease progression, the site must complete the 
tumor assessment pages in TAO documenting disease progression and submit a fresh biopsy 
sample of metastatic site to Central Lab for biomarker analysis as specified in Section 5.6.3.
In addition, participants receiving nivolumab and ipilimumab treatment beyond progression must 
continue tumor assessments until such treatment has been discontinued.
Refer to the study Imaging Manual for further guidance on obtaining and submitting study related 
scans.
Revised Protocol No.: 05
Date: 19-Dec-2019
84
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
5.4.1
Primary Efficacy Assessment
The primary endpoints are OS in participants with PD-L1 CPS ≥ 20 and all randomized
participants. See Section 8.3.1 for the definitions of OS. Every effort will be made to collect 
survival data on all participants including participants 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 participant is not reported, all dates in this study representing a date of 
participant contact will be used in determination of the participant’s last known date alive.
5.4.2
Secondary Efficacy Assessment
Secondary efficacy endpoints include OS in selected subgroups and ORR in participants with PD-
L1 CPS ≥20 and in all randomized participants. See Section 8.3.2 for the definition of ORR. All 
randomized participants will be monitored by radiographic assessment every 6 weeks (± 1 week) 
for the first 12 months (until Week 48) and every 12 weeks (± 1 week) until progression or 
treatment is discontinued, whichever occurs later, [beginning from the first on-study assessment 
on Week 6 (± 1 week)], to determine changes in tumor size. RECIST 1.1 criteria will be used for 
the assessment.
The assessments of progression from the blinded independent central review (BICR) will be used 
for the principal analyses of PFS.
The assessments of best overall response from the blinded independent central review (BICR) will 
be used for the principal analyses of ORR. For details regarding response criteria using RECIST 
1.1 refer to Appendix 3.
5.5
Pharmacokinetic Assessments
Samples for PK and immunogenicity assessments will be collected for all participants receiving 
nivolumab and ipilimumab as described in Table 5.5-1. All time points are relative to the start of 
study drug administration. All on-treatment time points are intended to align with days on which 
study drug is administered, if dosing occurs on a different day, the PK and immunogenicity 
sampling should be adjusted accordingly. Further details of sample collection, processing, and 
shipment will be provided in the laboratory procedures manual.
Pharmacokinetic and Immunogenicity Collection and Processing 
A detailed schedule of PK and immunogenicity evaluations is provided in Table 5.5-1. PK samples 
will be analyzed for nivolumab/ipilimumab by a validated ligand binding assay. Immunogenicity 
samples will be analyzed for anti-nivolumab antibodies / anti-ipilimumab antibodies by a validated 
immunogenicity assay; samples may also be analyzed for neutralizing antibodies by a validated 
method. Serum samples may be analyzed by an exploratory method that measures anti-drug 
antibodies for technology exploration purposes; exploratory results will not be reported. Serum 
samples designated for PK or biomarker assessments may also be used for immunogenicity 
analysis if required (eg, insufficient volume for complete immunogenicity assessment or to follow 
up on suspected immunogenicity related AE).
Revised Protocol No.: 05
Date: 19-Dec-2019
85
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Table 5.5-1:
Pharmacokinetic (PK) and Immunogenicity Sample Collections for Nivolumab and Ipilimumab (Arm 
A)
Study Daya
(1 Cycle = 6 weeks)
Event 
(Relative To 
Dosing)
Hour
Time 
(Relative To 
Dosing)
Hour: Min
Pharmacokinetic 
Blood Sample 
for Nivolumab
Immunogenicity 
Blood Sample for 
Nivolumab
Pharmacokinetic 
Blood Sample for 
Ipilimumab
Immunogenicity 
Blood Sample 
for Ipilimumab
C1D1
(Nivolumab dose 1 & 
Ipilimumab dose 1)
Predoseb
00:00
X
X
X
X
C1D1
0.5 (EOIc
See footnote c
X
X
C1D15
(Nivolumab dose 2)
Predoseb
00:00
X
X
X
X
C2D15
(Nivolumab dose 5)
Predoseb
00:00
X
X
X
X
C4D15
(Nivolumab dose 11) 
Predoseb
00:00
X
X
X
X
D15 of every 4th cycle after 
C4D15 until end of study 
treatment or maximum up to 
two years of treatment
Predoseb
00:00
X
X
X
X
a If ipilimumab is discontinued and nivolumab continues, ipilimumab PK and ADA should be collected only for the next 2 time points (corresponding to nivolumab 
sample collection) according to the PK table.
b Predose samples should be taken prior to the start of the first drug (preferably within 30 minutes). If it is known that a dose is going to be delayed, then the 
predose sample should be collected just prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an additional 
predose sample should not be collected.
c EOI: End of Infusion. This sample should be collected at the end of infusion of the second drug administered. If the end of infusion is delayed to beyond the 
nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI samples may not be collected from the same IV access as drug 
was administered.
Revised Protocol No.: 05
Date: 19-Dec-2019
86
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
5.6
Biomarker Assessments
A variety of factors that could potentially predict clinical response to nivolumab in combination 
with ipilimumab will be investigated in peripheral blood and in tumor specimens taken from all 
participants prior to- and on-treatment and as outlined in Table 5.6-1. Data from these 
investigations will be evaluated for associations with response, survival (OS, PFS) and/or safety 
(adverse event) data. In addition, analyses of markers between the treatment arms will provide the 
necessary data to identify and validate biomarkers with predictive vs. prognostic value. All 
samples collected may also be used for future exploratory analyses (unless restricted by local 
requirements) to assess biomarkers associated with SCCHN or immunotherapy treatment. 
Complete instructions on the collection, processing, handling and shipment of all samples 
described herein will be provided in a separate procedure manual.
Table 5.6-1:
Biomarker Sample Collection Schedule (Arms A and B): 
Study Day
Seruma
Plasmaa
Whole Blood
Tumorb,c
Saliva
Soluble 
Biomarkers
ctDNA
Gene 
expression
SNP
Biopsy
Oral 
microbiome
Screening
X
D1
X
X
X
X (pre-dose)
X (pre-dose) 
W3,D1d
X
X
X
W7,D1d
X
X
X
Xe
X
W15,D1d
X
X
X
Progressione
Xf
Xf
Xf
Xf
a Plasma, serum and whole blood should be collected on all patients on study, including active and newly enrolled 
patients.
b All tumor samples may be obtained ± 7 days of the indicated time.
c Tumor sample prior to therapy is mandatory. If a recent tumor sample (obtained within 6 months of enrollment) is 
not available at screening, a fresh biopsy will be taken at any point prior to randomization obtained from core 
biopsy, punch biopsy, excisional biopsy or surgical specimen
d The Biomarker week collections correspond to the following Cycle visits: W3D1 corresponds to C1D15 for 
treatment Arms A and B (in cases of no dose delays) W7D1 corresponds to C2D1 for Arm A and C3D1 for Arm B 
(in cases of no dose delays). W15D1 corresponds to C3D15 for Arm A and C5D15 for Arm B (in cases of no dose 
delays). Blood samples can follow Cycle visits in cases of dose delays, however the Week 7 biopsy should be 
collected at week 7 irrespective of dosing delays.
e Week 7 (± 7days) Biopsy is optional. If progression occurs within 6 months from first dose and a week 7 biopsy 
was done, then biopsy samples upon progression (± 7 days) are optional. If progression occurs at greater than 6 
months from first dose then progression biopsy is required. On study biopsies should be done if deemed medically 
safe per investigators judgement.
f For samples at progression, the timing of this collection should be after the participant has come off study medication 
and before they have started new therapy (subsequent anti-cancer therapy). For participants that have consented to 
be treated beyond progression, it is better to wait to perform the biopsy after further progression of the disease, after 
they have come off study therapy and before they have started new therapy (subsequent anti-cancer therapy). 
Revised Protocol No.: 05
Date: 19-Dec-2019
87
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
5.6.1
Exploratory Serum Biomarkers
Blood samples for exploratory serum biomarker analyses will be drawn at the time points indicated 
in Table 5.6-1. Samples may be assessed by ELISA, seromics and/or other relevant 
multiplex-based protein assay methods for immune or SCCHN-related factors that may predict 
benefit or correlate with efficacy to study treatment. These factors may include levels of soluble 
PD-L1, anti-tumor antibodies, cytokines, chemokines, inflammatory factors and/or microRNAs 
(such as, but not limited to, soluble CD25, soluble PD-1, soluble LAG-3, and CXCL-9).
5.6.2
Circulating Tumor DNA in Plasma
Circulating tumor DNA (ctDNA) may be extracted to assess tumor mutation burden or other 
mutations in the blood. Additional use of these data may include correlative analyses aimed at 
identifying genotypic associations with clinically-relevant biomarkers identified by other 
methodologies described in this section. 
5.6.3
Tumor Tissue Specimens
Screening Biopsies:
The screening tumor biopsy tissue needs to be shipped and to the central laboratory prior to 
randomization for tumor cell PD-L1 and HPV p-16 testing (if needed). Two FFPE blocks or 25 
slides should be submitted. Contact the Study Director if sufficient tissue is not available. In the
event the tumor sample is deemed unevaluable due to insufficient tumor content, the medical 
monitor may request the site to send another specimen, if available. The presence of either an 
archival or a fresh biopsy specimen is an inclusion criterion and hence a prerequisite for full 
eligibility of a participant.
An archived biopsy prior to therapy is acceptable if the fresh biopsy cannot be obtained and if the 
archived tissue meets the defined criteria as stated below.
•
Obtained in the metastatic setting or from an unresectable site of disease obtained within 
6 months of enrollment
•
An archived biopsy (block or slides) must contain tumor tissue.
•
The patient has not received systemic therapy subsequent to archived biopsy and prior to 
screening.
•
If an archived block is not available, 25 slides containing tumor are available for exploratory 
use.
Biopsy at 7 weeks:
An on-treatment tumor biopsy to be collected at Week 7 (± 7 days) is optional but strongly 
encouraged. This time point coincides with the completion of the first full cycle of nivolumab + 
ipilimumab treatment combination and also with the first on-treatment tumor assessment. 
Pharmacodynamic changes within candidate biomarkers (see Section 5.6.1) within the tumor and 
tumor microenvironment may inform on mechanism(s) associated with rapid progression (ie,
intrinsic resistance) as well as inform on mechanism(s) associated with disease control. Those 
Revised Protocol No.: 05
Date: 19-Dec-2019
88
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
biomarkers will be evaluated for their potential utility as early response/non-response prediction 
biomarkers.
Biopsy at time of Progression:
Changes in biomarkers (including but not limited to genomic alterations, gene expression, and 
protein expression) in the tumor biopsy collected at progression will be evaluated for their utility 
in informing the mechanism(s) underlying acquired resistance to nivolumab + ipilimumab 
combination treatment. For the biopsy at progression, the biopsy should be after the participant
has come off study medication and before they have started new therapy (subsequent anti-cancer 
therapy).
Tumor sample collection details
A minimum of 2 formalin-fixed paraffin embedded (FFPE) tumor tissue block (preferred) OR a 
minimum of 25 unstained sections are required for assessment of tumor cell PD-L1 status and 
other biomarker evaluations. Specimens should contain a minimum of 100 evaluable tumor cells.
Tissue Biomarkers:
Tumor samples may be assessed for global gene expression, global protein expression, and/or for 
tumor mutation burden using a variety of methodologies inclusive of, but not limited to RNA seq 
(or similar), mass-spectrometry, whole exome sequencing and fluorescent in-situ hybridization 
(FISH).
Immunohistochemistry (IHC) may be used to assess the number and composition of immune 
infiltrates in order to define the immune cell subsets present within formalin-fixed, 
paraffin-embedded (FFPE) tumor tissue before and after exposure to therapy. These IHC analyses 
will include, but not necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, 
PD-L1, and PD-L2. HLA and antigen loss variants may be investigated in tumor tissues, focused 
on HLA class I, antigen processing machinery (APM) components, and expression of common 
SCCHN tumor antigens including but not limited to HPV oncogenes, EGFR, p53, etc. In cases 
where fresh tumor is available prior to therapy and/or on treatment, separation and isolation of TIL 
from tumor and stromal cells may be performed. Isolated TIL may be utilized to assess the gene 
expression, phenotype, and function of immune cells.
The investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the procedure and find it acceptable. Biopsies may be done with local anesthesia 
or conscious sedation. Institutional guidelines for the safe performance of biopsies should be 
followed. Excisional biopsies may be performed to obtain tumor biopsy samples. Invasive 
procedures that require general anesthesia should not be performed to obtain a biopsy specimen. 
However, if a surgical procedure is performed for a clinical indication, excess tumor tissue may 
be used for research purposes with the consent of the participant.
5.6.4
Peripheral Blood Gene Expression
Gene expression analyses from whole blood may provide important information on the broad 
effects of nivolumab on immune modulation. Thus, genomic expression patterns of whole blood 
Revised Protocol No.: 05
Date: 19-Dec-2019
89
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
collected at baseline and during on-study treatment as specified in Table 5.6-1 may be assessed by 
global gene expression profiling using a platform such as, but not limited to RNA seq. 
5.6.5
T cell Repertoire Analysis (Whole Blood and Tumor Tissue Sample)
A standing theory in immuno-oncology therapy suggests that a diverse and activated immune 
environment is better adept at eradicating tumor compared to a skewed repertoire of naïve and 
tolerized T cells. In order to explore whether a diverse T cell repertoire is predictive of response 
to therapy, next generation, high-throughput, DNA sequencing will be performed on DNA isolated 
from peripheral blood and from tumor tissue to quantitate the T-cell receptor repertoire prior to, 
and on-treatment.
5.6.6
Characterization of Oral Microbiome
The oral microflora of an individual can harbor up to 750 distinct bacterial species. Certain species 
may induce chronic inflammation or lead to the presence of alcohol or tobacco-related 
carcinogens. The association of clinical outcomes to nivolumab in combination with ipilimumab 
with the composition of oral microflora is uncharacterized. In order to better understand whether 
components of the oral microbiome are associated with drug treatments or disease progression, 
saliva will be taken prior to therapy and prior to the Week 7 dose for preparation of DNA. 
Pyrosequencing, or a similar technique, will be performed to characterize oral microflora prior to 
and post treatment.
5.6.7
Whole Blood for Genomic Analyses
Whole blood samples for exploratory pharmacogenetic assessment will be collected from all 
participants (unless restricted by local regulations) and put in frozen storage. Genomic DNA will 
be extracted and subsequently assessed for single nucleotide polymorphisms (SNPs) and other 
genetic variations in candidate genes that may predispose participants to clinical benefit or adverse 
events (unless restricted by local requirements.) Such genes may include, but are not limited to,
the PD-1 axis as well as to other genes related to immune function. Additional use of these data 
may include correlative analyses aimed at identifying genotypic associations with clinically-
relevant biomarkers identified by other methodologies described in this section. Additionally, 
genomic DNA from whole blood will be collected and may be used as a comparator for participants 
with tumors examined by whole exome for tumor mutation burden analyses. 
5.6.8
HPV Assessment
Tumor p-16 status is an established clinical surrogate of tumor HPV status, which is a stratification 
factor in this study (positive/negative status required only for oropharyngeal CA). Evaluation of 
tumor p-16 status may be performed locally, but the assay is to be performed by use of a mouse 
monoclonal antibody to p-16 (CINtec E6H4, MTM Laboratories, Heidelberg, Germany) 
visualized with the Ventana XT.54 Determination of p-16 status by PCR or ISH is also acceptable.
If documentation of p-16 expression status as per inclusion criterion 2f (local HPV p-16 result) is 
not available, then a sample needs to be sent to the central laboratory for analysis to ensure full 
eligibility. Tissue requirements for the central laboratory are either tissue on microscopic slides, 
Revised Protocol No.: 05
Date: 19-Dec-2019
90
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
tissue block or a fresh tissue biopsy in formalin. More detail will be provided in the laboratory 
manual.
5.7
Outcomes Research Assessments
The evaluation of health-related quality of life is an increasingly important aspect of clinical 
efficacy in oncology trials. Such data provide an understanding of the impact of treatment from 
the patient’s perspective and offer insights into patient experience that may not be captured through 
physician reporting. Additionally, generic health-related quality of life measures provide data 
needed for calculating utility values to inform health economic models. 
Participants will be asked to complete the EQ-5D-3L and FACT-H&N before any clinical 
activities are performed during on-study clinic visits and at follow up visits 1 and 2. In addition, 
the EQ-5D and FHNSI-10 will be completed at designated time points during the survival follow-
up phase. The questionnaires will be provided in the participant’s preferred language if available 
and may be administered by telephone during the survival follow-up phase. A standardized script 
will be used to facilitate telephone administration of the EQ-5D. A similar script does not exist for 
the FHNSI-10, though participants will be provided with a hard copy of the questionnaire to take 
home and use as a visual aid during telephone interviews. Participants not able to vocalize 
responses over the phone will be afforded the opportunity to complete the questionnaires by pen 
and paper (initialing and dating each page) and return them by mail to the study site. Table 5.1-2
and Table 5.1-3 provide information regarding the timing of participant-reported outcomes 
assessments.
The EQ-5D is a standardized instrument used to measure self-reports of health status and 
functioning. The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting 
"no health problems," "moderate health problems," and "extreme health problems." A dimension 
for which there are no problems is said to be at level 1, while a dimension for which there are 
extreme problems is said to be at level 3. Thus, the vectors 11111 and 33333 represent the best 
health state and the worst health state, respectively, described by the EQ-5D. Altogether, the 
instrument describes 35 = 243 health states. Empirically derived weights can be applied to an 
individual’s responses to the EQ-5D descriptive system to generate an index measuring the value 
to society of his or her current health. Such preference-weighting systems have been developed 
for the UK, US, Spain, Germany, and numerous other populations. In addition, the EQ-5D includes 
a VAS that allows respondents to rate their own current health on a 101-point scale ranging from 
“best imaginable” to “worst imaginable” health. The EQ-5D is available for use in over 
150 languages.
The FACT-H&N questionnaire will be used to assess the effects of disease symptoms on 
functioning and well-being. As a generic cancer-related core, the FACT-H&N includes the 27-
item FACT-General (FACT-G) to assess physical well-being (PWB; seven items), social/family 
well-being (SWB; seven items), emotional well-being (EWB; six items), and functional well-being 
(FWB; seven items). The FACT-H&N includes a 12-item disease-specific Head and Neck Cancer 
(HNC) subscale that assesses concerns related to vocalization, communication, breathing, eating, 
swallowing, appearance, and bother due to adverse events. Ten items included in the PWB, EWB, 
Revised Protocol No.: 05
Date: 19-Dec-2019
91
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
FWB, and HNC subscales contribute to the scoring of the FHNSI-10, which can be used to provide 
a targeted assessment of the effects of head and neck cancer symptoms. Each FACT-H&N item is 
rated on a five-point scale ranging from 0 (not at all) to 4 (very much). Scores for the PWB, FWB, 
SWB, and EWB subscales can be combined to produce a FACT-G total score, which provides an 
overall indicant of generic quality of life, while the FACT-G and HNC subscale scores can be 
combined to produce a total score for the FACT-H&N, which provides a composite measure of 
general and targeted quality of life. A variant of the total score that is often more sensitive to 
physical and functional outcomes, the Trial Outcome Index (TOI), can be derived by summing 
scores for the PWB, FWB, and HNC subscales. All scores are scaled so that higher values indicate 
better functioning as well as lower symptom burden. The FACT-H&N is available for use in over 
40 languages.
In addition to the aforementioned participant-reported outcomes, health care resource utilization 
data will be collected for all randomized participants using an internal case report form developed 
for use in previous trials. The form, which is completed by study staff, records information about 
hospital admissions, including number of days spent in various wards and discharge diagnosis, as 
well as non-protocol specified visits related to study therapy, including date of visit, reason for 
visit, and type of visit. The health care resource utilization data will be used to support subsequent 
economic evaluations.
5.8
Additional Research
Additional research collections and retention are mandatory for all participants, except where 
prohibited by local laws or regulations, ethics committees, or where a waiver is provided by BMS 
or their designee. This protocol will include residual sample storage for additional research (AR). 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression, and response to treatment, etc. All requests for access to samples or data 
for additional research will be vetted through a diverse committee of the study sponsor’s senior 
leaders in Research and Development to ensure the research supports appropriate and well-defined 
scientific research activities. Additionally, residual blood and tissue collection will also be retained 
by the BMS Biorepository in Hopewell, NJ or at a BMS approved third party storage management 
facility for additional research purposes. Additional research samples will be retained for 15 years 
or the maximum allowed by applicable law. No additional sampling is required for residual 
collections. Further details of sample collection and processing will be provided to the site in the 
laboratory procedure manual.
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 participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
Revised Protocol No.: 05
Date: 19-Dec-2019
92
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of study treatment, whether or not considered related to 
the study treatment.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
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.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or results 
from other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator. Note that abnormal lab tests or other safety assessments 
should only be reported as AEs if the final diagnosis is not available. Once the final diagnosis 
is known, the reported term should be updated to be the diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Revised Protocol No.: 05
Date: 19-Dec-2019
93
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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 participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; 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 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
Revised Protocol No.: 05
Date: 19-Dec-2019
94
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Revised Protocol No.: 05
Date: 19-Dec-2019
95
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
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 participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). For participants 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 SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. 
SAEs must be recorded on the SAE Report Form; 
Pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). 
The required 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. When paper forms are used, the original paper forms are to remain 
on site. In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
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.
Follow-up of AEs and SAEs
Revised Protocol No.: 05
Date: 19-Dec-2019
96
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
A SUSAR (Suspected, Unexpected Serious Adverse Reaction) is a subset of SAEs and will be 
reported to the appropriate regulatory authorities and investigators following local and global 
guidelines and requirements.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the participants. All nonserious 
adverse events (not only those deemed treatment-related) are to be collected continuously during 
the treatment period and for a minimum of 100 days following the last dose of study treatment.
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 system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
Revised Protocol No.: 05
Date: 19-Dec-2019
97
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 hours 
of awareness of the pregnancy.
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant participant may continue study drug after a thorough 
discussion of benefits and risk with the participant, if allowed by local regulations.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdose, as a verbatim term (as reported 
by the investigator), should not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae and should specify "intentional overdose" as the verbatim term. 
All instances of accidental overdose and/or dosing errors should be reported on the Dosage 
Administration Record CRF. (see Section 6.1.1 for reporting details.).
Revised Protocol No.: 05
Date: 19-Dec-2019
98
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
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 
participants 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.
Table 6.7.1-1 below provides a summary of the IMAEs category and their respective PTs. This list 
is participant 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.: 05
Date: 19-Dec-2019
99
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
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 participants enrolled in this study. The 
DMC will be charged with assessing such actions in light of an acceptable risk/benefit profile for 
nivolumab. The DMC will act in an advisory capacity to BMS and will monitor participant safety 
data for the study.
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.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The primary objectives of this study are to compare OS between treatment groups, in all 
randomized participants and randomized participants with PD-L1 CPS ≥ 20. OS will be compared 
at the 0.025 alpha level for each of the above two populations.
Revised Protocol No.: 05
Date: 19-Dec-2019
100
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
The OS comparison in all randomized participants will require up to 741 deaths. This number of
events ensures that a two-sided, alpha = 0.025 group sequential test using the O’Brien and Fleming 
spending function and with an interim analysis after approximately 80% of events will have overall 
97% power for a HR of 1.2 for the first 7 months and 0.55 thereafter. 
Delayed separation of KM curves is included in the alternative hypotheses for OS because it was 
observed in CA209141, a randomized phase 3 study of nivolumab versus investigator's choice 
therapy in platinum-refractory, recurrent/metastatic SCCHN,35 and in KEYNOTE-048, a 
randomized phase 3 study of pembrolizumab or pembrolizumab with chemotherapy versus 
cetuximab with chemotherapy in untreated recurrent/metastatic SCCHN.55
The final analysis of OS in all randomized participants is projected to occur 51 months after the 
first patient was randomized. An interim analysis in this population will be performed when 
approximately 593 deaths occur, or all randomized participants have been followed up for at least 
12 months, whichever is later. It is projected for 39 months after the first patient was randomized.
Power for OS comparisons in randomized participants with PD-L1 CPS ≥ 20
At the same time as the OS analysis is done for all randomized participants, OS will also be 
compared between arms in the randomized participants with PD-L1 CPS ≥ 20 via a two-sided, 
alpha = 0.025 group sequential test procedure incorporating the O’Brien and Fleming alpha 
spending function. The group sequential test would have an interim analysis and the final analysis 
of OS, at which approximately 298 and 372 deaths, respectively, are expected. With this many 
events, the test procedure would have an overall 99% power if the HR was 1.06 for the first 7
months and 0.45 thereafter. Table 8.1-1 summarizes the statistical assumption and power 
calculation.
Table 8.1-1:
Statistical Assumption and Power Calculation
Primary endpoints
OS for ITT (N = 930)
OS for PD-L1 CPS ≥ 20 (N = 465)
Median OS months (N+I/EXTREME
regimen)
13/10.8
14.9/10.8
Average hazard ratio
0.74
0.61
Alpha level (IA/FA)
0.01/0.022
0.01/0.022
Event Number (IA/FA)
593/741
298/372
Critical hazard ratio (IA/FA)
0.81/0.845
0.74/0.788
Power (IA/FA)
66%/97%
87%/99%
Estimated time of LPLV (IA/FA)
39/51 months
39/51 months
All sample size and power calculations were done using EAST 6.4.1. 
8.2
Populations for Analyses
•
All Enrolled Participants: All participants who signed an informed consent form and were 
registered into the IVRS. 
Revised Protocol No.: 05
Date: 19-Dec-2019
101
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
All Randomized Participants: All enrolled participants who were randomized to either
treatment arm. 
•
All Randomized PD-L1 CPS ≥ 20 Participants: All randomized participants with PD-L1 CPS 
≥ 20
•
All Randomized PD-L1 CPS ≥ 1 Participants: All randomized participants with PD-L1 CPS ≥ 
1.
•
All Treated Participants: All participants who received at least one dose of nivolumab, 
ipilimumab, cetuximab, cisplatin, carboplatin or 5-FU. 
•
Treated Participants with PD-L1 CPS ≥ 20: All participants who received at least one dose of 
nivolumab, ipilimumab, cetuximab, cisplatin, carboplatin or 5-FU and have PD-L1 CPS ≥20 
at baseline.
•
All PK Participants: All participants with available serum time-concentration data
•
Immunogenicity Evaluable Participants:
−
Nivolumab ADA Evaluable Participants: all treated participants with baseline and at least 
1 post-baseline pre-infusion nivolumab immunogenicity assessment. 
−
Ipilimumab ADA Evaluable Participants: all treated participants with baseline and at least 
1 post-baseline pre-infusion ipilimumab immunogenicity assessment. 
•
All PD-L1 Tested participants: All participants, randomized or not, who had a tumor biopsy 
specimen available for tumor cell expression testing. This includes both randomized and screen 
failure participants.
Key analyses of study conduct, demographics, and efficacy will be done on the all randomized 
population and repeated on the randomized PD-L1 CPS ≥ 20 population. Participants in these 
analyses will be grouped as assigned at randomization.
Key analyses of exposure and safety will be done on the all treated population and repeated on the 
treated PD-L1 CPS ≥ 20 population. Participants in these analyses will be grouped by treatment 
received rather than treatment assigned at randomization. (Treatment arm received will be equal 
to treatment arm as randomized, unless the participant received the non-assigned regimen for all 
doses.)
8.3
Endpoints
8.3.1
Primary Endpoints 
•
OS in randomized participants with PD-L1 CPS ≥20 
•
OS in all randomized participants
OS is defined as the time between randomization and death. For participants without 
documentation of death, OS will be censored on the last date the participant was known to be alive.
8.3.2
Secondary Endpoints 
Overall survival (OS) in randomized participants with PD-L1 CPS ≥ 1. OS is defined the same 
way as for the primary endpoints.
Revised Protocol No.: 05
Date: 19-Dec-2019
102
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
PFS is defined as the time from randomization to disease progression, using RECIST 1.1 criteria, 
or, if there is no documented progression, death. (The date of progression will be based on the 
BICR assessment of progression). Participants who neither progress nor die will be censored on 
the date of their last tumor assessment. Participants who receive subsequent anti-cancer therapy 
prior to documented progression, including tumor-directed radiotherapy and tumor-directed 
surgery, will have their PFS time censored on the date of their last tumor assessment prior to 
subsequent therapy.
The Objective Response Rate (ORR) is defined as the number of participants with a best overall 
response (BOR) of complete response (CR) or partial response (PR), divided by the number 
randomized in the population.
The BOR is defined as the best response, based on RECIST 1.1 criteria, recorded between 
randomization and either progression or subsequent anticancer therapy (including tumor-directed 
radiotherapy and tumor-directed surgery), whichever occurs first. (The BOR will be based on 
BICR assessments). For participants without evidence of RECIST 1.1 progression or subsequent 
anticancer therapy, all available tumor evaluations will contribute to the BOR assessment. 
Duration of objective response (DOR) is the time between the first documented response (CR or 
PR) and progression, per RECIST 1.1, or, if no progression is reported, death. The DOR of a 
participant who neither progresses nor dies will be censored as in the primary definition of PFS. 
DOR is calculated on the subset of participants whose best response was either CR or PR, 
according to BICR assessments.
8.3.3
Exploratory Endpoint(s) 
Overall survival (OS) in randomized participants with tumor cell PD-L1 < 1%, or PD-L1 CPS of 
< 20, or tumor inflammation score measured as GEP ≥ 10, or tumor mutation burden (TMB) ≥7
is defined the same way as for the primary endpoints.
PFS, ORR, and DOR in randomized participants with tumor cell PD-L1 < 1%, or CPS of <20, or 
tumor inflammation score measured as GEP ≥ 10, or tumor mutation burden (TMB) ≥7 is defined 
the same way as for the secondary endpoints.
ORR and DOR in subpopulation based on selected biomarkers are defined the same way as in the 
secondary endpoints. Time to Objective Response (TTR) is defined as the time from 
randomization to the first documented response (CR or PR).
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 National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Tumor cell PD-L1 expression is defined as the percent of tumor cell membrane staining in a 
minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay. Participant’s PD-L1 
expression status using ≥1% expression level will be determined prior to randomization:
Revised Protocol No.: 05
Date: 19-Dec-2019
103
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Tumor cell PD-L1 expressing (≥1% tumor cell membrane staining in a minimum of a hundred 
evaluable tumor cells)
•
Tumor cell PD-L1 non-expressing (< 1% tumor cell membrane staining in a minimum of a 
hundred evaluable tumor cells)
•
Tumor cell PD-L1 non-evaluable
Time to symptom deterioration (TTSD) is defined as the time from randomization to a clinically 
meaningful decline from baseline in the FHNSI-10 score. A clinically meaningful decline will be 
defined as a reduction of FHNSI-10 score ≥3 points. 56 Subjects who die without a reported 
deterioration will be considered to have deteriorated on the date of their death. Those who neither 
deteriorate nor die will be censored at the time of their last FHNSI-10 assessment.
Serum concentration will be used to characterize the PK of nivolumab and ipilimumab using a 
population PK approach.
Other exploratory endpoints are discussed in detail in the statistical analysis plan
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized by treatment arm as randomized 
using descriptive statistics. These analyses will be done PD-L1 CPS ≥ 20 population and on the
all randomized population.
8.4.2
Efficacy Analyses
Efficacy analyses will be performed using all randomized participants by treatment group as 
randomized.
8.4.2.1
Analysis Methods for Primary Endpoints
OS will be compared between arms via a two-sided, overall alpha = 0.025, group sequential log-
rank test for each of the two primary endpoints population. The significance levels may be updated 
through graphical approach where the family-wise error rate will be protected in the strong sense. 
Rules for updating significance levels following the Bonferroni-based graphic approach by Maurer 
and Bretz (2013) will be detailed in the SAP. Figure 8.4.2.1-1: is the graphic display of the testing 
hierarchy for the endpoints to be tested in this study. The numbers next to the arrows indicate the 
fraction of alpha that could be passed from the source endpoint to the target endpoint if the source 
endpoint is statistically significant.
Revised Protocol No.: 05
Date: 19-Dec-2019
104
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Figure 8.4.2.1-1:
testing hierarchy for the endpoints
The nominal significance levels for each look of the group sequential log-rank test will be 
determined by the alpha spending function with the O’Brien and Fleming boundary based on the 
actual number of events observed at the time of the analysis. These tests will be stratified by the 
stratification factors used in the randomization.
An estimate of the hazard ratio (HR) and a corresponding two sided 100*(1 - adjusted α)% 
confidence interval for the HR will be generated for each endpoint using a stratified Cox 
proportional hazards model with treatment arm as the sole covariate. The stratification factors will 
be the same as those used for testing. The level for the confidence interval for the OS hazard ratio 
will be based on the same nominal significance level for the group sequential log-rank test,.
Survival distributions will be estimated, by arm, via the Kaplan-Meier (KM) product-limit method. 
Median survival times along with 95% confidence intervals for the medians, will also be presented. 
The confidence interval for the median will be constructed using a generalization of the 
Brookmeyer and Crowley method based on a log {-log} transformation of the survival function.57
Greater detail on the analyses of primary endpoints, including sensitivity analyses of OS, will be 
provided in the statistical analysis plan.
8.4.2.2
Analysis Methods for Secondary Endpoints
The analyses of OS in the randomized participants with PD-L1 CPS ≥ 1 population will be similar 
to those in the randomized participants with PD-L1 CPS ≥ 20, except that testing will be contingent 
upon a significant result for the primary OS comparison in PD-L1 CPS ≥ 20 population, On the 
other hand, if the test for this secondary endpoint is significant and the initial test for OS in all 
randomized participants is not significant, the latter can be retested with full alpha = 0.05.
The analysis of PFS in the participants with PD-L1 CPS ≥ 20 and in all randomized participants
will be performed using a stratified Cox proportional hazards model with treatment arm as the sole 
covariate. An estimate of the hazard ratio (HR) and a corresponding two sided 95% CI for the HR 
will be generated. Survival distributions will be estimated, by arm, via the Kaplan-Meier (KM) 
Revised Protocol No.: 05
Date: 19-Dec-2019
105
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
product-limit method. Median survival times along with 95% CI for the medians, will also be 
presented. The confidence interval for the median will be constructed using a generalization of the 
Brookmeyer and Crowley method based on a log {-log} transformation of the survival function.
No statistical test will be performed.
ORR and its associated 95% CI will be presented per arm, in all randomized participants and 
participants with PD-L1 CPS ≥ 20. The confidence interval for ORR will be computed using the 
Clopper and Pearson method. The odds ratio (OR) and 95% confidence interval for the ratio will 
be generated using the Cochran-Mantel-Haenszel (CMH) method. 
The distribution of DOR will be estimated via the KM method for participants whose best response 
is PR or CR, by arm. Medians and 6, 9, and 12 month rates will also be estimated. These analyses 
will be conducted on the all randomized population and PD-L1 CPS ≥ 20 subpopulation.
No statistical test will be performed for ORR, DOR for all randomized participants and participants 
with PD-L1 CPS ≥ 20.
8.4.3
Safety Analyses
Safety analyses are restricted to treated participants. Descriptive statistics of safety will be 
presented using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 by treatment arm. All AEs, drug-related AEs, SAEs and drug-related 
SAEs will be tabulated using the worst grade per NCI CTCAE v 4.0 criteria by system organ class 
and preferred term. On-study lab parameters including hematology, coagulation, chemistry, liver 
function and renal function will be summarized using worse grade per NCI CCAE v 4.0 criteria.
These analyses will be performed on both the population of treated participants with PD-L1 
expressing tumors and on all treated participants.
8.4.4
Pharmacokinetic Analyses
The nivolumab and ipilimumab concentration data obtained in this study may be combined with 
data from other studies in the clinical development program to develop or refine a population PK 
model. This model may be used to evaluate the effects of intrinsic and extrinsic covariates on the 
PK of nivolumab and to determine measures of individual exposure (such as steady-state peak, 
trough, and time-averaged concentration). In addition, model determined exposures may be used 
for exposure-response analyses. Results of population PK and exposure response-analyses will be 
reported separately.
8.4.5
Biomarker Analyses
Analyses of PD-L1 expression will include:
•
KM Plots of efficacy by arm for each PD-L1 CPS status subset (analyses with PD-L1 CPS 
cutoff of ≥20, ≥1, < 20, and other exploratory cut-points). This analysis will include HRs of 
the experimental to control arm within subset and corresponding 95% CI.
•
KM Plots of PFS and OS by arm for each tumor cell PD-L1 status subset (< 1%, ≥ 1%, 
unknown). (Similar analyses with 5%, 10%, 50%, other exploratory PD-L1 cutoffs will be 
conducted). This analysis will include HRs of the experimental to control arm within subset
and corresponding 95% CI.
Revised Protocol No.: 05
Date: 19-Dec-2019
106
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Box plots of PD-L1 expression at baseline versus response status, by treatment group
•
Odds ratios for tumor response of the experimental to the control arm by PD-L1 status subset 
and corresponding 95% CI
•
Model-based assessment of the interaction between treatment and PD-L1 status for PFS, OS, 
and ORR.
The analyses of tumor mutational burden (TMB) and tumor inflammation gene expression profile 
(GEP) will also include KM plots by TMB and GEP subgroups, box plots of TMB by response, 
and model based assessments of interaction between treatment and TMB/GEP for PFS, OS, and 
ORR. 
Associations between other potential biomarkers and efficacy and safety may be investigated as 
well. These analyses will be completed with biomarkers measured in blood and in tumor samples 
and will focus primarily on SNPs in select genes associated with immunity or on the expression 
of PD-1 and PD-L2 proteins in tumor specimens. Similar analyses may be completed with data 
regarding serum-soluble factors, serum miRNA content, T-cell populations, and putative 
additional analyses to be completed using FFPET. Associations between biomarkers and efficacy 
measures will be analyzed on all randomized participants with available biomarker data. Efficacy 
measures will include response, PFS, and OS. Demographic and case-history factors will be 
examined to determine whether stratification or adjustments should be made within the subsequent 
statistical analyses, and if necessary, the appropriate stratification or adjustment will be made. 
Biomarkers will be summarized graphically as they relate to efficacy and safety endpoints, as 
applicable. Summary statistics may be tabulated. SNP allele frequencies may be summarized. The 
relationships between binary measures (eg. response) and candidate biomarkers will be 
investigated using logistic regression. Associations may be summarized in terms of point and 
interval estimates of hazard ratios, odds ratios, or other statistics, as appropriate for the analyses 
completed. Models to predict clinical activity based on combinations of biomarkers may also be 
investigated. Additional post hoc statistical analyses not specified in the protocol, such as 
alternative modeling approaches may be completed. All analyses described above are based on the 
availability of the data.
8.4.6
Outcomes Research Analyses
Exploratory analyses of EQ-5D and FACT-H&N (including FHNSI-10) data will be performed in 
randomized participants who have an assessment at baseline (Day 1, assessment prior to 
administration of drug on day of first dose) and at least 1 subsequent assessment while on 
treatment. Questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number, will be calculated and summarized at each assessment point.
EQ-5D data will be described by treatment group as randomized in the following ways: 
•
EQ-5D index scores and post-baseline changes in scores will be summarized at each 
assessment time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, 
first and third quartiles, minimum, maximum). In the base case, scores will be calculated using 
the UK preference-weighting algorithm. 
Revised Protocol No.: 05
Date: 19-Dec-2019
107
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
EQ-5D VAS scores and post-baseline changes in scores will be summarized at each 
assessment time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, 
first and third quartiles, minimum, maximum). 
•
The proportion (N) of participants reporting no, moderate, or extreme problems will be 
presented for each of the 5 EQ-5D dimensions at each assessment time point. Participants with 
missing data will be excluded from the analysis. 
•
A by-participant listing of the level of problems in each dimension, corresponding EQ-5D 
health state (ie, 5-digit vector), EQ-5D index score, and EQ-5D VAS score will be provided. 
FACT-H&N data collected during on-study clinic visits and at follow up visits 1 and 2 will be 
described by treatment group as randomized in the following ways: 
•
Scores and post-baseline changes in scores for the following components of the FACT-H&N 
will be summarized at each assessment time point using descriptive statistics (ie, N, mean 
with SD and 95% CI, median, first and third quartiles, minimum, maximum): FACT-G, PWB, 
SWB, EWB, FWB, HNC, FHNSI-10, FACT-H&N TOI, FACT-H&N total, and individual 
FACT-H&N items. 
FHNSI-10 data will be described by treatment group as randomized in the following ways: 
•
Scores and post-baseline changes in scores will be summarized at each assessment time point 
(i.e., first, second, third, etc. survival follow-up visit recognizing that the timing of visits will 
vary among participants) using descriptive statistics (ie, N, mean with SD and 95% CI, median, 
first and third quartiles, minimum, maximum). 
•
The proportion (N) of participants with symptomatic deterioration, defined as a clinically 
meaningful decline in score (worsening from baseline ≥3 points) or death, will be summarized 
at each assessment time point (ie, first, second, third, etc. survival follow-up visit recognizing 
that the timing of visits will vary among participants).
•
Time to symptom deterioration (TTSD) will be estimated using the KM product-limit method, 
by arm as randomized. Two-sided 95% confidence intervals for median TTSD will be 
computed.
Analyses of patient-reported outcomes will be performed on both the randomized PD-L1 CPS ≥20 
population and the all randomized population.
8.4.7
Other Analyses 
Methodology for exploratory analyses including immunogenicity is described in the statistical 
analysis plan.
8.5
Interim Analyses
A formal interim analysis for superiority of OS will be performed after approximately 593 OS 
events (out of 741 required) have occurred on all randomized participants, or all randomized 
participants have been followed up for at least 12 months, whichever is later. Both primary 
endpoints will be tested at interim using the group sequential test procedure with initial overall 
Revised Protocol No.: 05
Date: 19-Dec-2019
108
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
alpha = 0.025 for each. The overall alpha will be updated following the graphical procedure (Figure 
8.4.2.1-1:). The stopping boundaries for the interim and final analyses will be determined by the
O’Brien and Fleming alpha spending function, based on the actual number of events observed. 
If interim comparison of OS in either all randomized participants or randomized participants with 
PD-L1 CPS ≥ 20 is significant, the DMC will inform the sponsor, as described in the DMC charter.
If comparison of OS in the randomized participants with PD-L1 CPS ≥ 20 is significant, OS in 
randomized participants with PD-L1 CPS ≥ 1 will be subsequently tested using group sequential 
testing procedure. The overall alpha for this secondary endpoint will be determined following the 
graphical procedure which is detailed in the SAP.
The DMC will have access to periodic un-blinded interim reports of efficacy and safety to allow a 
risk/benefit assessment. Details will be included in the DMC charter.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
participants currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
Revised Protocol No.: 05
Date: 19-Dec-2019
109
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
9.1.3
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. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.3.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.4
Study Treatment Records
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
Revised Protocol No.: 05
Date: 19-Dec-2019
110
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
9.1.5
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records
Supplied by BMS (or its vendors)
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s) Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each participant, including unique participant identifiers
•
amount transferred to another area/site for dispensing or storage
•
non study disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
retain samples for bioavailability/bioequivalence, if applicable dates and initials of person 
responsible for Investigational Product dispensing/accountability, as per the Delegation of 
Authority Form.
Source 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)
Revised Protocol No.: 05
Date: 19-Dec-2019
111
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
The investigator or designee accepts responsibility for documenting traceability and study 
treatment integrity in accordance with requirements applicable under law and the SOPs/standards 
of the sourcing pharmacy.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
•
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported 
on the electronic SAE form and Pregnancy Surveillance form, respectively. If electronic SAE 
form is not available, a paper SAE form can be used. Spaces may be left blank only in those 
circumstances permitted by study-specific CRF completion guidelines provided by Sponsor or 
designee.
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a sub investigator and who is delegated this task on the 
Delegation of Authority Form. Sub investigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.2.4
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
Study Steering Committee 
Revised Protocol No.: 05
Date: 19-Dec-2019
112
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
9.2.4.1
Scientific Publications
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing [Study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1. Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work.
Revised Protocol No.: 05
Date: 19-Dec-2019
113
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
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
ANC
Absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BID, bid
bis in die, twice daily
BICR
Blinded Independent Central Review
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
CBC
complete blood count
CD279
Cluster of differentiation 279
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
cm
centimeter
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CPS
combined positive score
CR
Complete Response
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CTA
Clinical Trial Agreement
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Revised Protocol No.: 05
Date: 19-Dec-2019
114
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Term
Definition
CV
coefficient of variation
CT
Computed tomography
CTC
Common Terminology Criteria
D/C
discontinue
DILI
Drug Induced Liver Disease
Dl
deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg,
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
ECOG
Eastern Cooperative Oncology Group
ESR
Expedited Safety Report
5-FU
Fluoracil
FACT-H&N
Functional Assessment of Cancer Therapy-Head & Neck
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescent in-situ hybridization
FU-1
Follow up visit 1
FU-2
Follow up visit 2
FSH
follicle stimulating hormone
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
h
hour
Revised Protocol No.: 05
Date: 19-Dec-2019
115
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Term
Definition
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HCG
chorionic gonadotrophin
HIV
Human Immunodeficiency 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
IMP
investigational medicinal products
IND
Investigational New Drug
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
IVRS
Interactive Voice Response System
K
slope of the terminal phase of the log concentration-time curve
K+
potassium
kg
kilogram
KM
Kaplan-Meier
L
liter
LDH
lactate dehydrogenase
Revised Protocol No.: 05
Date: 19-Dec-2019
116
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Term
Definition
mg
milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
Ml
milliliter
MRI
Magnetic resonance imaging
MRT
mean residence time
MS
mass spectrometry
MTD
maximum tolerated dose
μg
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
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PFS
Progression free survival
PK
pharmacokinetics
PO
per os (by mouth route of administration)
QD, qd
quaque die, once daily
RANK-L
Receptor activator of nuclear factor kappa-B ligand
RBC
red blood cell
Revised Protocol No.: 05
Date: 19-Dec-2019
117
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Term
Definition
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCCHN
Squamous Cell Carcinoma Head and Neck
SD
standard deviation
SmPC
summary of product characteristics
SOP
Standard Operating Procedures
t
temperature
T
time
T3
triiodothyronine
T4
thyroxine
TAO
Trial Access Online, the BMS implementation of an EDC capability
TID, tid
ter in die, three times a day
TTSD
Time To Symptom deterioration
TSH
Thyroid-stimulating hormone
VAS
Visual Analog Scale
WBC
white blood cell
WOCBP
women of childbearing potential
Revised Protocol No.: 05
Date: 19-Dec-2019
118
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
11
REFERENCES
1
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer 
J Clin 2011 ; 6(2):69-90
2
NCI SEER Statistics Review http://seer.cancer.gov/statfacts/html/oralcav.htmlaccessed March 
5,2016
3
Leemans CR, Braakhuis B, Brakenhoff R. Molecular biology of head and neck cancer. Nature 
Reviews Cancer Vol 11 Jan 2011
4
NCCN Guidlines Version 2.2014 Head and Neck Cancers
5
Vermoken et al Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl 
J Med 2008;359:1116-27
6
Ferris et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell 
carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with 
analyses by tumor PD-L1 expression. Oral Oncology 81 (2018) 45–51
7
Cohen et al. The Lancet. VOLUME 393, ISSUE 10167, P156-167, JANUARY 12, 2019)
8
B Burtness, K J Harrington, R Greil, et al. Phase III study of first-line pembrolizumab (P) for 
recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Annals of 
Oncology, Volume 29, Issue suppl_8, October 2018, mdy424.045
9
Phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck 
squamous cell carcinoma (R/M HNSCC). Annals of Oncology, Volume 29, Issue suppl_8, 
October 2018, mdy424.045
10 Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human papillomavirus-
related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 
2008;26:612-9
11 Argiris A, Heron DE, Smith RP, et al. Induction Docetaxel, Cisplatin, and Cetuximab Followed 
by Concurrent Radiotherapy, Cisplatin, and Cetuximab and Maintenance Cetuximab in 
Patients With Locally Advanced Head and Neck Cancer. J Clin Oncol 2010;28:5294-300.
12 Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising 
oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011 Nov 10;29(32):4294-
301.
13 Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with 
Oropharyngeal Cancer. NEJM 2010;363:24-35.
14 Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without 
concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 
1998;338:1798-804
Revised Protocol No.: 05
Date: 19-Dec-2019
119
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
15 Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation 
therapy and two schedules of concurrent chemo radiotherapy in patients with unresectable 
squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.
16 Gilbert J, Li Y, Pinto HA, et al. Phase II trial of taxol in salivary gland malignancies (E1394): 
a trial of the Eastern Cooperative Oncology Group. Head Neck 2006;28:197-204
17 Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with 
docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.
18 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell 
carcinoma of the head and neck. N Engl J Med 2006;354:567-78
19 Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-
positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer 
Inst 2008;100:261-9.
20 Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 2011 Dec 
22;29 4 8 0:480-89
21 Alberts AE, Strauss L, Liao T, et al. T cell-tumor interaction directs the development of 
immunotherapies in head and neck cancer. Clinical and Developmental Immunology 2010 doi: 
10.1155/2010/236378 epub.
22 Leibowitz MS, Pedro A, Fiho A, Ferrone S, Ferris RL. Deficiency of activated STAT 1 head 
and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer 
Immunol Immunotherapy 2011;60:525-535
23 Cho YA, Hong SD. Relation between expression of PDL-1 and tumor infiltrating lymphocytes 
in oral squamous cell carcinoma. Oral Oncology 2011;12:1148
24 Albers A, Abe K, Hunt J, et al. Antitumor activity of human papillomavirus type 16 E7-specific 
T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 
2005;65(23):11146-55.
25 Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med 
2003;81(5):281-7
26 Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor 
prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 
2006;66(7):3381-5
27 Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 
and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 
2005;11(8):2947-53.
28 Wu C, Zhu Y, Jiang J, et al. Immunohistochemical localization of programmed death-1 ligand-
1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006;108(1):19-
24.
Revised Protocol No.: 05
Date: 19-Dec-2019
120
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
29 Nomi T, Sho S, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin 
Cancer Res 2007;13(7):2151-7
30 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol 2006;6:715-27.
31 Taube, J. Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-H1 
expression in human melanocytic lesions supports an adaptive resistance mechanism of 
immune escape. Sci Transl Med 2012;4(127):127ra37
32 Seiwert TY. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-
associated and non-HPV-associated head and neck (H/N) cancer. J Clin Oncol. 32:5s, 2014 
suppl; abstr 6011
33 https://www.agilent.com/cs/library/usermanuals/public/29219_pd-l1-ihc-22C3-pharmdx-
gastric-interpretation-manual_us.pdf
34 Brahmer J, Reckamp K, Baas P et al. Nivolumab versus docetaxel in squamous-cell non-small-
cell lung cancer. N Engl J Med 2015;373:123-35.
35 Robert L. Ferris, George Blumenschein Jr, Jerome Fayettec, Joel Guigay et al.Nivolumab for 
Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016; 375:1856-
1867
36 Robert L. Ferris, George Blumenschein Jr, Jerome Fayettec, Joel Guigayd,et al. Nivolumab vs 
investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 
2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. 
Oral Oncology. Volume 81, June 2018, Pages 45–51. 
37 Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34.
38 Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin, 
Pemetrexed/Cisplatin, 
Carboplatin/Paclitaxel, 
Bevacizumab 
Maintenance, 
Erlotinib, 
Ipilimumab or as Monotherapy in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer 
(NSCLC) (CheckMate 012) ClinicalTrials.gov Identifier: NCT01454102 
39 An Open-Label, Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus 
Platinum-doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Subjects With 
Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227) ClinicalTrials.gov 
Identifier: NCT02477826
40 Andrea Ardizzoni; Rafael Rosell, et al. Cisplatin- Versus Carboplatin-Based Chemotherapy in 
First-Line Treatment of Advanced Non – Small-Cell Lung Cancer: An Individual Patient Data 
Meta-analysis JNCI J Natl Cancer Inst (2007) 99 (11): 847-857
41 Brahmer J, et al, Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small –Cell 
Lung Cancer. N Engl J Med 2015;373:123-35.
Revised Protocol No.: 05
Date: 19-Dec-2019
121
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
42 Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non–Small-Cell Lung Cancer. N Engl J Med 2015; 373:1627-1639.
43 Belani CP, Ramalingam S, Perry MC, et al. Randomized, phase III study of weekly paclitaxel 
in combination with carboplatin versus standard every-3-weeks administration of carboplatin 
and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J 
Clin Oncol 2008; 26: 468-73.
44 F. Hodi et al, Improved Survival with Ipilimumab in Patients with Metastatic Melanoma, N 
Engl J Med 2010; 363:711-723August 19, 2010.
45 Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of 
nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics 
of long-term survivors. Oral presentation presented at: American Association for Cancer 
Research (AACR) Annual Meeting; April 1-5, 2017; Washington, DC, USA.
46 Caroline Robert et al. Long-term outcomes in patients with ipilimumab-naive advanced 
melanoma in the phase 3 KeyNote-006 study who completed pembrolizumab treatment; 
Journal of Clinical Oncology 2017 35:15_suppl, 9504-9504.
47 Schadendorf D. Efficacy and quality of life outcomes in patients with advanced melanoma 
who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a 
phase III trial (CheckMate 067). 2016 Annual Meeting of the European Association of 
Dermato-Oncology.
48 Spigel DR, et al. Randomized results of continuous vs 1-year fixed-duration in patients with 
advanced non-small cell lung cancer. Oral presentation at the European Society of Medical 
Oncology Annual Meeting. 2017 Sep 8-12; Madrid, Spain.
49 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nat Immunol 2007;8(3):239-45)
50 Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and 
Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International 
Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 
20/5/2014)
51 Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: Releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012; 18:153-159
52 Nivolumab (BMS-936558) Investigator Brochure
53 Ipilimumab (BMS-734016) Investigator Brochure
54 Ventana CINtec p-16 Histology Prescribing Information. Ventana Medical System. Tucson, 
AZ. 2015.
Revised Protocol No.: 05
Date: 19-Dec-2019
122
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
55 Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus 
cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head 
and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915-
1928.
56 Yount S et al. A randomized validation study comparing embedded versus extracted FACT 
Head and Neck Symptom Index scores. Qual Life Res (2007) 16:1615–1626.
57 Klein, JP, Moeschberger, ML, Survival Analysis, Techniques for Censored and Truncated 
Data, New York, Springer-Verlag, 1997.
Revised Protocol No.: 05
Date: 19-Dec-2019
123
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
APPENDIX 1
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS a
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
Revised Protocol No.: 05
Date: 19-Dec-2019
124
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
APPENDIX 2
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
Revised Protocol No.: 05
Date: 19-Dec-2019
125
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
126
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
127
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
128
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
129
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
130
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
131
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
132
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Revised Protocol No.: 05
Date: 19-Dec-2019
133
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
APPENDIX 3
RECIST 1.1 GUIDELINES
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
Revised Protocol No.: 05
Date: 19-Dec-2019
134
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
3
RESPONSE CRITERIA
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Revised Protocol No.: 05
Date: 19-Dec-2019
135
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a 
normal lymph node is defined as having a short axis of < 10 mm. Case report forms or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 
SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions.
3.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm.
3.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
Revised Protocol No.: 05
Date: 19-Dec-2019
136
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
3.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10mm short 
axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
3.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy (see examples in Appendix 2 and further details below). A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
3.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point. While 
Revised Protocol No.: 05
Date: 19-Dec-2019
137
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore the increase must be substantial.
3.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
Revised Protocol No.: 05
Date: 19-Dec-2019
138
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
3.3.2-1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When patients have non-measurable (therefore 
non-target) disease only, Table 3.3.2-2 is to be used. 
Table 3.3.2-1:
Time Point Response - Patients With Target (+/- Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2:
Time Point Response - Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
Revised Protocol No.: 05
Date: 19-Dec-2019
139
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
3.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
of ≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 
3.3.3-1.
Special note on response assessment: When nodal disease is included in the sum of target 
lesions and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the nodes are normal in 
order not to overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case report 
form (CRF).
Table 3.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationb met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
b Minimum criteria for SD duration is 6 weeks.
Revised Protocol No.: 05
Date: 19-Dec-2019
140
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
3.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of 
the initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
Revised Protocol No.: 05
Date: 19-Dec-2019
141
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months after the end of 
study treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be 
used by WOCBP participants in studies where hormonal contraception is prohibited)b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
Revised Protocol No.: 05
Date: 19-Dec-2019
142
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (These methods of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited) b
•
intrauterine hormone-releasing system (IUS)(This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited) b, c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
Revised Protocol No.: 05
Date: 19-Dec-2019
143
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional 
contraception methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end 
of treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4.
Revised Protocol No.: 05
Date: 19-Dec-2019
144
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
APPENDIX 5
HEAD AND NECK SQUAMOUS CELL CARCINOMAS 
CLASSIFIED AS FOLLOWS: 
•
oral cavity: 
−
anterior two thirds of the tongue 
−
tongue unspecified, 
−
lip 
−
gum 
−
floor of the mouth 
−
hard palate 
−
palate unspecified 
−
other oral cavity—including buccal mucosa and retromolar area 
−
oral cavity unspecified 
•
oropharynx: 
−
base of the tongue 
−
soft palate 
−
tonsil 
−
uvula 
−
other parts of the oropharynx 
−
Waldeyer’s ring   
−
oropharynx unspecified
•
larynx: 
−
glottis
−
supraglottis
−
subglottis 
−
other and unspecified larynx subsites 
−
Hypopharynx cases are classified as belonging to the larynx, including pyriform sinus
Revised Protocol No.: 05
Date: 19-Dec-2019
145
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
APPENDIX 6
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 04, 20-Jun-2018
Evolving data in SCCHN in the recent years suggest that PD-L1 combined positive score (PD-L1 
CPS) is a more appropriate PD-L1 measure for selecting participants who derive the best benefit 
for immunotherapy. Additionally, recent data demonstrate the potential for nivolumab + 
ipilimumab to benefit a broader SCCHN patient population than PD-L1 expressers alone. The 
primary end-points of the current study (CheckMate 651) will be revised to compare: (a) OS of 
participants with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab to
those receiving EXTREME regimen (changed from tumor cell PD-L1 ≥ 1%) and (b) OS of all 
study participants (irrespective of PD-L1 expression) who are receiving nivolumab combined 
with ipilimumab to those receiving EXTREME regimen. Additionally, OS for nivolumab +
ipilimumab versus EXTREME regimen in participants with PD-L1 CPS ≥1 will be added as a 
key secondary end-point. The primary end-point of PFS for nivolumab + ipilimumab versus 
EXTREME regimen will be removed as evolving data suggest that PFS is not an appropriate 
end-point for immunotherapy in SCCHN.
Summary of key changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.2: Rationale 
for revised protocol 04
Updated section with 
emerging data (CheckMate 
141, KeyNote-040, and 
KeyNote-048)
Emerging data from multiple studies
in the recent years demonstrated 
long-term OS benefit with PD-1 
inhibitor (nivolumab and 
pembrolizumab) therapy compared 
to standard of care in R/M SCCHN 
population. These studies while 
suggesting OS benefit in all study 
participants also showed with a 
trend towards better efficacy in 
participants who express PD-L1 in 
either their tumor or immune cells.
Revised Protocol No.: 05
Date: 19-Dec-2019
146
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.2.6: Rationale 
for 24 Months 
Maximum Treatment 
Duration  
Updated literature references 
in this section
Literature references in this section 
was updated to support rationale for 
24 months maximum treatment 
duration
Section 1.4.1: Primary 
Objective
The following changes were 
made to the primary 
objectives:
(a) Modify: Compare OS for 
participants who are 
receiving nivolumab + 
ipilimumab versus 
EXTREME regimen in 
participants with PD-L1 CPS 
≥ 20 (changed from tumor 
PD-L1 ≥ 1) and 
(b) Add: OS for nivolumab + 
ipilimumab versus 
EXTREME regimen in all 
study participants 
(irrespective of PD-L1 
expression). 
(c) Remove: The primary 
end-point of PFS for 
nivolumab + ipilimumab 
versus EXTREME regimen. 
In all of the recent studies of PD-1 
inhibitors in SCCHN, PFS did not 
capture the benefit of PD-1 therapy 
versus standard of care therapy in 
both biomarker selected and 
unselected population. Emerging 
data from multiple studies in the 
recent years (CheckMate141, 
KeyNote-040, KeyNote-048) 
demonstrated long term OS benefit 
with PD-1 inhibitor (nivolumab and 
pembrolizumab) therapy in R/M 
SCCHN population. 
 
 
 
These studies while 
suggesting OS benefit in all study 
subjects also showed with a trend 
towards better efficacy in 
participants who express PD-L1 in 
either their tumor or immune cells. 
Summary of this data also suggest
that CPS is a more appropriate PD-
L1 measure for selecting 
participants who derive the best 
benefit for immunotherapy. 
Additionally, recent data 
demonstrate the potential for 
nivolumab + ipilimumab to benefit a 
broader SCCHN patient population 
than tumor cell PD-L1 expressers 
alone.
Revised Protocol No.: 05
Date: 19-Dec-2019
147
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.4.2: 
Secondary Objective
The key secondary objective 
was changed to OS in subject 
with CPS ≥ 1
Emerging data in the last year 
demonstrates long-term OS benefit 
with PD-1 inhibitor (nivolumab and 
pembrolizumab) therapy in R/M 
SCCHN population, with a trend 
towards better efficacy in subjects 
who express PD-L1 in either their 
tumor or immune cells. Study 
KeyNote-048 demonstrated 
improved efficacy benefit for 
pembrolizumab at CPS > 1. The 
summary of this data suggests that 
Nivolumab + Ipilimumab may 
benefit the population selected based 
on PDL-1 CPS cut-off ≥ 1
Section 1.4.3: 
Exploratory Objective
(1) Efficacy evaluation based 
on biomarker subgroups
were added
(2) Exploratory objectives 
for PROs were changed PD-
L1+ positive participant to 
participants with PD-L1 
CPS ≥ 20
To investigate biomarkers (PD-L1, 
TMB, GEP etc.) which may be
predictive of efficacy.
Align with primary analysis 
population
Section 1.6: Overall 
Risk/Benefit 
Assessment
Updated overall risk-benefit 
with data from CheckMate 
141, CheckMate 012, 
 and 
KeyNote-048.
More data from recent studies were 
added as a reference to have better 
understanding about Risk/Benefit.
Section 2
Updated section with new 
language
Section 2 was updated to align with 
current standards for BMS clinical 
studies.
Section 2.1.1: Good 
Clinical Practice
Updated section with new 
language
Section 2.1 was updated to align 
with current standards for BMS 
clinical studies
Section 3.1:Study 
Design and Duration
Updated schema to reflect 
the changes in end point
The study schema was updated to 
reflect the changes in end points
Revised Protocol No.: 05
Date: 19-Dec-2019
148
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.4.1: 
Prohibited and/or 
Restricted Treatments
Added “Any live / attenuated 
vaccine (eg varicella, zoster, 
yellow fever, rotavirus, oral 
polio and measles, mumps, 
rubella (MMR) during 
treatment and until 100 days 
post last dose.”
Added guidance for the use 
of marijuana and its 
derivatives 
To align with current standards for 
BMS studies
Section 4.5.4.1: Criteria 
to Resume Nivolumab 
Dosing (Arm A)
Added criteria to clarify that  
participants 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
≤ 10 mg/day.
To align with current standards for 
BMS clinical studies
Section 6: Adverse 
Events 
Added criteria for meeting or 
not meeting AE definition.
To align with current standards for 
BMS clinical studies
Section 6.1: Serious 
Adverse Events
Added text for evaluating 
AEs and SAEs
To align with current standards for 
BMS clinical studies
Section 6.1: Overdose
Updated overdose reporting 
criteria 
To align with current standards for 
BMS clinical studies
Section 8.4.2.1: 
Analysis Methods for 
Primary Endpoints
Updated testing hierarchy in 
Figure 8.4.2.1-1 for the 
endpoints to be tested in this 
study.
Align with updated 
objectives/endpoints.
Section 8.4.2.2: 
Analysis Methods for 
Secondary Endpoints
Updated analysis methods 
for Secondary endpoints was 
changed.
Align with updated secondary 
objectives.
Section 8.4.6: 
Outcomes Research 
Analyses
Changed PD-L1+ positive 
population to randomized 
subjects with PD-L1 CPS 
≥20
Based on new endpoints, study 
population was changed.
Revised Protocol No.: 05
Date: 19-Dec-2019
149
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 04
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.1.2: Financial 
disclosure
Added statement to 
compliance section
To align with current standards for 
BMS clinical studies
Section 9.2.2: Study 
Drug Records
Added statement to 
compliance section regarding 
records for study treatments
To align with current standards for 
BMS clinical studies
Section 9.2.4: Clinical 
Study Report and 
Publications
Section updated with new 
language
To align with current standards for 
BMS clinical studies
Section 9.2.4.1: 
Scientific Publications
Section updated with new 
language
To align with current standards for 
BMS clinical studies
Throughout the 
document
Term “subject” changed to 
“participant”
To align with current standards for 
BMS clinical studies
Appendix 4
Updated “Highly Effective 
Methods That Are User 
Independent”
To align with current standards for 
BMS clinical studies
Overall Rationale for the Revised Protocol 03, 01-May-2018
The rationale for the key changes is based on the recent data from the 2-year survival update of 
CheckMate 141 (CA209141) study of nivolumab versus standard of care chemotherapy in 
recurrent or metastatic SCCHN patients post platinum therapy. The data from this update showed 
that, in the overall study population, nivolumab demonstrated 32% reduction in risk of death 
compared to chemotherapy (HR = 0.68 [95% CI: 0.54, 0.86]). Furthermore, in patients whose 
tumors expressed PD-L1 ≥1% (PD-L1 expressors), nivolumab demonstrated a 45% reduction in 
risk of death versus chemotherapy (HR = 0.55 [95% CI: 0.39, 0.78]). This recent data, while 
confirming the long-term survival benefit of check-point inhibitors in the over-all SCCHN 
population (irrespective of baseline biomarker status), also demonstrates a relatively better 
efficacy in PD-L1 expressors. Based on the summary of the above data, the current Phase 3 
CA209651 study will compare the co-primary end-points of PFS and OS between study arms in 
PD-L1 expressor population. The PFS and OS in over-all study population will be evaluated as 
secondary end-points.
It has been shown that approximately 60% of the SCCHN tumors may express PD-L1. 
Therefore, the required number of events and sample size were increased to allow adequate 
power to analyze the co-primary end-points of PFS and OS in this biomarker-selected group. The 
primary objective, endpoints, sample size and statistical analysis sections of the protocol were 
revised accordingly.
Revised Protocol No.: 05
Date: 19-Dec-2019
150
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Primary Objectives; 
Section 1.3.1
The primary objectives were 
changed from PFS and OS in
all randomized subjects to 
PFS and OS in subjects with 
PD-L1 expressing tumors.
CheckMate 141 compared 
nivolumab monotherapy to 
investigator choice monotherapy 
in platinum refractory SCCHN 
subjects. The updated analysis of 
CheckMate 141 (2-year OS 
update) provided evidence of 
efficacy in both the tumor PD-
expressor and PD-L1non-
expressor (<1%) groups. 
However, the efficacy was 
greatest in the PD-L1 expressor
group. Based on these results, the 
primary comparisons of PFS and 
OS will be conducted in the 
subjects with PD-L1 expressing 
tumors. Comparisons of these 
endpoints in all study subjects
will become secondary 
objectives.
Synopsis, Study Design; 
Statistical Considerations, 
Sample Size; Section 8.1
Sample Size determination 
was updated with sample 
size increased from 700 to 
930.
Based on the 2-year survival 
update of CheckMate 141 study, 
subjects with PD-L1 expressing 
tumors had a relatively better 
efficacy with nivolumab 
treatment. Hence, the primary 
analysis population was changed 
from all study subjects to subjects 
with PD-L1 expressing tumors. 
The required number of events 
and sample size were increased in 
order to provide adequate power 
in this biomarker-selected group. 
Power was provided for the 
primary comparisons of PFS and 
OS and for the secondary 
comparisons of these endpoints in 
all subjects.
Section 8.4.2.1, Analysis 
Methods for Co-primary 
Endpoints
Indicated that the primary 
analyses would be in PD-L1
expressors rather than in the 
entire study population.
In line with the change in the 
primary objectives.
Revised Protocol No.: 05
Date: 19-Dec-2019
151
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Section 8.4.2.2, Analysis 
Methods for Secondary 
Endpoints
Made PFS and OS in all 
study subjects secondary 
endpoints. Indicated that PFS 
in all subjects would be 
tested hierarchically after 
PFS in subjects with PD-L1 
expressing tumors and that 
OS in all subjects would be 
tested hierarchically after OS 
in subjects with PD-L1 
expressing tumors. 
Needed to ensure that the 
familywise type I error rate was 
controlled and thus needed to pre-
specify the testing hierarchy for 
secondary endpoints.
Section 8.4.5, Biomarker 
Analyses
Added brief description of 
how TMB would be 
analyzed. 
Assessment of TMB was 
introduced as an exploratory 
objective in revised protocol 02. 
However, no description of TMB
analyses was given at that time.
Nivolumab Dose 
Discontinuation
4.5.1.1 Nivolumab plus 
Ipilimumab (Arm A)
Grade 3 drug-related 
myocarditis was added into 
nivolumab dose 
discontinuation criteria.
Rare cases of myocarditis have 
been reported with nivolumab or 
nivolumab in combination with 
ipilimumab. For grade 3 
myocarditis, nivolumab or
nivolumab in combination with 
ipilimumab should be 
permanently discontinued based 
on nivolumab IB v16. 
All
Minor formatting and 
typographical corrections.
Minor, therefore have not been 
summarized.
Revised Protocol No.: 05
Date: 19-Dec-2019
152
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Overall Rationale for the Revised Protocol 02, 26-Oct-2017
The purpose of this revised protocol is to increase the sample size to account for a delay in 
separation of the Kaplan-Meier (KM) curves for both progression-free survival (PFS) and overall 
survival (OS) between the 2 treatment arms. Delayed separation of the Kaplan-Meier curves for 
nivolumab and standard of care chemotherapy was observed in CA209141, the Phase 3 study of 
nivolumab in platinum-refractory squamous cell carcinoma of the head and neck.
In addition, a maximum duration of nivolumab and ipilimumab treatment of 24 months from the 
start of treatment was added. Accumulating evidence from different clinical trials in different 
tumor types with nivolumab or nivolumab combined to ipilimumab indicates that no additional 
benefit is obtained for subjects treated beyond 24 months, and responses remain durable.
Duration of response has been changed from an exploratory objective to a secondary objective 
based on the expected improvement in duration of response as seen in other nivolumab trials. 
Response to first therapy after disease progression was changed to an exploratory endpoint to 
limit the secondary objectives only to critical endpoints. 
Tumor mutational burden has been shown to be a predictive biomarker of efficacy for checkpoint 
inhibitors in several tumors. Therefore, exploratory biomarker objectives were added in order to 
evaluate the potential associations between efficacy outcomes (such as objective response rate, 
PFS, and OS) with select biomarkers, including tumor mutational burden, from tumor tissue and 
peripheral blood. The amount of tumor tissue required for study entry was increased to allow 
enough samples for these additional exploratory analyses. 
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Investigational 
Product Arm A; Synopsis, 
Study Design; Section 
1.1.4, Rationale for 
24 Months Maximum 
Treatment Duration;
Section 3.1, Study Design 
and Duration; Section 3.2, 
Post Study Access to 
Therapy; Section 3.5, 
Discontinuation of 
Subjects Following any 
Treatment with Study 
Drug; Section 4.5.6, 
Treatment Beyond 
Disease Progression
Added the maximum 
treatment duration of 
nivolumab and ipilimumab 
of 24 months from first 
nivolumab treatment. 
Accumulating evidence from 
different clinical trials in different 
tumor types with nivolumab or 
nivolumab combined to 
ipilimumab indicates that no 
additional benefit is obtained for 
subjects treated beyond 24 
months, and responses remain 
durable. 
Synopsis, Primary 
Objectives; Section 1.3.1, 
The primary objectives of 
progression-free survival and 
For clarity.
Revised Protocol No.: 05
Date: 19-Dec-2019
153
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Primary Objectives
overall survival were 
reformatted. 
Synopsis, Secondary 
Objectives; Section 1.3.2, 
Secondary Objectives 
Moved duration of responses
(duration of response) to a 
secondary objective.
Measuring the durability of 
response is particularly important 
with IO agents because some 
subjects on IO agents have stay in 
response for an extended period 
of times. The objective was 
elevated to a secondary objective. 
Synopsis, Exploratory 
Objectives; Section 1.3.3, 
Exploratory Objectives
Moved time to symptom 
deterioration to an 
exploratory endpoint. 
Time to symptom deterioration 
was moved to an exploratory 
objective in order to limit the list 
of secondary objectives focused 
on critical endpoints.
Removed response to first 
subsequent therapy after 
disease progression 
objective.
Reliable data cannot be collected 
on this endpoint. In addition, this 
endpoint is of limited value.
Strengthened the objective 
related to the association 
between biomarkers and 
clinical outcomes. 
Added exploratory endpoint to 
support the collection of 
additional biological samples for 
biomarker analysis. 
Added an exploratory 
objective related to the 
association between tumor 
mutational burden and 
clinical outcomes.
Tumor mutational burden has 
been shown to be a predictive 
biomarker of efficacy for 
checkpoint inhibitors in several 
tumors. Therefore, it is important 
to elevate this endpoint. 
Added an exploratory 
objective related to the 
association between 
biomarker and clinical 
outcomes. 
It is important to identify the 
predictive biomarkers of response 
and prognosis in SCCHN. 
Therefore, an exploratory 
objective was added to evaluate 
select blood and tissue based 
biomarkers in tumor and blood 
samples. 
Synopsis, Study Design; 
Synopsis, Statistical 
Considerations, Sample 
Size; Section 8.1, Sample 
The sample was increased 
from 490 to 700 subjects. 
The sample size calculations were 
revised to account for the delayed 
separation of Kaplan-Meier curve 
observed in PFS and OS in 
Revised Protocol No.: 05
Date: 19-Dec-2019
154
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Size Determination
CA209141 between nivolumab 
and standard of care 
chemotherapy. Increasing the 
sample size is calculated to 
compensate for this delayed 
separation. 
Synopsis, Study 
Population
Adjusted Inclusion Criteria b 
to match the body of the 
protocol.
For clarity for sites. 
Adjusted the Exclusion 
Criteria to match the body of 
the protocol.
For clarity for sites.
Synopsis, Statistical 
Considerations, Analyses, 
Interim Analysis; Section 
8.5, Interim Analysis
Added a second interim 
analysis of OS.
Added an interim analysis of OS 
at the time of the final PFS 
analysis. 
Section 1.1.1, Rationale 
for the Combination of 
Nivolumab and 
Ipilimumab
Added text to regarding the 
results of Checkmate 141. 
To provide updated data from 
Checkmate 141.
Section 3.3.1, Inclusion 
Criteria
Adjusted Criterion 2.c for 
clarity. 
Edited for clarity. 
Revised Criterion 2.h 
regarding palliative 
radiotherapy as 2.l.
The window between radiation 
and study drug administration 
was modified to allow for patients 
with recent treatment with 
radiation based on evolving data 
on checkpoint inhibitors in 
combination with or in sequence 
with radiation that  have shown 
manageable toxicity profile.
Added criterion 2.j regarding 
life expectancy of at least 
3 months.
To provide guidance to the 
investigators on proper patient 
selection. 
Changed the duration of 
contraception use after the 
last dose for both male and 
female subjects 
To align with the Prescribing 
Information in the United States 
and the Summary of Product 
Characteristics in the European 
Union.
Revised Protocol No.: 05
Date: 19-Dec-2019
155
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 3.3.2, Exclusion 
Criteria
Added a sub-criterion to 
Criterion 2.d.
Allows for entry into the study for 
subjects who have a second 
primary SCCHN. 
Removed Criterion 2.g.
Removes exclusion criteria 
specific for pulmonary cancers 
which is not applicable to 
SCCHN.
Added Criterion 2.i.
To reduce potential for any drug-
drug interactions.
Revised Criterion 3.c.v to 
appear as Criterion 3.c.viii. 
Updated lower limit of creatinine 
to reflect clinical standards. 
Section 3.4.1, Prohibited 
and/or Restricted 
Treatments
Added botanical preparations 
as prohibited treatments.
To reduce potential for any drug-
drug interactions.
Section 3.4.2, Other 
Restrictions and 
Precautions
Adjusted exclusion from 
MRI to adhere to the center’s 
standard of care. 
Provided additional guidance for 
subject contraindicated for 
contrast agents. 
Section 1.1.4, Duration of 
Treatment
Added section. 
Described above. 
Section 3.3.1, Inclusion 
Criteria
Adjusted Criterion 2.c for 
clarity. 
Edited for clarity. 
Added Criterion 2.j and 2.k.
Edited for clarity. 
Section 3.4.3, Permitted 
Therapy
Adjusted requirements for 
pre-study radiotherapy.
To align with Inclusion Criteria
Section 4.5.1.1, 
Nivolumab plus
Ipilimumab (Arm A)
Added additional dosing 
details.
To align with the nivolumab 
program standards. 
Section 4.5.1.2, 
EXTREME Regimen 
(Arm B)
Adjusted order of this section 
and added details regarding 
platinum therapy. 
Edited for clarity.
Section 4.5.3.2, 
Nivolumab and 
Ipilimumab
Updated the dose delay 
criteria. 
To align with the Summary of 
Product Characteristics Dose 
Delay Criteria. 
Section 4.5.2.2, 
EXTREME Regimen
Provided additional guidance 
regarding dose delays for 
participants in the 
EXTREME regimen.
For clarity for the site. 
Revised Protocol No.: 05
Date: 19-Dec-2019
156
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 4.5.4.1, Criteria to 
Resume Nivolumab 
Dosing (Arm A)
Updated the criteria to 
resume treatment.
To provide clarity and eliminate 
redundancy with other sections.
Section 4.5.5.1, 
Nivolumab Dose 
Discontinuation
Updated the dose 
discontinuation criteria.
To align with the Summary of 
Product Characteristics Dose 
Delay Criteria.
Section 4.5.6, Treatment 
Beyond Disease 
Progression
Adjusted the frequency of 
subsequent scans. 
Adjusted scan frequency to same 
frequency for on study scans. 
Section 5.1, Flow 
Chart/Time and Events  
Schedule, Table 5.1-1, 
Screening Procedural 
Outline (CA209651) 
Increased the amount of 
tissue required.
Provided additional tissue for 
completion of procedures 
required during screening period. 
Clarified the imaging 
requirements for tumor 
assessments. 
Clarified the requirement for 
obtaining CT or MRI scans with 
and without contrast. 
Removed whole blood 
sample and saliva sample 
assessments, which were not 
planned for screening. 
For clarity for the sites.
Section 5.4, Efficacy 
Assessments 
Tumor assessments were 
aligned with the Time and 
Events Tables. 
For clarity for the sites. 
Section 5.5, 
Pharmacokinetic 
Assessment, Table 5.5-1, 
Pharmacokinetic (PK) and 
Immunogenicity Sample 
Collections for 
Nivolumab and 
Ipilimumab (Arm A)
Changed collection time for 
Cycle 1 Day 1.
To decrease subject burden.
Section 5.6, Biomarker 
Assessments 
Added footnote e regarding 
biopsy at progression.
To provide guidance to the sites 
on obtaining tumor biopsies after 
progression. 
Section 5.6.1, Exploratory 
Serum/plasma biomarkers
Added Plasma.
For clarity.
Section 5.6.2, Circulating 
Free DNA in Plasma
Section added.
Updated biomarker section to 
explore less invasive emerging 
technologies.
Revised Protocol No.: 05
Date: 19-Dec-2019
157
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 5.6.3, Tumor 
Tissue Specimens
Increase the tumor tissue 
requirements. 
The analysis of tumor mutational 
burden to the biomarker plan 
requires additional samples to be 
collected. 
Section 5.6.7, Whole 
Blood for Genomic 
Analyses
Changed the heading title 
and added detail regarding 
genomic testing.
Describes the addition of whole 
blood genomic testing to the 
biomarker plan. 
Section 5.7, Outcomes 
Research Assessments
Added an option for subjects 
not able to vocalize 
responses on the phone. 
Added to accommodate SCCHN 
subjects with speech impairment 
alternatives for the completion of 
questionnaires. 
Section 6.1.1, Serious 
Adverse Event Collection 
and Reporting
Added the definition of a 
SUSAR.
For clarity for the sites. 
Section 8.3.2, Secondary 
Endpoints
Added the definition of 
duration of objective 
response. 
Moved the definition of DOR to 
the section on secondary 
endpoints now that it is being 
considered a secondary objective.
Section 8.4.2.1, Analysis 
Methods for Co-primary 
Endpoints
Spelled out the levels to be 
used for the confidence 
intervals for the HRs of PFS 
and OS.
For greater clarity. 
Section 8.4.2.2, Analysis 
Methods for Secondary 
Endpoints
Spelled out the nominal 
significance level for 
comparing ORR between 
arms and the corresponding 
level for the confidence 
interval for the odds ratio.
For greater clarity.
Section 8.4.5, Biomarker 
Analyses
Added the plan for the 
analysis of the biomarker 
endpoints. 
Added to support the exploratory 
endpoint for biomarker analysis. 
Section 8.4.6, Outcome 
Research Analyses
Added analysis for TTSD.  
For clarity. 
Revised Protocol No.: 05
Date: 19-Dec-2019
158
Approved
6.0
v
Approved
1.0
v


Clinical Protocol
CA209651
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Appendix 4
Updated the Methods of 
Contraception Appendix to 
include the definition of 
women of childbearing 
potential and provide more 
detail on the methods of 
contraception allowed in the 
study. 
To update to the current 
nivolumab program standards. 
All
Minor formatting and 
typographical corrections.
Minor, therefore have not been 
summarized.
Revised Protocol No.: 05
Date: 19-Dec-2019
159
Approved
6.0
v
Approved
1.0
v

SAP_001.pdf: 
Official Title of Study: 
An Open Label, Randomized, Two Arm Phase III Study of Nivolumab in Combination with Ipilimumab 
versus Extreme Study Regimen (cetuximab + cisplatin/carboplatin + fluorouracil) as First Line Therapy in 
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) 
 
 (CheckMate 651: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 651) 
 
PROTOCOL(S) CA209-651 
 
NCT Number: NCT02741570 
  
Document Date (Date in which document was last revised): January 07, 2020 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
An Open Label, Randomized, Two Arm Phase III Study of Nivolumab in Combination with
Ipilimumab versus Extreme Study Regimen (cetuximab + cisplatin/carboplatin + fluorouracil) as
First Line Therapy in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
(SCCHN)
PROTOCOL CA209651
VERSION # 2.0
DATE: 07-JAN-2020
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................6
1
BACKGROUND AND RATIONALE......................................................................7
2
STUDY DESCRIPTION ..........................................................................................8
2.1
Study Design ............................................................................................................8
2.2
Treatment Assignment............................................................................................10
2.3
Blinding and Unblinding.........................................................................................10
2.4
Protocol Amendments.............................................................................................10
2.5
Data Monitoring Committee ...................................................................................12
2.6
Blinded Independent Central Review (BICR) .........................................................12
3
OBJECTIVES ........................................................................................................13
3.1
Primary Objectives .................................................................................................13
3.2
Secondary Objectives .............................................................................................13
3.3
Exploratory Objectives ...........................................................................................13
4
ENDPOINTS..........................................................................................................14
4.1
Primary Endpoints..................................................................................................14
4.1.1
Overall Survival .....................................................................................................14
4.2
Secondary Endpoints ..............................................................................................14
4.2.1
Overall Survival .....................................................................................................14
4.2.2
Progression-Free Survival......................................................................................14
4.2.2.1
Primary Definition of Progression-Free Survival (Accounting for Subsequent 
Therapy).................................................................................................................15
4.2.2.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy) ..............................................................................................17
4.2.3
Objective Response Rate.........................................................................................18
4.2.4
Duration of Response .............................................................................................18
4.3
Exploratory Endpoints............................................................................................19
4.3.1
PFS2 ......................................................................................................................19
4.3.2
Safety and Tolerability............................................................................................20
4.3.3
Pharmacokinetics ...................................................................................................20
4.3.4
Immunogenicity ......................................................................................................20
4.3.5
EuroQoL EQ-5D-3L...............................................................................................20
4.3.6
FACT-H&N............................................................................................................22
4.3.7
Time to Disease-related Symptom Deterioration.....................................................22
5
SAMPLE SIZE AND POWER...............................................................................22
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................23
6.1
Study Periods..........................................................................................................23
6.2
Treatment Regimens...............................................................................................25
6.3
Populations for Analyses ........................................................................................25
7
STATISTICAL ANALYSES..................................................................................26
7.1
General Methods ....................................................................................................26
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
3
7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select Adverse 
Events, Other Events of Special Interest and Immune-Mediated Adverse 
Events.....................................................................................................................26
7.1.1.1
Select Adverse Events (EU Submission) ..................................................................27
7.1.1.2
Other Events of Special Interest..............................................................................28
7.1.1.3
Immune-Mediated Adverse Events (US Submission)................................................28
7.1.2
Laboratory Tests.....................................................................................................28
7.1.3
Immunogenicity Data..............................................................................................29
7.2
Study Conduct........................................................................................................29
7.3
Study Population ....................................................................................................29
7.3.1
Subject Disposition.................................................................................................30
7.3.2
Demographics and Other Baseline Disease Characteristics....................................30
7.3.3
Medical History......................................................................................................31
7.3.4
Prior Therapy Agents .............................................................................................31
7.3.5
Physical Examinations............................................................................................31
7.3.6
Baseline Physical Measurements ............................................................................31
7.4
Extent of Exposure .................................................................................................31
7.4.1
Administration of Study Therapy.............................................................................31
7.4.2
Modifications of Study Therapy ..............................................................................33
7.4.2.1
Dose Delays ...........................................................................................................33
7.4.2.2
Infusion Interruptions and Rate Changes................................................................33
7.4.2.3
Dose Escalations ....................................................................................................33
7.4.2.4
Dose Reductions.....................................................................................................33
7.4.2.5
Dose Omissions ......................................................................................................34
7.4.2.6
Partial Discontinuation of Ipilimumab in the Arm A ...............................................34
7.4.3
Concomitant Medications.......................................................................................35
7.4.3.1
Immune Modulating Medication .............................................................................35
7.4.3.2
Subsequent Cancer Therapy ...................................................................................36
7.5
Efficacy..................................................................................................................36
7.5.1
Analysis of Objective Response Rate.......................................................................37
7.5.2
Time to Tumor Response and Duration of Response ...............................................37
7.5.3
Analysis of DCR .....................................................................................................38
7.5.4
Analysis of Progression-Free Survival....................................................................38
7.5.5
Supportive Analyses of Progression-Free Survival..................................................39
7.5.6
Analysis of Overall Survival....................................................................................39
7.5.7
Supportive Analyses of Overall Survival .................................................................40
7.5.8
Subset Analyses of Overall Survival........................................................................41
7.5.9
Current Status of PFS and OS Follow-up................................................................41
7.5.10
Interim Analyses of Overall Survival.......................................................................42
7.5.11
PFS2 ......................................................................................................................42
7.6
Safety.....................................................................................................................43
7.6.1
Deaths ....................................................................................................................43
7.6.2
Serious Adverse Events...........................................................................................43
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................43
7.6.4
Adverse Events Leading to Dose Modification........................................................43
7.6.5
Adverse Events .......................................................................................................44
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
4
7.6.6
Select Adverse Events (EU Submission) ..................................................................44
7.6.6.1
Incidence of Select AE ............................................................................................44
7.6.6.2
Time-to Onset of Select AE .....................................................................................45
7.6.6.3
Time-to Resolution of Select AE..............................................................................45
7.6.7
Immune-Mediated Adverse Events (US Submission)................................................45
7.6.8
Other Events of Special Interest..............................................................................46
7.6.9
Multiple Events.......................................................................................................47
7.6.10
Laboratory Parameters...........................................................................................47
7.6.10.1
Hematology ............................................................................................................47
7.6.10.2
Serum Chemistry ....................................................................................................47
7.6.10.3
Electrolytes.............................................................................................................47
7.6.10.4
Additional Analyses................................................................................................48
7.6.11
Vital Signs and Pulse Oximetry...............................................................................48
7.6.12
Physical Measurements ..........................................................................................48
7.6.13
Non-Protocol Medical Procedures..........................................................................49
7.6.14
Immunogenicity Analysis ........................................................................................49
7.6.15
Pregnancy ..............................................................................................................49
7.6.16
Adverse Events by Subgroup...................................................................................49
7.7
Pharmacokinetics....................................................................................................50
7.8
Biomarkers .............................................................................................................50
7.8.1
Distribution of PD-L1 CPS.....................................................................................50
7.8.2
Association Between PD-L1 CPS and Efficacy........................................................50
7.8.3
Analyses of TPS, GEP and TMB .............................................................................51
7.9
Clinical Outcomes Assessments..............................................................................51
7.9.1
EQ-5D-3L...............................................................................................................51
7.9.2
FACT-HN...............................................................................................................52
8
CONVENTIONS....................................................................................................53
9
CONTENT OF REPORTS .....................................................................................54
10
DOCUMENT HISTORY........................................................................................54
APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION 
AND CONVENTIONS FOR SELECT ADVERSE EVENTS, 
IMMUNE-MEDIATED ADVERSE EVENTS AND EVENTS OF 
SPECIAL INTEREST............................................................................55
APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS ...............................................57
APPENDIX 3
IMMUNOGENICITY ANALYSIS: BACKGROUND AND 
RATIONALE.........................................................................................59
APPENDIX 4
SEQUENTIALLY REJECTIVE PROCEDURE.....................................62
11
REFERENCES.......................................................................................................64
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
5
LIST OF TABLES
Table 2.4-1:
Protocol Amendments ............................................................................10
Table 4.2.2.1-1:
Censoring Scheme Used in Primary Definition of PFS ...........................16
Table 4.2.2.2-1:
Censoring Scheme for Secondary Definition of PFS...............................18
Table 4.3.5-1:
Time Windows for EQ-5D and FACT-HN (FHNSI-10)..........................21
Table 5-1:
Statistical Assumption and Power Calculation ........................................23
Table 7.4.1-1:
Study Therapy Parameter Definitions- Nivolumab and Ipilimumab ........31
Table 7.4.1-2:
Study Therapy Parameter Definitions-Cetuximab/5-FU..........................32
Table 7.4.1-3:
Study Therapy Parameter Definitions- Cisplatin/Carboplatin..................32
Table 7.4.2.4-1:
Dose Levels for Cetuximab, Cisplatin, Carboplatin and 5-FU.................34
Table 7.4.2.4-2:
Calculated Dose Ranges and Related Dose Levels..................................34
Table 10-1:
Document Revision History....................................................................54
Table A1-1:
Derivation of Clustered AE ....................................................................56
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
6
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic.........................................................................10
Figure 4.2.2.1-1:
PFS Primary Definition ..........................................................................16
Figure 4.2.2.2-1:
PFS Secondary Definition ......................................................................17
Figure 4.2.2.2:
PFS2 Definition......................................................................................19
Figure 7.5.6-1:
Testing Hierarchy for the Endpoints .......................................................39
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
7
1
BACKGROUND AND RATIONALE
Head and neck cancers are among the most common cancers worldwide, accounting for more than 
550,000 cases and around 300,000 deaths each year,1 and these trends are increasing. In the United 
States, there were ~45,780 new cases of oral cavity and pharynx cancer and ~8,650 people were 
expected to die of this disease in 2015.2 Approximately 90% of all head and neck cancers are 
squamous cell carcinomas. Most SCCHNs arise from the epithelial lining of the oral cavity, oro-
pharynx, larynx and hypopharynx. The most important risk factors identified in SCCHNs, include 
tobacco and alcohol use, and, in a subgroup of SCCHNs (particularly oropharynx tumors), human 
papillomavirus (HPV) as a strong independent prognostic factor, with HPV positive-infected tu-
mors associated with more favorable clinical outcomes.3
The treatment approach and prognosis for patients with SCCHN is mostly determined by the tumor 
stage at presentation. About one-third of patients present with early stage disease, whereas the 
majority present with advanced disease with lymph node metastasis. With standard of care treat-
ment, the 5-year survival for localized oral cavity and pharynx cancer is 83%, but survival drops 
to 37.7% for metastatic disease2 Approximately half of the treated population returns with recur-
rent or refractory disease, and for these patients, the 1-year survival rate ranges from 5% to 33% 
with a median overall survival (OS) of 6 to 9 months. Recurrent disease that is not amenable to 
curative-intent radiation or surgery have the same treatment approach as metastatic disease, and 
participation in a clinical trial is a recommended treatment option for these patients.4 A Phase 3 
randomized trial in first-line recurrent or metastatic (1L R/M) SCCHN showed that cetuximab plus 
platinum-fluorouracil chemotherapy (EXTREME regimen) improved survival over platinum-
fluorouracil alone as first-line treatment with a median OS of 10.1 months versus 7.4 months (Haz-
ard Ratio [HR] = 0.80, 95% CI 0.64-0.99, p = 0.04). As a result, the EXTREME regimen has been 
adapted as a standard treatment approach in this population. While the addition of cetuximab to 
platinum-fluorouracil chemotherapy improved response rates and disease control rates, the dura-
tion of response did not differ significantly between treatment regimens. Since the introduction of 
the EXTREME regimen in 2008,4 no marked improvement in survival has been achieved, with 
patients still frequently developing recurrences and distant metastasis. After progression, the lim-
ited treatment options available are associated with substantial morbidity and mortality. Thus, new 
treatment approaches need to be explored as the first-line treatment in this population.5
Checkmate 1416 showed that nivolumab monotherapy, as a second line therapy (2L) in R/M 
SCCHN, increased the length of time patients lived when compared with standard, single agent 
chemotherapy in in all study participants (HR = 0.68, 95% CI 0.54 to 0.86; p = 0.01).
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may improve 
antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-γ production 
2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased antitumor activity of 
the combination was also observed in 3 of 5 syngeneic murine cancer models. In a murine mela-
noma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
8
CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade in-
creased tumor infiltration of T effector cells and decreased intratumoral T regulatory cells, as com-
pared to either agent alone7.
The combination of ipilimumab with nivolumab showed increased activity versus nivolumab alone 
in multiple tumor types, including melanoma, multiple types of lung cancer, gastric cancer, and 
renal cancer. 
Given the similarity in patient profiles of NSCLC and SCCHN, this study will evaluate the efficacy 
and safety profile of the combination of ipilimumab with nivolumab as first-line therapy in recurrent 
or metastatic squamous cell carcinoma of the head and neck (SCCHN). 
Research Hypothesis:  
•
Subjects with PD-L1 Combined Positive Score (CPS) ≥ 20 who receive nivolumab in combi-
nation with ipilimumab for first-line treatment of recurrent or metastatic SCCHN will have 
longer OS than comparable subjects who receive the EXTREME regimen 
•
Subjects who receive nivolumab in combination with ipilimumab for first-line treatment of 
recurrent or metastatic SCCHN will have longer OS than comparable subjects who receive 
the EXTREME regimen
Schedule of Analyses:
A formal interim analysis for superiority of OS will be performed after approximately 593 OS 
events (out of 741 required, 80%) have occurred on all randomized subjects or all randomized 
subjects have been followed up for at least 12 months, whichever is later. An interim analysis for 
superiority of OS for subjects with PD-L1 CPS ≥ 20 will be performed simultaneously. An inde-
pendent statistician external to BMS will perform these analyses. 
Final analysis of OS will be conducted when approximately 741 events have occurred on all ran-
domized subjects across the two treatment arms.
2
STUDY DESCRIPTION
2.1
Study Design
Protocol CA209651 is a randomized open-label, Phase 3 trial in subjects ≥18 years old with un-
treated metastatic or recurrent SCCHN that is not amenable to curative therapy, evaluating 
nivolumab + ipilimumab versus the EXTREME regimen (cetuximab + cisplatin/carboplatin + 
fluorouracil) as a first-line treatment.
Subjects will undergo screening evaluations to determine eligibility prior to randomization. Ap-
proximately 930 subjects will be randomized to the two treatment arms in a 1:1 ratio and stratified 
by the following factors: 
•
Tumor cell PD-L1 status (expressing [≥1%] vs non-expressing [< 1%] or non-evaluable). Up 
to 10% of randomized subjects per cohort can be included into the study as “non-evaluable.” 
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 “ex-
pressing” or non-expressing” in order to randomize the subject. 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
9
•
HPV p-16 status (oropharyngeal HPV p-16 positive vs oropharyngeal HPV p-16 negative or 
non-oropharyngeal).
•
Prior chemotherapy (adjuvant/neoadjuvant/multimodal treatment) status (Yes/No)
The dose and treatment schedules for each arm are as follows:
•
Arm A: Nivolumab + Ipilimumab Arm:
−
Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until pro-
gression, unacceptable toxicity, or a maximum of 24 months from first study treatment.
•
Arm B: EXTREME regimen Arm: 
−
Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin 
(100 mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluor-
ouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed 
by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing 
information) until disease progression or unacceptable toxicity; the choice of cisplatin or 
carboplatin is at the discretion of the investigator.
Tumor progression or response will be assessed by investigator using RECIST 1.1 criteria. Treat-
ment with study medication will continue until RECIST 1.1 defined progression, unacceptable 
toxicity, a maximum of 24 months from the first study treatment, or withdrawal of consent. 
Dose reductions will be not be allowed for nivolumab or ipilimumab.
Treatment beyond initial investigator-assessed progression (either clinical or radiographical) is 
permitted for nivolumab and ipilimumab if the subject has an investigator-assessed clinical benefit 
and is tolerating study drug.
In addition to investigator assessment of response and progression, there will be a blinded inde-
pendent central review (BICR) of tumor scans and study sites will need to submit tumor scans for 
central radiology review.
A 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 pro-
tocol CA209651.
The maximum duration of the study from start of randomization to final analysis of OS is projected 
to be 51 months, assuming 26 months accrual duration. Additional survival follow-up may con-
tinue for up to 5 years from the time of this analysis. The study will end once survival follow-up 
has concluded.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
10
The study design schematic is presented in Figure 2.1-1.
Figure 2.1-1:
Study Design Schematic
2.2
Treatment Assignment
This is an open label, randomized, Phase 3 trial in subjects ≥18 years old with untreated metastatic 
or recurrent SCCHN that is not amenable to curative therapy. 
Subjects in each arm will be stratified by:
•
Tumor cell PD-L1 status (expressing [≥1%] vs non-expressing [< 1%] or non-evaluable)
•
HPV p-16 status (oropharyngeal HPV p-16 positive vs oropharyngeal HPV p-16 negative or 
non-oropharyngeal)
•
Prior chemotherapy (adjuvant/neoadjuvant/multimodal treatment) status (Yes/No)
Subjects will be randomized in 1:1 and treated with one of open-label treatments Arm A or Arm 
B.
2.3
Blinding and Unblinding
This is an open label study. However, the sponsor is strictly prohibited from looking at unblinded 
aggregate efficacy data while the study is still ongoing. The sponsor is forbidden from looking at 
data by arm while the study is ongoing.
2.4
Protocol Amendments
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Changes
Revised Protocol 
05
    19-Dec-2020
•
Removed second interim analysis of OS.
•
Added a Myocarditis adverse event management algorithm.
Revised Protocol 
04
    20-Jun-2019
•
The primary objectives were changed to compare:
- OS for subjects who are receiving nivolumab + ipilimumab versus 
EXTREME regimen in subjects with PD-L1 CPS ≥ 20 (changed 
from tumor PD-L1 ≥ 1) and
- OS for subjects who are receiving nivolumab + ipilimumab versus 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
11
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Changes
EXTREME regimen in all study subjects (irrespective of PD-L1 ex-
pression).
•
Description  of the  statistical  analyses  were  changed  based  on the 
changes in objectives
•
Key secondary objective was changed to OS in subject with PD-L1
CPS ≥ 1.
•
Efficacy  evaluation  based  on  biomarker  subgroups  were added  
to exploratory objectives.
•
Added supporting data for change in objectives from recent years 
and updated literature references
•
Updated protocol to align with current standards for BMS clinical 
studies.
•
Minor formatting and typographical corrections.
Revised Protocol 
03
01-May-2018
•
The primary objectives were changed from PFS and OS in all ran-
domized subjects to PFS and OS in subjects with PD-L1 expressing 
tumors.
•
PFS and OS in all study subjects moved to secondary endpoints.
•
The hierarchy for the analysis was updated -PFS in all study subjects 
would be tested hierarchically after PFS in subjects with PD-L1 ex-
pressing tumors. OS in all study subjects would be tested hierarchi-
cally after OS in subjects with PD-L1 expressing tumors.
•
The sample size was increased to allow for evaluation of the updated
primary end-points. The sample size determination was updated ac-
cordingly.
•
Added brief description of the analysis of TMB data.
•
Change in medical monitor and study director for the study (Admin-
istrative Letter 04 (date of issue:20-Mar-2018))
•
Added that nivolumab should be permanently discontinued in case 
of grade 3 drug-related myocarditis.
•
Minor formatting and typographical corrections.
Revised Protocol 
02
26-Oct-2017
•
The sample size was increased.
•
A maximum duration of nivolumab and ipilimumab treatment of 24
months from the start of treatment was added.
•
Duration of response has been changed from an exploratory objec-
tive to a secondary objective based on the expected improvement in-
duration of response as seen in other nivolumab trials. Response to 
first therapy after disease progression was changed to an exploratory 
endpoint to limit the secondary objectives only to critical endpoints.
•
Exploratory biomarker objectives were added in order to evaluate 
the potential associations between efficacy outcomes (such as objec-
tive response rate, PFS, and OS) with select biomarkers, including 
tumor mutational burden, from tumor tissue and peripheral blood.
Administrative 
Letter 03
06-Oct-2016
Change in medical monitor. 
Administrative 
14-Sep-2016
Change to section 5.8, Additional Research section modified.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
12
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Changes
Letter 02
Revised Protocol 
01
22-Jun-2016
Incorporates Amendment 02
Amendment 02
22-Jun-2016
Week 7 biopsy optional instead of required, Section 5.8 “Additional Re-
search” added, PK and IMG Follow up visit samples no longer required
to be collected, Radiographic Imaging wording updated for clarification.
Updated Algorithms for Renal, Pulmonary and Skin to match with up-
dated Nivolumab IB v15 (includes Nivo IB 15 erratum update). Other
minor edits, clarifications, corrections.
Original Protocol
23-Mar-2016
Not applicable
* Other protocol amendments are site specific and did not require protocol to be updated.
2.5
Data Monitoring Committee
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. The DMC will act in an advisory capacity to BMS and will monitor subject safety data 
for the study.
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 are specified in the DMC charter.
2.6
Blinded Independent Central Review (BICR)
A BICR will be employed for interpretation of radiographic progression events. At the time of 
investigator-assessed initial radiographic progression per RECIST 1.1 criteria in any given subject, 
the site must request the independent central review from the third party radiology vendor for 
confirmation of progression. 
Tumor assessments for each subject should be submitted to the radiology vendor as they are per-
formed on an ongoing basis. The blinded, independent radiologists will review all available tumor 
assessments for that given subject and determine if RECIST 1.1 criteria for progression have been 
met. The independent assessment of whether or not the given subject met criteria for progression 
will be provided to the site. Subjects whose disease progression is not confirmed centrally will be 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
13
required to continue treatment and tumor assessments according to the protocol-specified sched-
ule. Subsequent tumor assessments must be submitted to the third party radiology vendor for sub-
sequent review and may be discontinued when the investigator and independent radiologists both 
assess the subject to have met criteria for progression.
The BICR will also review tumor images in all randomized subjects to determine RECIST 1.1 best 
overall response for the analyses of ORR. 
At time of analysis of ORR, tumor assessments will use BICR in all randomized subjects to deter-
mine progression and response for the analyses of PFS and ORR. Details of the BICR responsibil-
ities and procedures will be specified in the BICR charter.
3
OBJECTIVES
3.1
Primary Objectives
•
To compare the OS of subjects with PD-L1 CPS ≥ 20 who are receiving nivolumab combined 
with ipilimumab to those receiving EXTREME regimen.
•
To compare the OS of all study subjects who are receiving nivolumab combined with 
ipilimumab to those receiving EXTREME regimen
3.2
Secondary Objectives
•
To compare the OS of subjects with PD-L1 CPS ≥ 1 who are receiving nivolumab combined 
with ipilimumab to those receiving EXTREME regimen
•
To evaluate progression-free survival (PFS) based on BICR in all study subjects and those 
with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen.
•
To evaluate objective response rate (ORR) based on BICR in all study subjects and those with 
PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen. 
•
To evaluate the duration of response (DOR) based on BICR in all study subjects and those 
with PD-L1 CPS ≥ 20 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen.
3.3
Exploratory Objectives
•
To evaluate OS of subjects with tumor cell PD-L1 < 1% and PD-L1 CPS < 20 who are 
receiving nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate the OS of subjects with tumor inflammation score measured as gene expression 
profile (GEP) ≥ 10 who are receiving nivolumab combined with ipilimumab, and those 
receiving EXTREME regimen. 
•
To evaluate the OS of subjects with tumor mutation burden (TMB) ≥ 7 who are receiving 
nivolumab combined with ipilimumab, and those receiving EXTREME regimen. 
•
To evaluate clinical outcomes (OS, PFS, ORR, DOR) by select baseline and on-treatment 
biomarker expression levels in peripheral blood and tumor biopsy specimens.
•
To assess safety and tolerability of nivolumab in combination with ipilimumab and of 
EXTREME regimen, in all study subjects
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
14
•
To characterize pharmacokinetics and immunogenicity of nivolumab in combination with 
ipilimumab as first line therapy in subjects with recurrent or metastatic SCCHN
•
To evaluate time to symptom deterioration (TTSD) in each arm as assessed using the
Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) 10-item Symptom 
Index (FHNSI-10), in subjects with PD-L1 CPS ≥ 20 and also in all study subjects
•
To assess the subject’s overall health status and health utility using the 3-level version of the 
EQ-5D (EQ-5D-3L) visual analog scale (VAS) and utility index, respectively, in subjects with 
PD-L1 CPS ≥ 20 and also in all study subjects
•
To assess the subject’s cancer-related symptoms and quality of life using components of the 
FACT-H&N questionnaire, in subjects with PD-L1 CPS ≥ 20 and also in all study subjects.
4
ENDPOINTS
4.1
Primary Endpoints
4.1.1
Overall Survival
•
OS in randomized subjects with PD-L1 CPS ≥ 20 
•
OS in all randomized subjects
Overall survival (OS) is defined as the time from randomization to the date of death from any 
cause. For subjects that are alive, their survival time will be censored at the date of last contact
date (or “last known alive date”). Overall survival will be censored at the date of randomization
for subjects who were randomized but had no follow-up.
OS rate at time T is defined as the probability that a subject is alive at time T following randomi-
zation.
Survival follow-up will be conducted every 3 months after subject’s off-treatment date.
4.2
Secondary Endpoints
4.2.1
Overall Survival 
Overall survival (OS) in randomized subjects with PD-L1 CPS ≥ 1 is defined the same way as for 
the primary endpoints.
4.2.2
Progression-Free Survival
Two definitions are used for analysis of Progression-Free Survival (PFS). The primary definition 
accounts for subsequent therapy by censoring at the last evaluable tumor assessment on or prior to 
the date of subsequent therapy. The secondary definition is irrespective of subsequent therapy and 
does not account for subsequent therapy. 
Clinical deterioration in the absence of unequivocal evidence of progression (per RECIST v1.1
criteria) is not considered progression for purposes of determining PFS.
PFS rate at time T is defined as the probability that a subject has not progressed and is alive at 
time T following randomization.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
15
The first on-study tumor assessment is scheduled to be conducted at 6 weeks (± 1 week) following 
randomization. Subsequent tumor assessments are scheduled every 6 weeks (± 1 week) up to 
12 months, then every 12 weeks until disease progression.
4.2.2.1
Primary Definition of Progression-Free Survival (Accounting for 
Subsequent Therapy)
The primary definition of PFS (PFS truncated at subsequent therapy) is defined as the time between 
the date of randomization and the date of first documented tumor progression, based on BICR 
assessments (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Figure 
4.2.2.1-1 show the graphic display of primary definition of PFS. 
Subjects who die without a reported progression will be considered to have progressed on the date 
of their death. The following censoring rules will be applied for the primary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on 
their date of randomization.
•
Subjects who receive subsequent anti-cancer therapy prior to documented progression will be 
censored at the date of the last evaluable tumor assessment conducted on or prior to the date 
of initiation of the subsequent anti-cancer therapy.
•
Subjects who did not have a documented progression and received subsequent anti-cancer 
therapy will be censored at the date of the last evaluable tumor assessment conducted on or 
prior to the initiation of the subsequent anti-cancer therapy.
Censoring rules for the primary definition of PFS (PFS truncated at subsequent therapy) are pre-
sented as follows and in Table 4.2.2.1-1.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
16
Figure 4.2.2.1-1:
PFS Primary Definition
Table 4.2.2.1-1:
Censoring Scheme Used in Primary Definition of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments*
Date of randomization
Censored 
No on study tumor assessments and 
no death*
Date of randomization
Censored
Subsequent anti-cancer therapy 
started without death or progression 
per RECIST v1.1 reported prior or 
on the same day
Date of last evaluable tumor assess-
ment prior to or on the date of initi-
ation of the subsequent anti-cancer 
therapy
Censored 
Documented progression per RE-
CIST v1.1 and no new anti-cancer 
started before
Date of the first documented pro-
gression per RECIST v1.1
(excludes clinical progression)
Progressed 
No progression and no death, and 
no new anti-cancer therapy started
Date of last evaluable tumor assess-
ment 
Censored 
Death without progression per RE-
CIST v1.1 and no new anti-cancer 
started before
Date of death
Progressed 
* Tumor assessments and death if any, occurring after start of subsequent anti-cancer therapy are not considered.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
17
4.2.2.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy)
The secondary definition of PFS (ITT definition) is defined as the time between the date of ran-
domization and the date of first documented tumor progression, based on BICR assessments (per 
RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Figure 4.2.2.2-1 show 
the graphic display of secondary definition of PFS. 
Subjects who die without a reported progression will be considered to have progressed on the date 
of their death. The following censoring rules will be applied for the secondary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on 
their date of randomization.
Censoring rules for the secondary definition of PFS (ITT definition) are presented as follows and 
in Table 4.2.2.2-1.
Figure 4.2.2.2-1:
PFS Secondary Definition
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
18
Table 4.2.2.2-1:
Censoring Scheme for Secondary Definition of PFS
Situation
Date of Progression of Censoring
Outcome
No baseline tumor assessment
Date of randomization
Censored
No on-study tumor assessments and 
no death
Date of randomization
Censored
Documented progression per RE-
CIST v1.1 
Date of first documented progres-
sion per RECIST v1.1 criteria (ex-
cludes clinical progression)
Progressed
No progression and no death
Date of last evaluable tumor assess-
ment
Censored
Death without progression per RE-
CIST v1.1
Date of death
Progressed
4.2.3
Objective Response Rate
Objective Response Rate (ORR) is defined as the number of randomized subjects who achieve a 
best response of complete response (CR) or partial response (PR) based on BICR assessments 
(using RECIST v1.1 criteria) divided by the number of all randomized subjects. Best Overall Re-
sponse (BOR) is defined as the best response, as determined by the BICR, recorded between the 
date of randomization and the date of objectively documented progression per RECIST v1.1 cri-
teria or the date of subsequent therapy (including tumor-directed radiotherapy and tumor-directed 
surgery), whichever occurs first. For subjects without documented progression or subsequent ther-
apy, all available response designations will contribute to the BOR determination. Confirmation 
of response is required at least 4 weeks after the initial response.
4.2.4
Duration of Response
Duration of Response (DOR) is defined as the time between the date of first documented response 
(CR or PR) to the date of the first documented tumor progression as determined by the BICR (per 
RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Subjects who start sub-
sequent therapy without a prior reported progression will be censored at the last evaluable tumor 
assessments prior to initiation of the subsequent anticancer therapy. Subjects who die without a 
reported prior progression will be considered to have progressed on the date of their death. Subjects 
who neither progress nor die, DOR will be censored on the date of their last evaluable tumor as-
sessment. DOR will be evaluated for responders (confirmed CR or PR) only.
As a supportive endpoint to DOR, Time to Response (TTR) is usually provided along with DOR 
and is defined as the time from randomization to the date of the first confirmed documented re-
sponse (CR or PR), as assessed by the BICR. TTR will be evaluated for responders (confirmed CR 
or PR) only.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
19
4.3
Exploratory Endpoints
Efficacy endpoints (OS, PFS, ORR, DOR) in selected subgroups (based on biomarkers such as 
PDL1 CPS, PDL1 TPS, GEP and TMB) are defined the same way as described in Section 4.1 and 
4.2. Other exploratory endpoints are described as follows. 
4.3.1
PFS2
Although not specified in the protocol, PFS on next-line therapy (PFS2) is added as an exploratory 
endpoint to further evaluate the efficacy of the investigational therapy vs the Extreme Regimen.
PFS2 is defined as the time from randomization to objectively documented progression, per inves-
tigator assessment, after the next line of therapy or to death from any cause, whichever occurs first. 
Subjects who were alive and without progression after the next line of therapy will be censored at 
last known alive date. 
The following censoring rules will be applied for PFS2:
1. Subjects who did not receive subsequent anti-cancer therapy (i.e. second-line therapy):
−
Subjects who died, the death date is the event date;
−
Else the subject’s PFS2 is censored at the last known alive date.
2. Subjects who received subsequent anti-cancer therapy (i.e. second-line therapy):
−
Subjects who had a disease progression after the start of subsequent anti-cancer therapy,
this disease progression date is the event date;
−
Else if a subject died or started second next line therapy, the date of min (death, start date
of second next line therapy) is the event date;
−
Else the subject’s PFS2 is censored at the last known alive date.
Figure 4.2.2.2:
PFS2 Definition
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
20
4.3.2
Safety and Tolerability
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, adverse events leading to dose modifi-
cation, select adverse events (select AEs) for EU Submission, immune-mediated AEs (IMAEs) for 
US Submission, other events of special interest (OEOSI), and deaths. The use of immune modu-
lating concomitant medication will be also summarized. In addition clinical laboratory tests, and 
immunogenicity (i.e. development of anti-drug antibody) will be analyzed.
4.3.3
Pharmacokinetics
PK will be determined from serum concentrations of nivolumab in combination with ipilimumab. 
Samples will be collected to characterize pharmacokinetics of nivolumab in combination with 
ipilimumab and to explore exposure-safety and exposure-efficacy relationships. 
4.3.4
Immunogenicity
Serum samples collected for immunogenicity will be assessed for nivolumab and ipilimumab anti-
drug-antibodies (ADA) and characterization of neutralizing antibodies.  The immunogenicity data 
will be used to determine immune response rates and relationship of ADA with clinical safety and
efficacy.
4.3.5
EuroQoL EQ-5D-3L
Subjects’ reports of general health status will be assessed using the EuroQoL Group’s EQ-5D-3L8. 
EQ-5D-3L essentially has 2 components: the descriptive system and the visual analogue scale 
(VAS).
The instrument’s descriptive system consists of 5 dimensions:  mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting "no health prob-
lems," "moderate health problems," and "extreme health problems." A dimension for which there 
are no problems is said to be at level 1, while a dimension for which there are extreme problems 
is said to be at level 3.  Thus, the vectors 11111 and 33333 represent the best health state and the 
worst health state, respectively, described by the EQ-5D-3L. Altogether, the instrument describes 
35 = 243 health states. Empirically derived weights can be applied to an individual’s responses to 
the EQ-5D-3L descriptive system to generate an index measuring the value to society of his or her 
current health. Such preference-weighting systems have been developed for the UK, US, Spain, 
Germany, and numerous other populations. For this study, EQ-5D-3L utility index values will be 
computed using a scoring algorithm based on the United Kingdom Time-Trade-Off9 (UK TTO) 
value set.
In addition, the EQ-5D-3L includes a VAS, which allows respondents to rate their own current 
health on a 101-point scale ranging from 0=”worst imaginable” health to 100=“best imaginable”
health state.
A change from baseline of 0.08 for the EQ-5D-3L utility index score and of 7 for the EQ-5D-3L 
VAS are considered minimally important differences10 for the EQ-5D-3L.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
21
All questionnaires completed at baseline and on-study will be assigned to a time-point according 
to the windowing criteria in Table 4.3.5-1 and included in the analysis. In case a subject has two 
on-study assessments within the same window, the assessment closest to the time-point will be 
used. And, in the case of two assessments at a similar distance to the time-point, the latest one will 
be chosen. In the event where the subject has no assessment at all in a specific window, the obser-
vation will be treated as missing for that time-point.
Table 4.3.5-1:
Time Windows for EQ-5D and FACT-HN (FHNSI-10)
Nominal Time-Point
Time Window
Week 1 (Baseline)
≤ Date of first dose of study therapy  
On-Treatment: (until last dose date)
   Week 7 (Day 43)
Day 2 - ≤ Day 64
   Week 13 (Day 85) 
Day 65 - ≤ Day 106
   Week 19 (Day 127) 
Day 107 - ≤ Day 148
    Every 6 weeks thereafter while on treatment 
Nominal Day (+ 21 days / - 20 days,  inclusive)
Follow-up Visits 1 and 2
     Follow-up 1
If assessment is post last dose and within 76 days of 
last dose (if date of discontinuation is within 35 day af-
ter last dose)
If assessment is post last dose and within 45 days of 
date of discontinuation (if date of discontinuation is 
greater than 35 days after last dose)
     Follow-up 2
If assessment is post 76 days of last dose and within 
173 days of last dose (if date of discontinuation is 
within 35 day after last dose)
If assessment is post 45 days of date of discontinuation 
and within 137 days of date of discontinuation (if date 
of discontinuation is greater than 35 days after last 
dose)
Survival Follow-up Visit 
     Survival Follow-up Visit 1
If 173 < assessment date - last dose date 
≤173 + 90 (if date of discontinuation is within 
35 days after last dose)
If 137 < assessment date - date of discontinuation ≤
137 + 90 (if date of discontinuation is greater than 35 
days after last dose
     Survival Follow-up  Visit i
If 173 + (i-1) * 90 < assessment date - last dose date 
≤173 + i * 90 (if date of discontinuation is within 
35 days after last dose)
If 137 + (i-1) * 90 < assessment date - date of discon-
tinuation ≤137 + i * 90 (if date of discontinuation is 
greater than 35 days after last dose
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
22
Table 4.3.5-1:
Time Windows for EQ-5D and FACT-HN (FHNSI-10)
Nominal Time-Point
Time Window
  ......
......
4.3.6
FACT-H&N
The FACT-H&N questionnaire will be used to assess the effects of disease symptoms on function-
ing and well-being. As a generic cancer-related core, the FACT-H&N includes the 27-item 
FACT-General (FACT-G) to assess physical well-being (PWB; seven items), social/family 
well-being (SWB; seven items), emotional well-being (EWB; six items), and functional well-being 
(FWB; seven items). The FACT-H&N includes a 12-item disease-specific Head and Neck Cancer 
(HNC) subscale that assesses concerns related to vocalization, communication, breathing, eating, 
swallowing, appearance, and bother due to adverse events. Ten items included in the PWB, EWB, 
FWB, and HNC subscales contribute to the scoring of the FHNSI-10, which can be used to provide 
a targeted assessment of the effects of head and neck cancer symptoms. Each FACT-H&N item is 
rated on a five-point scale ranging from 0 (not at all) to 4 (very much). Scores for the PWB, FWB, 
SWB, and EWB subscales can be combined to produce a FACT-G total score, which provides an 
overall indicant of generic quality of life, while the FACT-G and HNC subscale scores can be 
combined to produce a total score for the FACT-H&N, which provides a composite measure of 
general and targeted quality of life. A variant of the total score that is often more sensitive to 
physical and functional outcomes, the Trial Outcome Index (TOI), can be derived by summing 
scores for the PWB, FWB, and HNC subscales. All scores are scaled so that higher values indicate 
better functioning as well as lower symptom burden.
The analysis window is the same as presented in Table 4.3.5-1.
4.3.7
Time to Disease-related Symptom Deterioration 
Time to disease-related symptom deterioration (TTSD) is defined as the time from randomization 
to a clinically meaningful decline from baseline FHNSI-10 score (worsening from baseline ≥3 
points11).
5
SAMPLE SIZE AND POWER
The primary objectives of this study are to compare OS between treatment groups, in all random-
ized subjects and randomized subjects with PD-L1 CPS ≥ 20. OS will be compared at the 0.025 al-
pha level for each of the above two populations.
The OS comparison in all randomized subjects will require up to 741 deaths. This number of events 
ensures that a two-sided, alpha = 0.025 group sequential test using the O’Brien and Fleming spend-
ing function and with an interim analysis after approximately 80% of events, will have overall 
97% power for a HR of 1.2 for the first 7 months and 0.55 thereafter. 
Delayed separation of KM curves is included in the alternative hypotheses for OS because it was 
observed in CA209141, a randomized phase 3 study of nivolumab versus investigator’s choice 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
23
therapy in platinum-refractory, recurrent/metastatic SCCHN12 and in  KEYNOTE-048, a random-
ized phase 3 study of pembrolizumab or pembrolizumab plus chemotherapy versus cetuximab with 
chemotherapy in untreated recurrent/metastatic SCCHN13.
The final analysis of OS in all randomized subjects is projected to occur 51 months after the first 
patient was randomized. An interim analysis in this population will be performed when approxi-
mately 593 deaths occur, or all randomized subjects have been followed up for at least 12 months, 
whichever is later. It is projected for 39 months after the first patient was randomized. 
At the same time as the OS analysis is done for all randomized subjects, OS will also be compared 
between arms in the randomized subjects with PD-L1 CPS ≥ 20 population via a two-sided, alpha 
= 0.025 group sequential test procedure incorporating the O’Brien and Fleming alpha spending 
function. The group sequential test would have an interim analysis and the final analysis of OS, 
at which approximately 298 and 372 deaths, respectively, are expected. With this many events, the 
test procedure would have an overall 99% power if the HR was 1.06 for the first 7 months and 
0.45 thereafter. Table 5-1 summarizes the statistical assumption and power calculation.
Table 5-1:
Statistical Assumption and Power Calculation
Primary endpoints
OS for ITT (N = 930)
OS for PD-L1 CPS ≥ 20 (N = 465)
Median OS months (N+I/ EXTREME 
regimen)
13/10.8
14.9/10.8
Average hazard ratio
0.74
0.61
Alpha level (IA/FA)
0.01/0.022
0.01/0.022
Event Number (IA/FA)
593/741
298/372
Critical hazard ratio (IA/FA)
0.81/0.845
0.74/0.788
Power (IA/FA)
66%/97%
87%/99%
Estimated time of LPLV (IA/FA)
39/51 months
39/51 months
If comparison of OS in the randomized subjects with PD-L1 CPS ≥ 20 is significant, OS in ran-
domized subjects with PD-L1 CPS ≥ 1 will be subsequently tested at the same time using group 
sequential testing procedure. The interim and final analyses of this endpoint are expected to ob-
serve approximately 505, and 632 deaths at time of analyses, and the corresponding power is 74%, 
and 98% respectively with an average hazard ratio of 0.7.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Baseline period:
−
Baseline evaluations or events will be defined as evaluations or events that occur before 
the date and time of the first dose of study treatment. Evaluations (laboratory tests, pulse
and vital signs) on the same date and time of the first dose of study treatment will be 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
24
considered as baseline evaluations. Events (AEs) on the same date and time of the first 
dose of study treatment will not be considered as pre-treatment events.
−
In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
♦Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment;
♦Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations with a date on or prior to the day of first dose of study treatment.
−
If there are multiple valid assessments on or prior to the first dose of study treatment:
♦For laboratory tests, the latest non missing labs value on or before first dose date (and 
time if collected) will be used as the baseline in the analyses. For 'LIPASE' and 
'GLUCOSE', for treated subjects only, the last predose assessment with non-missing 
toxicity grade will be considered as baseline. If multiple assessments exist with the 
same collection date (and time if collected) and entry date and time, then the first 
observation is used as baseline.
♦For Eastern Cooperative Oncology Group (ECOG) performance status (PS), the latest 
ECOG PS value prior to or on the first dose date (and time if collected) will be used as 
the baseline in the analyses. If multiple records fall on the last date then the record with 
the highest value of ECOG PS will be considered as baseline.
♦For PD-L1, among the records prior to or on first dose date (and time if collected), 
identify first those with quantifiable test result. If there are no records with quantifiable 
test result, then select those with indeterminant result (“INDETERMINATE”). If there 
are no records with indeterminant test result, then select those with unavailable result 
(“NOT EVALUABLE). If there are no records with unavailable test result, then select 
those with not reported or not available result (all other records). The latest record will 
be used as the baseline in the analyses. If there is more than one record for the latest 
date, then choose the one with the greatest specimen ID.
♦For Anti-Drug Antibody (ADA), the record related to the most recent assessment 
among those records where date (and time if collected) of nivolumab/ipilimumab
immunoglobulin (IMG) assessment is less than or equal to the date (and time if 
collected) of the first nivolumab/ipilimumab dose date.
•
Post baseline period:
−
On-treatment AEs will be defined as AEs with an onset date and time on or after the date 
and time of the first dose of study treatment (or with an onset date on or after the day of 
first dose of study treatment if time is not collected or is missing). For subjects who are off 
study treatment, AEs will be included if event occurred within a safety window of 100 days 
after the last dose of study treatment. No “subtracting rule” will be applied when an AE 
occurs both pre-treatment and post-treatment with the same preferred term and grade.
−
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations taken after the day (and time, if collected and not missing) of first dose of 
study treatment. For subjects who are off study treatment, evaluations should be within a 
safety window of 100 days after the last dose of study treatment.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
25
−
Late-emergent drug-related AEs will be defined as drug-related AEs with an onset date
greater than 100 days after the last dose of study treatment in subjects who are off study
treatment.
6.2
Treatment Regimens
Treatment group “as randomized” corresponds to the treatment group assigned by the Interactive 
Response Technology (IRT) system.
•
Arm A:  Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until
progression, unacceptable toxicity, or a maximum of 24 months from first study treatment.
•
Arm B: Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin
(100 mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil
(1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by mainte-
nance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information)
until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at
the discretion of the investigator.
The treatment group “as treated” will be same as the treatment group “as randomized” by IRT 
unless a subject received the incorrect study treatment for the entire period of treatment, in which 
case the subject’s treatment group “as treated” will be defined as the incorrect study treatment.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Unless otherwise specified, the efficacy analysis will be based on the treatment group “as random-
ized”.
6.3
Populations for Analyses
•
All Enrolled Subjects: All subjects who signed an informed consent form and were registered
into the IVRS.
•
All Randomized Subjects: All enrolled subjects who were randomized to either treatment arm.
•
All Randomized PD-L1 CPS ≥ 20 Subjects: All randomized subjects with PD-L1 CPS ≥ 20
•
All Randomized PD-L1 CPS ≥ 1 Subjects: All randomized subjects with PD-L1 CPS ≥1.
•
All Randomized Tumor PD-L1 expression < 1% Subjects: All randomized subjects with Tu-
mor PD-L1 expression < 1%
•
All Randomized PD-L1 CPS < 20 Subjects: All randomized subjects with PD-L1 CPS <20
•
All Randomized GEP ≥ 10 Subjects: All randomized subjects with GEP ≥ 10.
•
All Randomized TMB ≥ 7 Subjects: All randomized subjects with TMB ≥ 7.
•
All Treated Subjects: All subjects who received at least one dose of nivolumab, ipilimumab,
cetuximab, cisplatin, carboplatin or 5-FU.
•
Treated Subjects with PD-L1 CPS ≥ 20: All subjects who received at least one dose of
nivolumab, ipilimumab, cetuximab, cisplatin, carboplatin or 5-FU and have PD-L1 CPS ≥20
at baseline.
•
All PK Subjects: All subjects with available serum time-concentration data
•
Immunogenicity Evaluable Subjects:
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
26
−
Nivolumab ADA Evaluable Subjects: all treated subjects with baseline and at least
1 post-baseline pre-infusion nivolumab immunogenicity assessment.
−
Ipilimumab ADA Evaluable Subjects: all treated subjects with baseline and at least
1 post-baseline pre-infusion ipilimumab immunogenicity assessment.
•
All PD-L1 CPS Tested subjects: All subjects, randomized or not, who had a tumor biopsy
specimen available for tumor cell expression testing. This includes both randomized and screen
failure subjects.
Key analyses of study conduct, demographics, and efficacy will be done on the all randomized 
population and repeated on the randomized PD-L1 CPS ≥ 20 population. Subjects in these analyses 
will be grouped as assigned at randomization.
Key analyses of exposure and safety will be done on the all treated population and repeated on the 
treated PD-L1 CPS ≥ 20 population. Subjects in these analyses will be grouped by treatment re-
ceived rather than treatment assigned at randomization. Treatment arm received will be equal to 
treatment arm as randomized, unless the subject received the non-assigned regimen for all doses.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment. Percentages given in these tables will be 
rounded to the first decimal and, therefore, may not always sum to 100%. Percentages less than 
0.1 will be indicated as ‘< 0.1’. Continuous variables will be summarized by treatment group using 
the mean, standard deviation, median, minimum, and maximum values.
Time-to-event variables (e.g. time-to resolution) will be analyzed using the Kaplan-Meier tech-
nique. When specified, the median will be reported along with 95% CI using Brookmeyer and 
Crowley method14 (using log-log transformation for constructing the confidence intervals15).
The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select 
Adverse Events, Other Events of Special Interest and Immune-Mediated 
Adverse Events
Drug-related AEs are those events with relationship to study drug “Related”, as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Serious adverse events consist of AEs deemed serious by the Investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken regarding study 
drug(s) = “Drug was discontinued”. 
Adverse events leading to dose delay are AEs with action taken regarding study drug(s) = “Drug
was delayed”.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
27
Adverse events leading to dose reduction are AEs with action taken regarding study drug(s) = 
“Dose was reduced”.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and the most recent version of the dictionary at the time of the database lock will be used. Adverse 
events results will be graded for severity using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) and the most recent version of the criteria at the time of the database lock will 
be used.
In the AE summary tables, unless otherwise specified, subjects will be counted only once at the 
Preferred Term (PT), only once at the System Organ Class (SOC), and only once at subject level 
for the counting of total number of subjects with an AE. The AE tables will be sorted by the SOCs 
and then PTs. SOC will be ordered by descending frequency overall and then alphabetically. PTs 
will be ordered within SOC by descending frequency overall and then alphabetically. The sorting 
will be done based on the ‘Any Grade’ column of the experimental arm when arms are presented 
side-by-side.
Unless otherwise specified, the AE summary tables will be restricted to on-treatment events re-
gardless of the causality.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.6.9). To prepare these analyses, the CRF data will be processed according to stand-
ard BMS algorithms16 in order to collapse adverse event records into unique records based on the 
preferred term. These data will be presented as the rate per 100 person-years of exposure. These 
analyses will take into account all on-treatment events (allowing more than 1 event per subject) 
and the total exposure time. The person-year exposure will be computed as the sum over the sub-
jects’ exposure expressed in years where the exposure time is defined as 
•
(Date of last dose of study treatment - date of first dose of study treatment + 101 days )/365.25, 
for subject who are off study treatment and were followed for at least 30 days (or 100 days, 
depending on the analysis) after last dose of study treatment.
•
(Last known alive date - date of first dose of study treatment +1)/365.25, for subjects who are 
still on-treatment or who are off study treatment and were followed less than 100 days after 
last dose of study treatment.
7.1.1.1
Select Adverse Events (EU Submission)
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories, etc.). AEs that may differ from 
or be more severe than AEs caused by non-immunotherapies and AEs whose early recognition and 
management may mitigate severe toxicity are included as select AEs. Categories of select AEs 
may include subcategories (e.g. adrenal disorders, diabetes, pituitary disorders, and thyroid disor-
ders are subcategories of the endocrine event category).
The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/subcategories.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
28
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution,
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory of drug-related select AEs when applicable.
Further details on the definitions of select adverse event, time-to onset and time-to resolution are 
described in APPENDIX 1.
7.1.1.2
Other Events of Special Interest
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific 
category. The list of MedDRA preferred terms used to identify OEOSI is revisited quarterly and 
updated accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided.
7.1.1.3
Immune-Mediated Adverse Events (US Submission)
In order to further characterize AEs of special clinical interest, analysis of immune-mediated AEs 
(IMAE) will be conducted. IMAEs are specific events (or groups of PTs describing specific events) 
that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine 
(adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hy-
pophysitis), and other specific events, considered as potential immune-mediated events by inves-
tigator that meet the definition summarized below: 
•
those occurring within 100 days of the last dose, 
•
regardless of causality,
•
treated with immune-modulating medication (of note, endocrine AEs such as adrenal 
insufficiency, 
hypothyroidism/thyroiditis, 
hyperthyroidism, 
diabetes 
mellitus, 
and 
hypophysitis are considered IMAEs regardless of immune-modulating medication use, since 
endocrine drug reactions are often managed without immune-modulating medication).
•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
The list of MedDRA preferred terms used to identify IMAEs is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by catego-
ries will be provided.
7.1.2
Laboratory Tests
Clinical laboratory parameters (hematology, serum chemistry and electrolytes) will be evaluated.
Laboratory tests will be graded using the NCI Common Terminology Criteria, and the most recent 
version of the criteria at the time of the database lock will be used.
Clinical laboratory data will be first analyzed using International System of Units (SI). Analyses 
will be repeated using US conventional units.
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
subcategory and laboratory test code sequence number.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
29
7.1.3
Immunogenicity Data
Blood samples for immunogenicity analysis will be collected from subjects assigned to the exper-
imental treatment group according to the protocol schedule. Samples will be evaluated for devel-
opment of nivolumab and ipilimumab Anti-Drug Antibody (ADA) by a validated electrochemilu-
minescent (ECL) immunoassay and characterized for neutralizing antibodies by validated cell-
based assays.
7.2
Study Conduct
The following programmable deviations will be considered as relevant protocol deviations. 
Eligibility:
1) Subjects whose primary anatomical sites other than: oral cavity, oropharynx, hypopharynx and 
larynx
2) Subjects who received prior treatment with systemic anti-cancer therapy within 6 months of 
randomization
3) Subjects who progressed within 6 months of last dose of most recent prior systemic therapy 
4) Subjects without measurable disease at baseline
5) Subjects with ECOG PS > 1 at study entry (last measurement on or prior to randomization)
6) Subjects who received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-
4 antibody
7) Prior treatment with cetuximab or EGFR inhibitors  
On-study:
8) Subjects receiving concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, surgery for tumor resection*, radiation therapy directed at target lesions) 
while on study therapy (Surgery has to be for tumor resection.  Tumor biopsy, for example, 
would not count)
9) Subjects whose “as treated” arm different than their as randomized arm (subjects who received 
the wrong treatment, excluding the never treated)
The Relevant Protocol Deviations will be summarized based on the “all randomized” and “PD-L1 
CPS ≥ 20” populations, by treatment group and overall. A listing of all relevant protocol deviations 
will be provided.
Enrollment by country and site, and enrollment by month will be summarized and listed for all 
enrolled subjects.
A by-subject listing of batch numbers for all treated subjects will be provided.
7.3
Study Population
Analyses in this section will be tabulated for all randomized subjects by treatment group as ran-
domized, unless otherwise specified.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
30
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized. This analysis will be performed on the all enrolled sub-
jects population only.
Number of subjects randomized but not treated along with the reason for not being treated will be 
tabulated by treatment group as randomized.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. Reason for discontinuation will be derived from subject 
status CRF page. This analysis will be performed only on the all treated subjects population.
A by-subject listing for all treated subjects will be provided showing the subject’s off treatment 
date and whether the subject continue in the treatment period/study along with the reason for going 
off treatment period/study. A by-subject listing for all enrolled subjects will also be provided, 
showing whether the subject was randomized/treated along with the reason for not being random-
ized/treated.
7.3.2
Demographics and Other Baseline Disease Characteristics
The following demographic and baseline disease characteristics will be summarized and listed by 
treatment group as randomized:
•
Age (continuous)
•
Age categorization (< 65, ≥65 and < 75, ≥75 and < 85, ≥85, ≥75, ≥65)
•
Sex (Male vs. Female)
•
Race (White, Black or African American, Asian, Other)
•
Ethnicity (Hispanic/Latino and Not Hispanic/Latino)
•
Region (North America, EU, Asia, Rest of World)
•
Country by geographic region
•
Baseline ECOG performance status
•
Tobacco use (Never, Former, Current, Unknown)
•
Alcohol use
•
Disease stage at study entry (locally recurrent, locally recurrent and metastatic, metastatic)
•
Disease stage at initial diagnosis (stage I, II, III, IVA, IVB, IVC)
•
TNM Classification at initial diagnosis
•
Time from initial disease diagnosis to randomization (< 1 year, ≥1 year)
•
Sites of primary tumor per investigator
•
Subsites of diseases per investigator
•
Sites of diseases (all lesions) per BICR
•
Number of disease sites per subject (all lesions) per BICR
•
Number of target lesions, non-target lesions and disease sites at baseline as per BICR
•
Tumor burden: sum of the diameters of target lesions at baseline per BICR
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
31
•
Tumor burden: sum of the diameters of target lesions at baseline per investigator
•
HPV p-16 status per CRF
•
Tumor cell PD-L1 proportion score (TPS) per CRF
•
PD-L1 CPS
•
CNS metastasis
Summary table (cross-tabulation) by treatment group for stratification factor will be provided to 
show any discrepancies between what was reported through IRT vs. CRF at baseline. This sum-
mary will be performed based on all randomized subjects.
7.3.3
Medical History
A by-subject listing of general medical history for all randomized subjects will be provided.
7.3.4
Prior Therapy Agents
Prior cancer therapy will be summarized by treatment group and overall. Prior systemic cancer 
therapy will be summarized by treatment group and overall and listed by subject. Prior radiother-
apy and prior surgery related to cancer will be listed by subject.
7.3.5
Physical Examinations
Subjects with abnormal baseline physical examination will be listed by subject.
7.3.6
Baseline Physical Measurements
Baseline physical measurements will be listed by subject.
7.4
Extent of Exposure
Listings will include all available exposure data. Analyses will be performed by treatment group 
“as treated” in all treated subjects, unless otherwise specified.
7.4.1
Administration of Study Therapy 
The following parameters will be summarized (descriptive statistics) by treatment group:
•
Number of doses received
•
Cumulative dose
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%; ≥110%
Duration of study therapy will be summarized (descriptive statistics) by treatment group. 
A by-subject listing of dosing of study medication (record of study medication, infusion details,
and dose changes) will be also provided. 
Table 7.4.1-1:
Study Therapy Parameter Definitions- Nivolumab and Ipilimumab 
        Nivolumab 
Ipilimumab
Dosing schedule per protocol
3 mg/kg every 2 weeks
1 mg/kg every 6 weeks
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
32
Table 7.4.1-1:
Study Therapy Parameter Definitions- Nivolumab and Ipilimumab 
        Nivolumab 
Ipilimumab
Dose
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most re-
cent weight (kg). Dose adminis-
tered in mg at each dosing date and 
weight are collected on the CRF.
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most re-
cent weight (kg). Dose adminis-
tered in mg at each dosing date and 
weight are collected on the CRF.
Cumulative Dose
Cum dose (mg/kg) is sum of the 
doses (mg/kg) administered to a 
subject.
Cum dose (mg/kg) is sum of the 
doses (mg/kg) administered to a 
subject.
Relative dose intensity (%)
Cum dose (mg/kg)/[(Last 
Nivolumab dose date - Nivolumab 
start dose date + 14) x 3/14] x 100
Cum dose (mg/kg)/[(Last 
Nivolumab dose date - Nivolumab 
start dose date + 42) x 1/42] x 100
Duration of treatment (overall)
Last Nivolumab dose date -
Nivolumab start dose date +1
Last Ipilimumab dose date - Ipili-
mumab start dose date +1
Table 7.4.1-2:
Study Therapy Parameter Definitions-Cetuximab/5-FU
Cetuximab
5-FU
Dosing schedule per protocol
400 mg/ m² for the 1st dose and 250 
mg/ m² weekly or biweekly per local 
prescribing information
1000mg/ m² (from Day 1 to Day4) 
every 3 weeks 
Dose
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most recent 
BSA. Dose administered in mg at 
each dosing date is collected on the 
CRF and BSA is derived from most 
recent weight and baseline height 
also collected on the CRF.
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most re-
cent BSA. Dose administered in mg 
at each dosing date is collected on 
the CRF and BSA is derived from 
most recent weight and baseline 
height also collected on the CRF.
Cumulative Dose
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Relative dose intensity (%)
[Cum dose (mg/m²) - initial dose of 
cetuximab(mg/m²) ]/[(Last Cetuxi-
mab dose date - Cetuximab Start 
dose date )x250/7] x 100
Cum dose (mg/m²)/[(First dose date 
of  5-FU in Last Cycle - 5-FU Start 
dose date + 21) x 4000/21] x 100
Duration of treatment (overall)
Last dose date - Start dose date +1
Last dose date - Start dose date +1
Table 7.4.1-3:
Study Therapy Parameter Definitions- Cisplatin/Carboplatin  
Cisplatin
Carboplatin
Dosing schedule per protocol
100mg/ m² on day 1 every 3 weeks 
AUC 5 on day 1 of every 3 week 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
33
Table 7.4.1-3:
Study Therapy Parameter Definitions- Cisplatin/Carboplatin  
Cisplatin
Carboplatin
Dose
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most re-
cent BSA. Dose administered in mg 
at each dosing date is collected on 
the CRF and BSA is derived from 
most recent weight and baseline 
height also collected on the CRF.
Dose (AUC) is defined as Total 
Dose administered (mg)/(creatinine 
clearance +25). Dose administered 
in mg at each dosing date is col-
lected on the CRF and creatinine 
clearance derived from the CRF 
data.
Cumulative Dose
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Cum dose (AUC) is sum of the 
doses (AUC) administered to a sub-
ject.
Relative dose intensity (%)
Cum dose (mg/m²)/[(Last Cisplatin
dose date - Cisplatin Start dose date 
+ 21) x 100/21] x 100
Cum dose (AUC)/[(Last dose date 
of Carbo - Start dose date of Carbo
+ 21) x 5/21] x 100
Duration of treatment (overall)
Last dose date - Start dose date +1
Last dose date - Start dose date +1
7.4.2
Modifications of Study Therapy
7.4.2.1
Dose Delays
Each of study drug infusions may be delayed. A dose will be considered as actually delayed if the 
delay is exceeding 3 days (i.e. greater than or equal to 4 days from scheduled dosing date) for 
nivolumab and ipilimumab. All study drugs must be delayed until treatment can resume. Reason 
for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized by treatment group:
•
Number of subjects with at least one dose delayed, the number of dose delays per subject, the 
reason for dose delay and the length of dose delay.
7.4.2.2
Infusion Interruptions and Rate Changes
Each of study drug infusions can be interrupted and/or the IV infusion rate can be reduced. This 
information will be retrieved from CRF dosing pages.
The following parameters will be summarized by treatment group:
•
Number of subjects with at least one dose infusion interruption, the reason for interruption, 
and the number of infusion interruptions per subject.
•
Number of subjects with at least one IV infusion rate reduction, the reason for reduction and 
the number of infusion with IV rate reduction per subject.
7.4.2.3
Dose Escalations
Dose escalations (within subject) are not permitted for either nivolumab or ipilimumab.
7.4.2.4
Dose Reductions
Dose reductions (within subject) are not permitted for either nivolumab or ipilimumab. Therefore, 
no analyses on dose reductions will be presented for these two agents.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
34
Up to two dose level reductions are allowed for cetuximab, cisplatin, carboplatin and 5-FU.  The 
dose levels for each of these drugs are defined in the protocol as follows:
Table 7.4.2.4-1:
Dose Levels for Cetuximab, Cisplatin, Carboplatin and 5-FU
Cetuximab
(mg/m2)
Cisplatin
(mg/m2)
Carboplatin
(AUC)
5-FU
(mg/m2/day)
Starting Dose
250*
100
AUC 5.0
1000
Dose Level -1
200
75
AUC 4.0
750
Dose Level -2
150
56
AUC 3.0
560
Dose Level -3
Stop drug
Stop drug
Stop drug
Stop drug
*The dose level of cetuximab is 400 mg/m2 for the first dose and 250 mg/m2 afterwards.
For any cycle, it will be defined as a dose reduction if the observed dose level (based on calculated 
administered dose) is below the dose level of the previously administered dose. Dose ranges for 
dose levels of platinum doublet chemotherapy are defined in Table 7.4.2.4-2.
Table 7.4.2.4-2:
Calculated Dose Ranges and Related Dose Levels
Dose Level
Dose Range
Cetuximab
(mg/m2)
Cisplatin
(mg/m2)
Carboplatin
(AUC)
5-FU
(mg/m2/day)
Level 0
≥225
≥87.5
≥4.5
≥875
Level -1
<225 and ≥175
<87.5 and ≥65.5
<4.5 and ≥3.5
<875 and ≥655
Level -2
<175
<65.5
<3.5
<655
The reason for dose reduction as reported by the investigator will be tabulated for all instances of 
dose reduction based on the Dose Change CRF page. A category ‘Unknown’ will be defined for 
all reductions with no reason reported by the investigator.
The following will be summarized for chemotherapeutic agent arm only:
•
Number and percentage of subjects with at least one dose reduction and reason of the dose 
reduction, number and percentage of subjects with a dose reduction to dose level -1, number 
and percentage of subjects with a dose reduction to dose level -2.
7.4.2.5
Dose Omissions
Dose omissions are not permitted.
7.4.2.6
Partial Discontinuation of Ipilimumab in the Arm A
Subjects treated with nivolumab and ipilimumab may discontinue ipilimumab and continue to re-
ceive nivolumab (ie, partial discontinuation). 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
35
The following will be summarized for subjects receiving the immunotherapy in the arm A 
•
Number and percentage of subjects who had partial discontinuation of ipilimumab.
•
Reason for partial discontinuation.
Reason for partial discontinuation will be retrieved from dosing CRF pages.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the UMC WHO Drug Global Dictionary.
The following summary table will be provided: 
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term) 
Prior medications, defined as non-study medications with a start date before consent date, and 
current medications, defined as non-study medications with a start date before the first date of 
study medication and stop date after consent date, will be coded using the UMC WHO Drug Global 
Dictionary. 
The following summary table will be provided: 
•
Prior/current medications (subjects with any prior/current medication, subjects by medication 
class and generic term) 
A by-subject listing will accompany the table.
7.4.3.1
Immune Modulating Medication 
Immune modulating concomitant medications are medications entered on an immune modulating 
medication form or available from the most current pre-defined list of immune modulating medi-
cations. The list of anatomic class, therapeutic class and generic name used for the selection at the 
time of the database lock will be provided.
The percentage of subjects who received immune modulating concomitant medication for
•
management of adverse event 
•
premedication 
•
other use
•
any use
•
management of drug-related select adverse event (any grade, grade 3-5) by select AE category/ 
subcategory (EU Submission)
•
management of IMAEs (any grade, grade 3-5) by IMAE category (US Submission)
will be reported separately for each treatment group (percentages of treated subjects by medication 
class and generic term).
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs (any 
grade, grade 3-5), the following will be reported for each treatment group:
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
36
•
The total immune modulating medication treatment duration (excluding overlaps), duration of
high dose of corticosteroid, initial dose of corticosteroid, and tapering duration (summary
statistics)
Duration represents the total duration the subject received the concomitant medication of interest. 
If the subject took the medication periodically, then DURATION is the summation of all use. 
Initial dose represents the dose of the concomitant medication of interest received at the start of 
the event. In the case multiple medications started on the same date, the highest equivalent dose is 
chosen and converted to mg/kg by dividing by the subject’s recent weight.
These analyses, except the ones related to IMAEs will be conducted using the 30-day safety win-
dow. The analyses related to IMAEs will be conducted using the 100-day safety window.
7.4.3.2
Subsequent Cancer Therapy
Number and percentage of subjects receiving subsequent cancer therapies will be summarized for 
all randomized subjects. Categories include: 
•
Subsequent systemic therapy
•
Subsequent surgery for treatment of tumors
•
Subsequent radiotherapy for treatment of tumors
A by-subject listing of subsequent cancer therapy will also be produced for all randomized sub-
jects.
7.5
Efficacy
Principal analyses of progression free survival (PFS) and objective response rate (ORR) will be 
based on the Blinded Independent Central Review (BICR) evaluation, unless noted otherwise. 
Analyses in this section will be tabulated for all randomized subjects by treatment group as ran-
domized, unless otherwise specified.
Unless stated otherwise, whenever a stratified analysis is specified, the following stratifications 
factors (recorded at randomization as per IRT) will be used:
•
Tumor cell PD-L1 status (expressing [≥1%] vs non-expressing [< 1%] or non-evaluable).
•
HPV p-16 status (oropharyngeal HPV p-16 positive vs oropharyngeal HPV p-16 negative or
non-oropharyngeal).
•
Prior chemotherapy (adjuvant/neoadjuvant/multimodal treatment) status (Yes/No).
For assessing the secondary objectives of this study except to compare the OS of subjects with 
PD-L1 CPS ≥ 1 between treatment groups, no testing procedure will be used.
Confidence intervals (CI) for primary endpoint analyses will be based on nominal significance 
level adjusted for primary endpoints and interim analyses to preserve overall type one error rate.
Alpha (ߙሻfor the CI will be the same as nominal significance level for hypothesis testing. CIs for 
other endpoints will be at the two-sided 95% level. All p-values reported will be two-sided. P-
values will be rounded to the fourth decimal place. Point estimates and confidence bounds for 
efficacy variables will be rounded to the second decimal place.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
37
A by-subject listing of efficacy results will be presented including treatment group, treatment 
duration, BICR progression date, overall survival, death date, etc. 
7.5.1
Analysis of Objective Response Rate
One of the objectives of the study is to estimate the ORR per BICR in the treatment groups among 
all randomized subjects.
The number and percentage of subjects in each category of BOR per BICR (complete response 
[CR], partial response [PR], stable disease [SD], progressive disease [PD], or unable to determine 
[UTD]) will be presented, by treatment group. Estimates of response rate, along with its exact two-
sided 95% CI by Clopper and Pearson17 will be presented, by treatment group. 
Similar analyses will be repeated based on the investigator’s assessment of ORR. A cross tabula-
tion of BICR best response versus the investigator best response will be presented, by treatment 
group and by response categories. Concordance Rate of Responders will be computed as the fre-
quency with which investigator and BICR agree on classification of a subject as responder vs. non 
responder/UTD as a proportion of the total number of randomized subjects assessed by both the 
investigator and BICR.
The following subject-level graphics will also be provided:
•
For the responders only, time courses of the following events of interest will be graphically 
displayed: tumor response.
•
For response evaluable subjects (randomized subjects with baseline and at least one on-study 
tumor assessment), 
−
A bar plot showing the best % reduction from baseline in sum of diameter of target lesions 
based on BICR assessment for each subject will be produced (excluding assessments after 
PD and assessments after start of subsequent anti-cancer therapy).
−
A plot of individual time course of tumor burden change per BICR assessment will be 
produced. 
A by-subject listing of best overall response will be presented including treatment group, best 
overall response per BICR and dates of CR/PR/progression. 
A by-subject listing of per time point tumor response per BICR will be presented. 
7.5.2
Time to Tumor Response and Duration of Response
Duration of response (DOR) and time to response (TTR) will also be evaluated for subjects who 
achieved confirmed PR or CR. The DOR for each treatment group will be estimated using the 
Kaplan-Meier (KM) product limit method and will be displayed graphically. A table will be pro-
duced presenting number of events, number of subjects involved, medians, and 95% CIs for the 
medians. Median values of DOR, along with two-sided 95% CI in each treatment group will be 
computed based on a log-log transformation method. 
The status of subjects who are censored in the DOR KM analysis will be tabulated for each treat-
ment group including the following categories:
•
Ongoing follow-up (current [last scan within adequate window vs cutoff date], not current)
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
38
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
Received subsequent anticancer therapy.
TTR, which does not involve censoring, will be summarized by treatment group in all responders 
using descriptive statistics. 
A by-subject listing will be presented including treatment group, best response, time to response, 
duration of response, whether the subject was censored for duration of response, and, if so, the 
reason. 
7.5.3
Analysis of DCR
Similar to ORR analysis, BICR-determined DCR in arm A and B will be estimated and its corre-
sponding 95% exact two-sided CIs will be calculated using the Clopper Pearson method. This 
analysis will also be performed for DCR as assessed by the investigators.
7.5.4
Analysis of Progression-Free Survival
The PFS function for each treatment group will be estimated using the KM product limit method 
and will be displayed graphically. A two-sided 95% CI for median PFS in each treatment group 
will be computed via the log-log transformation method. PFS rates at fixed time points (e.g. 6 
months, depending on the minimum follow-up) will be presented along with their associated 95% 
CIs. These estimates will be derived from the Kaplan Meier estimate and corresponding CIs will 
be derived based on Greenwood18 formula for variance derivation and on log-log transformation 
applied on the survivor function19.
The estimate of the PFS hazard ratio between treatment groups will be calculated using a stratified
Cox proportional hazards model, with treatment as the sole covariate. A two-sided 95% CI for the 
hazard ratio will also be presented. Further, the estimate of the PFS hazard ratio based on weighted 
logrank test may be provided.
Analyses of PFS will be conducted based on the primary definition and secondary definition of 
PFS. 
The source of PFS event (progression or death) will be summarized by treatment group. The status 
of subjects who are censored (as per primary definition of PFS) in the PFS KM analysis will be 
tabulated for each treatment group including the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
No baseline tumor assessment
•
No on-study tumor assessment and no death
•
Received subsequent anticancer therapy
A by-subject listing will be presented including treatment group, PFS duration under the primary 
definition, PFS duration on the ITT definition, whether the subject was censored under the primary 
definition, and if censored, the reason, and whether the subject was censored under the ITT 
definition, and if censored, the reason.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
39
A by-subject listing of lesion evaluations per BICR will be presented.
7.5.5
Supportive Analyses of Progression-Free Survival
The following sensitivity analyses will be conducted using both the primary and the secondary 
definition of PFS in all randomized subjects:
•
A cross tabulation of PFS assessment by BICR versus PFS assessment by investigator will be
presented, by treatment group. Concordance Rate of event will be computed as the frequency
with which investigator and BICR agree on classification of a subject as event vs censored as
a proportion of the total number of randomized subjects assessed by both the investigator and
BICR.
•
A by-subject listing of PFS assessment per BICR and investigator will be presented.
7.5.6
Analysis of Overall Survival
The primary objectives of the study are to compare the overall survival between treatment groups 
in randomized subjects with PD-L1 CPS ≥ 20 and in all randomized subjects.
Overall survival will be compared between the treatment groups at the interim and final analyses, 
using a stratified log-rank test. The stratification factors will be tumor cell PD-L1 status, HPV p-
16 status and prior chemotherapy status. Graphic procedure20 (Figure 7.5.6-1:) and an O’Brien and 
Fleming α-spending function will be employed to determine the nominal significance levels for 
the interim and final analyses. Details of this sequentially rejective procedure will be provided in 
Appendix 4. 
Figure 7.5.6-1:
Testing Hierarchy for the Endpoints
The stratified hazard ratio between the treatment groups will be presented along with 100*(1- α)%
CI (adjusted for interim). In addition, two-sided p-value will also be reported for the analysis of 
OS.
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each treat-
ment group will be computed via the log-log transformation method. OS rates at fixed time points 
(e.g. 6 months, depending on the minimum follow-up) will be presented along with their associated 
95% CIs. These estimates will be derived from the Kaplan Meier estimate and corresponding CIs 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
40
will be derived based on Greenwoodformula for variance derivation and on log-log transformation 
applied on the survivor function.
The status of subjects who are censored in the OS KM analysis will be tabulated for each treatment 
group using the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
A by-subject listing will be presented including treatment group, first and last dose date, whether 
the subject died, and if censored, the reason, event/censored date and OS duration.
7.5.7
Supportive Analyses of Overall Survival
The following OS sensitivity analyses will be conducted in all randomized subjects:
1) Delayed effect of immunotherapy interventions may cause a late separation in the OS KM
curves and non-proportional hazards. OS will be compared between treatment groups via
two-sided stratified weighted log-rank test among subjects. The two-sided stratified
weighted log-rank p-value will be reported using G (rho = 0, gamma = 1) weights, in the
terminology of Fleming and Harrington13.
The Fleming Harrington test can be unstable, so it is possible, though uncommon, that the
p-value for this trial will not be estimable.
Further, Max-combo testing and estimating procedure might be applied.
2) A multivariate Cox regression model will be used in order to estimate the treatment effect
after adjustment for possible imbalances in known or potential prognostic factors. The fac-
tors used in the randomization, which, by definition, will be balanced across treatment
groups, will still be included in the model as stratification factors. However, all additional
factors will be incorporated as covariates. The additional factors, which are all measured
at baseline, will include, but not limited to:
a.
ECOG PS (0, ≥1)
b. SEX (Male, Female)
c.
AGE
The level of the covariate normally associated with the worst prognosis will be coded as 
the reference level. The hazard ratio associated with treatment and with each of the baseline 
covariates will be presented along with associated 100*(1- α)% CIs (adjusted for interim).
3) OS using stratification factors as obtained from the baseline CRF pages (instead of IRT).
The hazard ratio associated with treatment will be presented along with the associated
two-sided 100*(1- α)% CI (adjusted for interim). This analysis will be performed only if
at least one stratification variable/factor at randomization (as per IRT) and baseline are not
concordant for at least 10% of the randomized subjects.
4) OS using an un-stratified log rank test. The hazard ratio associated with treatment will be
presented along with the associated two-sided 100*(1- α)% CIs (adjusted for interim).
5) OS for subjects with no relevant protocol deviations. This analysis will be conducted only
if there are more than 10% subjects with relevant protocol deviations. The hazard ratio
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
41
associated with treatment will be presented along with the associated two-sided 100*(1-
α)% CIs (adjusted for interim).
6) OS will be compared between treatment groups using a two-sided stratified log-rank test
in the All Treated Subjects population, using arm as treated. This analysis will be
performed only if the proportion of randomized but never treated subjects exceeds 10%.
7) To examine the assumption of proportional hazards in the Cox regression model, in addi-
tion to treatment, a time-dependent variable defined by treatment by time interaction will
be added into the model. A two-sided Wald Chi-square p-value of less than 0.1 may indi-
cate a potential nonconstant treatment effect. In that case, additional exploratory analyses
may be performed.
7.5.8
Subset Analyses of Overall Survival
The influence of baseline and demographic characteristics on the treatment effect among all ran-
domized subjects will be explored via exploratory subset analyses. The median OS based on KM 
product-limit method along with two-sided 95% CIs will be produced for the following subgroups: 
•
Age categorization (<65 vs.>=65 vs. ≥65-<75 vs >75)
•
Sex (Male vs. Female)
•
Race (White, Black, Asian, Others)
•
Region (North America vs. EU vs. Asia vs. ROW)
•
ECOG performance status(0, ≥1)
•
Disease stage at initial diagnosis (Stage I, Stage II, Stage III, Stage IVA, Stage IVB, Stage
IVC)
•
Disease stage at study entry (locally recurrent, locally recurrent and metastatic, metastatic)
•
Time from initial disease diagnosis to randomization (< 1, 1-<2, 2-<3,3-<4, 4<-5, >=5 year )
•
Site of primary tumor (Oral cavity, Oropharynx, Hypopharynx, Larynx)
•
Tobacco use (Never, Former, Current, Unknown)
•
Alcohol use
•
Prior radiotherapy (yes/no)
•
Prior surgery (yes/no)
•
Prior systemic cancer therapy (yes/no)
•
Prior platinum-based chemotherapy (yes/no)
•
HPV status per IRT
A forest plot of the OS hazard ratios (along with the 95% CIs) will be produced for each level of
the subgroups listed above.
An analysis will be conducted if the number of subjects in the subgroup category is more than 10. 
7.5.9
Current Status of PFS and OS Follow-up
The extent of follow-up for survival, defined as the time between randomization date and last 
known alive date (for subjects who are alive) or death date (for subjects who died), will be sum-
marized descriptively (median, min, max, etc.) in months for all randomized subjects.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
42
The currentness of follow-up for survival, defined as the time between last OS contact (i.e., last 
known alive date or death date) and cutoff date (defined by last patient last visit date), will be 
summarized in months for all randomized subjects. Subjects who died and subjects with last known 
alive date on or after data cut-off date will have zero value for currentness of follow-up.
Minimum follow-up for OS, defined as the time from cutoff date to last subject’s randomization
date, will be summarized in months for all randomized subjects.
Time from last evaluable tumor assessment to cutoff date in months will be summarized by treat-
ment group and overall for all randomized subjects. Subjects who have a PFS event will be con-
sidered as current for this analysis. The secondary definition of PFS will be used for this summary. 
In addition, time to treatment discontinuation will be summarized and presented by treatment 
group using a Kaplan-Meier curve whereby the last dose date will be the event date for those 
subjects who are off study therapy. Median duration of study therapy and associated 95% CI will 
be provided. Subjects who are still on study therapy will be censored on their last dose date.
A by-subject listing will also be produced to accompany the subject time from last evaluable tumor 
assessment.
7.5.10
Interim Analyses of Overall Survival
An independent statistician external to BMS will perform the analyses. In addition to the formal 
planned interim analysis for OS, the Data Monitoring Committee (DMC) will have access to peri-
odic un-blinded interim reports of efficacy and safety to allow a risk/benefit assessment. Details 
are included in the DMC charter.
A formal interim analysis for superiority of OS will be performed after approximately 593 OS 
events (80% of 741 required) have occurred on all randomized subjects, or all randomized subjects 
have been followed up for at least 12 months, whichever is later. Both primary endpoints will be 
tested at interim using the group sequential test procedure with initial overall alpha = 0.025 for 
each. The overall alpha will be updated following graphical procedure20 (Figure 7.5.6-1:). The 
stopping boundaries for the interim and final analyses will be determined by the O’Brien and 
Fleming alpha spending function, based on the actual number of events observed. 
If interim comparison of OS in either all randomized subjects or randomized subjects with PD-L1 
CPS ≥ 20 is significant, the DMC will inform the sponsor, as described in the DMC charter. If 
comparison of OS in the randomized subjects with PD-L1 CPS ≥ 20 is significant, OS in random-
ized subjects with PD-L1 CPS ≥ 1 will be subsequently tested using group sequential testing pro-
cedure. The overall alpha for this secondary endpoint will be determined following the graphical 
procedure which will be illustrated in Appendix 4.
7.5.11
PFS2
PFS2 will be analyzed similarly to PFS:  
•
Median values based on KM method, along with two-sided 95% CI using Brookmeyer and
Crowley method will be calculated. The estimate of standard error will be calculated using the
Greenwood formula.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
43
•
The estimate of the PFS2 hazard ratio between treatment groups will be calculated using a
stratified Cox proportional hazards model, with treatment as the sole covariate. A two-sided
95% CI for the hazard ratio will also be presented
•
PFS2 will be graphically displayed along with the median and 95% CI.
A by-subject listing of PFS and PFS2 will be provided
7.6
Safety
All figures and summary tables for safety will be produced on the “all treated PD-L1 CPS ≥ 20,” 
and “all treated” populations. Safety listings will be done on the all treated populations but will 
have variables for PD-L1 CPS added to them.
Analyses in this section will be tabulated by treatment group as treated, unless otherwise specified.
7.6.1
Deaths
Deaths will be summarized by treatment group:
•
All deaths, reasons for death.
•
Deaths within 30 days of last dose received, reasons for death.
•
Deaths within 100 days of last dose received, reasons for death.
A by-subject listing of deaths will be provided for the all enrolled subjects population.
7.6.2
Serious Adverse Events
Serious adverse events will be summarized by treatment group:
•
Overall summary of SAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented by
SOC/PT.
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by SOC/PT.
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation will be summarized by treatment group:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade
3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any
grade, grade 3-4, grade 5) presented by SOC/PT.
The analyses will be conducted using the 30-day safety window.
A by-subject AEs leading to discontinuation listing will be provided.
7.6.4
Adverse Events Leading to Dose Modification
AEs leading to dose delay/reduction will be summarized by treatment group:
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
44
•
Overall summary of AEs leading to dose delay/reduction by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of related AEs leading to dose delay/reduction by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analysis will be conducted using the 30-day safety window.
A by-subject AEs leading to dose delay/reduction listing will be provided.
7.6.5
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) presented 
by SOC/PT.
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT. This table will be restricted to events with an incidence greater or equal to 5% in 
any treatment group.
•
Overall summary of any non-serious AEs presented by SOC/PT. This table will be restricted 
to events with an incidence greater or equal to 5% in any treatment group.
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) 
presented by SOC/PT. 
The following analyses will be conducted using the 30 days safety window and repeated using the 
100 days safety window:
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune mod-
ulating medications will also be provided.
7.6.6
Select Adverse Events (EU Submission)
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.6.6.1
Incidence of Select AE
Select AEs will be summarized by treatment group for each category/subcategory. 
The following analyses will be conducted using the 30-day safety window only:
•
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category or Subcategory/PT.
•
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by Category or Subcategory/PT.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
45
•
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade
(any grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Summary of frequency of unique select AEs by Category.
A by-subject select AE listing will be provided.
7.6.6.2
Time-to Onset of Select AE
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each cat-
egory/subcategory by treatment group.
Time-to onset analyses are restricted to treated subjects who experienced at least one drug-related 
select AE in the category/subcategory. The analyses will be conducted using the 30-day safety 
window.
Additional details regarding the time-to onset definition are described in time-to onset definition 
subsection of APPENDIX 1.
7.6.6.3
Time-to Resolution of Select AE
Time-to resolution of the following specific events will be summarized separately for each cate-
gory/subcategory.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) by treatment group
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated, by treatment group
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating med-
ication during the longest select AE.
The analyses will be conducted using the 30-day safety window.
The following summary statistics will be reported: percentage of subjects with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier es-
timation) and ranges.
See time-to resolution definition subsection of APPENDIX 1 for additional details.
7.6.7
Immune-Mediated Adverse Events (US Submission)
IMAEs will be summarized by treatment group for each immune-mediated category / PT using the 
100-day safety window:
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
46
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 
5) where immune modulating medication was initiated presented by Category / PT.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) where immune modulating medication was initiated presented 
by Category / PT.
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to dose delay or reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by Category / PT
•
Overall summary of endocrine IMAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category / PT.
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category.
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category.
A by-subject listing of IMAEs will be provided. By-subject listings of time-to resolution for long-
est IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. For new 
studies which collect investigator assessment of potential IMAE data, a by-subject listing of AEs 
considered as immune-mediated events per investigator but not qualified for IMAEs definition 
will also be provided.
In addition, for all nivolumab treated subjects who experienced at least one IMAE, the following 
data presentation will be provided:
•
Summary of subjects who were re-challenged with nivolumab by IMAE category, with 
extended follow-up 
•
Summary of subjects who were re-challenged with nivolumab or ipilimumab by IMAE 
category, with extended follow-up
For these, re-challenge is considered to have occurred when last nivolumab and/or ipilimumab 
infusion was administered after the onset of an IMAE.
7.6.8
Other Events of Special Interest
OEOSI will be summarized by treatment group for each category.
The following analyses will be conducted using the 100-day safety window:
•
Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
Category / PT
•
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT
A by-subject listing of OEOSI will be provided.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
47
7.6.9
Multiple Events
The following summary tables will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs.
•
A table showing the total number and rate (exposure adjusted) of occurrences for AEs
occurring in at least 5% of subjects in any treatment group.
In addition, the rate (exposure adjusted) and its 95% CI evaluated for different time intervals will 
be displayed graphically for each treatment group. This analysis will be limited to the rate of all 
AEs and all drug-related AEs. The analyses will be conducted using the 30-day safety window.
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.6.10
Laboratory Parameters
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test. Laboratory tests (in addition to the tests specified below) with CTC criteria col-
lected in the specific studies may also be included in the summaries.
7.6.10.1
Hematology
The following will be summarized by treatment group as worst CTC grade on-treatment per sub-
ject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per sub-
ject: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils count (ANC) 
and lymphocyte count (LYMPH).
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.2
Serum Chemistry
The following will be summarized by treatment group as worst CTC grade on-treatment per sub-
ject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per sub-
ject: ALT, AST, alkaline phosphatase (ALP), total bilirubin and creatinine. 
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.3
Electrolytes
The following will be summarized by treatment group as worst CTC grade on-treatment per sub-
ject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per sub-
ject: sodium (high and low), potassium (high and low), calcium (high and low), magnesium (high 
and low), and Glucose Serum (fasting hyperglycemia and hypoglycemia regardless of fasting sta-
tus)
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
48
7.6.10.4
Additional Analyses
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group:
Abnormal Hepatic Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
Abnormal Thyroid Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
TSH value > ULN and
−
with baseline TSH value ≤ULN
−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test.
•
TSH < LLN and
−
with baseline TSH value ≥LLN
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal
TSH test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
7.6.11
Vital Signs and Pulse Oximetry
Vital signs and pulse oximetry (i.e. % oxygen saturation) collected on the CRF will be provided 
in separate listings.
7.6.12
Physical Measurements
Physical measurements will be listed by subject.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
49
7.6.13
Non-Protocol Medical Procedures
Non-protocol medical procedures will be listed by subject.
7.6.14
Immunogenicity Analysis
Further details on immunogenicity background and rationale, definitions, population for analyses 
and endpoints are described in APPENDIX 3. 
Incidence of ADA
Number (%) of subjects will be reported for the following parameters based on Evaluable Subjects.
•
Baseline ADA-positive
•
ADA-positive
−
Persistent Positive (PP)
−
Not PP-Last Sample Positive
−
Other positive
−
Neutralizing Positive
•
ADA-negative
A listing of all ADA assessments will be provided. 
A spider plot of nivolumab ADA test result (titers) over time may be provided for nivolumab ADA 
positive subjects.
The effect of ADA on safety and efficacy
•
Summary of Select Adverse Events of Hypersensitivity/Infusion Reaction by ADA Status 
(Positive, Negative)
•
Swimmer plot of occurrence of ADA and NAb Occurrence in Relation to PFS, BOR per BICR 
and OS
7.6.15
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
7.6.16
Adverse Events by Subgroup
Overall summary of any AEs and drug-related AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT and for each treatment group for the following subgroups:
•
Sex (Male vs. Female)
•
Race
•
Age (< 65 vs. 65 - < 75 vs. 75 - < 85 vs. ≥85 vs. ≥75 vs. ≥65)
•
Region (North America vs. EU vs. Asia vs. ROW)
•
Prior chemotherapy status (Yes/No) 
These analyses will be conducted using the 30-day safety window only.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
50
7.7
Pharmacokinetics
The nivolumab/ipilimumab concentration data obtained in this study will be combined with data 
from other studies in the clinical development program to develop a population PK model. This 
model will be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of 
nivolumab/ipilimumab. In addition, exposure-response analyses with selected efficacy and safety 
endpoints may be conducted. Results of population PK and exposure response-analyses will be 
reported separately if conducted. 
7.8
Biomarkers
Analyses for Biomarkers such as PD-L1 CPS, PD-L1 TPS, Gene Expression Profile (GEP) and 
Tumor Mutation Burden (TMB) are described below. 
7.8.1
Distribution of PD-L1 CPS
Descriptive statistics of PD-L1 CPS:
•
Listing of all PD-L1 IHC data, all PD-L1 tested subjects.
•
Summary of tumor specimen acquisition and characteristics, all randomized subjects.
•
Summary statistics of PD-L1 CPS in all randomized subjects with quantifiable PD-L1 CPS.
•
Summary of BOR and ORR by baseline PD-L1 CPS in all randomized subjects.
•
Cumulative distribution plot of baseline PD-L1 CPS versus population percentile in all
randomized subjects with quantifiable PD-L1 CPS.
•
Box plots of PD-L1 CPS versus Response Status (BICR assessment) in all randomized subjects
with quantifiable PD-L1 CPS.
•
Waterfall plot of Individual PD-L1 CPS in all randomized subjects with quantifiable PD-L1
CPS.
•
Histogram of the distribution of PD-L1 CPS.
7.8.2
Association Between PD-L1 CPS and Efficacy
Analyses of association between PD-L1 CPS at baseline and efficacy measures will be performed 
for scheduled formal efficacy analyses in the study. The analysis population will be among all 
randomized subjects unless otherwise specified.
For each PD-L1 CPS subgroup (further specified in the DPP) at baseline:
•
OS/PFS curves for each treatment group will be estimated using the Kaplan-Meier product
limit method. Two-sided, 95% confidence intervals for median OS/PFS will be constructed
based on a log-log transformed CI for the survivor function S(t).
•
Forest plot of Hazard Ratios with 95% CIs
•
Frequency and percentage of BOR per BICR will be summarized for each treatment group.
•
ORR will be computed by treatment group along with exact 95% CIs using the Clopper
Pearson method.
The following analysis will be performed to evaluate the association between PD-L1 CPS level 
and BICR-determined PFS (per primary definition) or OS. 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
51
•
An exploratory Cox proportional hazards model will be fitted for PFS per BICR or OS with 
PD-L1, treatment arm and PD-L1 treatment arm interaction, among All PD-L1 Evaluable 
Subjects. An appropriate transformation of PD-L1 CPS may be considered depending on 
an assessment of fit of the model. 
•
A plot of estimated log(hazard ratio) with 95% confidence band vs PD-L1 CPS > 0 (X-
axis)
The following analysis will be performed to evaluate the evaluation of association between PD-
L1 CPS level and ORR (per BICR) among PD-L1 CPS evaluable subjects for each treatment arm.
•
A logistic regression model will be fitted for ORR with PD-L1 CPS among all PD-L1 
evaluable subjects. An appropriate transformation of PD-L1 CPS may be considered 
depending on an assessment of fit of the model.
•
A plot of estimated response probability with 95% confidence band vs PD-L1 CPS (X-
axis)
•
Box plot of PD-L1 CPS versus Response Status
Receiver Operating Characteristics (ROC) analysis with ORR (per BICR) will be performed to 
help assess in-study predictive accuracy of the logistic regression model and whether there is a 
clinically meaningful threshold of PD-L1 CPS. A plot of the ROC curve and a plot of estimated 
Youden’s index vs PD-L1 CPS will be provided for all PD-L1 CPS evaluable subjects.
7.8.3
Analyses of TPS, GEP and TMB
The following analyses will be performed for TPS, GEP and TMB:
•
Summary statistics of the biomarker in all randomized subjects with quantifiable biomarker.
•
Summary of BOR and ORR by baseline biomarker in all randomized subjects.
•
For each biomarker subgroup (further specified in the DPP) at baseline:
•
OS/PFS curves for each treatment group will be estimated using the Kaplan-Meier product 
limit method. Two-sided, 95% confidence intervals for median OS/PFS will be constructed 
based on a log-log transformed CI for the survivor function S(t)
•
Forest plot of Hazard Ratios with 95% CIs.
•
For GEP only, a histogram of the distribution of GEP between arms will be provided
Additional analyses may be performed to evaluate the association between these biomarkers and 
the efficacy.
7.9
Clinical Outcomes Assessments
The outcome research analyses will be performed using all randomized subjects at the time of final 
analysis of OS. 
The analyses of EQ-5D-3L and FACT-HN outcomes will be restricted to all randomized subjects
and the randomized subjects with PD-L1 CPS ≥ 20 who have an assessment at baseline and at least 
one post-baseline assessment.
7.9.1
EQ-5D-3L
The following descriptive analyses will be conducted: 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
52
•
EQ-5D-3L questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (i.e. number of subjects on treatment or in follow up), will 
be calculated and summarized for each assessment time point by treatment group. 
•
A by-subject listing of the level of problems in each dimension, corresponding to EQ-5D-3L 
health state (i.e., 5-digit vector), EQ-5D-3L utility index score, and EQ-5D-3L VAS score will 
be provided.
•
Proportion of subjects reporting problems for the 5 EQ-5D-3L dimensions at each assessment 
time point will be summarized by level of problem and by treatment group. Percentages will 
be based on number of subjects assessed at assessment time point. Separate analyses will be 
performed including or excluding cases with missing data
•
For the EQ-5D-3L utility index and VAS scores, separately:
−
Mean score and mean change from baseline at each assessment time point will be 
summarized by treatment group using descriptive statistics (N, mean with SD and 95% CI, 
median, first and third quartiles, minimum, maximum).
−
A line graph summarizing the mean changes from baseline will be produced.
7.9.2
FACT-HN
FACT-HN data will be described by treatment group as randomized in the following ways:
•
Scores and post-baseline changes in scores for the following components of the FACT-HN 
will be summarized at each assessment time point using descriptive statistics (ie, N, mean with 
SD and 95% CI, median, first and third quartiles, minimum, maximum): FACT-G, PWB, 
SWB, EWB, FWB, HNC, FHNSI-10, FACT-HN TOI, and FACT-HN total.
•
A line graph summarizing the mean changes from baseline will be produced.
•
The proportion (N) of subjects with symptomatic deterioration, defined as a clinically mean-
ingful decline in FHNSI-10 score (worsening from baseline ≥3 points), will be summarized at 
each assessment time point.
•
TTSD will be estimated using the Kaplan-Meier (KM) product limit method and will be dis-
played graphically. A table will be produced presenting number of events, number of subjects 
involved, medians, and 95% CIs for the medians. Median values of TTSD, along with two-
sided 95% CI in each treatment group will be computed based on a log-log transformation 
method.
•
The proportion (N) of subjects with symptomatic deterioration, defined as a clinically mean-
ingful decline in FHNSI-10 score (worsening from baseline ≥3 points), or death, will be sum-
marized at each assessment time point.
•
Time to symptomatic deterioration or death will be estimated using the Kaplan-Meier (KM) 
product limit method and will be displayed graphically. A table will be produced presenting 
number of events, number of subjects involved, medians, and 95% CIs for the medians. Median 
values of time to symptomatic deterioration or death, along with two-sided 95% CI in each 
treatment group will be computed based on a log-log transformation method.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
53
•
Proportion (N) of subjects endorsing each response option for item GP5, “I am bothered by
side effects of treatment,” will be summarized by treatment group at each assessment time
point. Separate analyses will be performed including or excluding cases with missing data.
•
Proportion (N) of subjects with post-baseline improvement, stability, or worsening in GP5 item
response will be summarized by treatment group at each assessment time point (except base-
line). Separate analyses will be performed including or excluding cases with missing data.
8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates: 
•
For missing and partial adverse event onset dates, imputation will be performed using the
Adverse Event Domain Requirements Specification21
•
For missing and partial adverse event resolution dates, imputation will be performed as follows
(these conventions may change):
−
If only the day of the month is missing, the last day of the month will be used to replace
the missing day. If the imputed date is after the death date or the last known alive date, then
the latest known alive date or death date is considered as the resolution date.
−
If the day and month are missing or a date is completely missing, it will be considered as
missing.
•
Missing and partial non-study medication domain dates will be imputed using the derivation
algorithm described in 4.1.3 of BMS Non-Study Medication Domain Requirements
Specification22.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described
in APPENDIX 2.
•
For death dates, the following conventions will be used for imputing partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the
missing day. The imputed date will be compared to the last known alive date and the
maximum will be considered as the death date.
−
If the month or the year is missing, the death date will be imputed as the last known alive
date.
−
If the date is completely missing but the reason for death is present, the death date will be
imputed as the last known date alive.
•
For date of progression after start of study therapy, the following conventions will be used for
imputing partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the
missing day. In case of the date of death is present and complete, the imputed progression
date will be compared to the date of death. The minimum of the imputed progression date
and date of death will be considered as the date of progression.
−
If the day and month are missing or a date is completely missing, it will be considered as
missing.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
54
•
For date of progression to prior therapies, the following conventions will be used for imputing
partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the
missing day.
−
If the day and month are missing or a date is completely missing, it will be considered as
missing.
•
For other partial/missing dates, the following conventions were used:
−
If only the day of the month is missing, the 15th of the month will be used to replace the
missing day.
−
If both the day and the month are missing, “July 1” will be used to replace the missing
information.
−
If a date is completely missing, it will be considered as missing.
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known alive date will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
9
CONTENT OF REPORTS
All analyses describe in this SAP will be included in the final Clinical Study Report. Refer to the 
Data Presentation Plan for mock-ups of all tables and listings.
10
DOCUMENT HISTORY
Table 10-1:
Document Revision History
Version 
Number
Author(s)
Description
1.0
Initial release dated 21-Oct-2019
2.0
•
Per US FDA feedback, removed the second formal interim
analysis (at 90% information fraction).
•
Added to Section 7.9.2 the analysis of time to symptomatic
deterioration or death.
•
Corrected a typo in Table 7.4.1-3 replacing number 75 with
100.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
55
APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-MEDIATED AD-
VERSE EVENTS AND EVENTS OF SPECIAL INTEREST
Time-to onset definition
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment and the onset date of the earliest AE (of any grade) in this category.
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE.
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined simi-
larly but restricted to drug-related AE.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this subcat-
egory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category
or subcategory will be collapsed into what will be termed “clustered” AEs. For example, if a sub-
ject (without pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with dif-
ferent PT but within same category) from 6th to 11th January and same AE from 10th to 
12th January, these will be collapsed into one clustered AE from 1st to 12th January. Table A1-1 is 
summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs
experienced by the subject in this category per adverse event criteria category. Events which wors-
ened into grade 5 events (death) or have a resolution date equal to the date of death are considered 
unresolved. If a clustered AE is considered as unresolved, the resolution date will be censored to 
the last known alive date. Improvement to the grade at baseline implies that all different events in 
the clustered adverse event should at least have improved to the corresponding (i.e. with same 
preferred term) baseline grade. This measure is defined only for subjects who experienced at least 
one AE in the specific category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune modu-
lating medication was initiated is defined similarly. For data presentation not restricted to IMAE, 
the additional condition that the subject started an immune modulating medication during the long-
est AE resolution period will be applied.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
56
Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table A1-1:
Derivation of Clustered AE
Type of clustered AE
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same cate-
gory
Resolution will be based on the onset date of  the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be collapsed 
when:
1) Multiple adverse event records have the same onset date.
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
3) The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
57
APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing then 
−
If month and year of procedure match month and year of first dose date then impute as date 
of first dose; 
−
If month and year of procedure don't match month and year of first dose date then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial then set end date equal to the last possible reported end date based 
on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed then compare end date to the death date or last known alive date if subject 
is not dead. If posterior then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.  
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
A. For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
•
If only day is missing then impute as the first day of the month; 
•
If both day and month are missing then then impute as 01JAN of the year; 
•
If date is completely missing or invalid then leave missing. 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
58
B. For data collected on other CRF pages (deemed to be on-treatment/subsequent surgeries): 
•
If only day is missing then 
−
If month and year of surgery match month and year of first dose date then impute the 
missing date as the date of first dose; 
−
If month and year of surgery don't match month and year of first dose date then impute as 
first day of that month and year; 
•
If both day and month are missing then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
59
APPENDIX 3
IMMUNOGENICITY ANALYSIS: BACKGROUND AND RA-
TIONALE
The following summary is from the FDA Guidance for Industry Immunogenicity Assessment for 
Therapeutic Protein Products and White Paper on Assessment and Reporting of the Clinical Im-
munogenicity of Therapeutic Proteins and Peptides – Harmonized Terminology and Tactical Rec-
ommendations by Shankar et al. The program-level definitions of sample- and subject-level ADA 
status are based on recommendation from the BMS Immunogenicity Council.
Immune responses to therapeutic protein products may pose problems for both patient safety and
product efficacy. Immunologically based adverse events, such as anaphylaxis and infusion reac-
tions, have caused termination of the development of therapeutic protein products or limited the 
use of otherwise effective therapies. Unwanted immune responses to therapeutic proteins may also 
neutralize the biological activity of therapeutic proteins and may result in adverse events not only 
by inhibiting the efficacy of the therapeutic protein product, but by cross-reacting to an endogenous 
protein counterpart, if present. Because most of the adverse effects resulting from elicitation of an 
immune response to a therapeutic protein product appear to be mediated by humoral mechanisms, 
circulating antibody has been the chief criterion for defining an immune response to this class of 
products.
ADA is defined as biologic drug-reactive antibody, including pre-existing host antibodies that are 
cross-reactive with the administered biologic drug (baseline ADA). Titer is a quasiquantitative 
expression of the level of ADA in a sample. By employing a serial dilution-based test method, titer 
is defined as the reciprocal of the highest dilution of the sample (e.g., dilution of 1/100 = titer of 
100). The ADA is also tested, via a cell-based biologic assay or a non cell-based competitive lig-
and-binding assay for a subpopulation of ADA known as neutralizing antibodies (NAb), which 
inhibits or reduces the pharmacological activity of the biologic drug molecule regardless of its in 
vivo clinical relevance. Non-neutralizing ADA (non-NAb) is ADA that binds to the biologic drug 
molecule but does not inhibits its pharmacological activity.
ADA should be tested using sensitive and valid methods and employing an appropriate strategy
for elucidating immunogenicity. Detection of ADA is typically performed in three tiers (screening, 
confirmatory, and titer) using statistically determined cutpoints and samples testing positive in the 
ADA assay are analyzed for neutralizing activity, especially in late-stage clinical studies. “Detec-
tion” of ADA implies that drug-specific ADA was confirmed. The ‘drug tolerance” of an assay 
(highest drug concentration that does not interfere in the ADA detection method) is not an absolute 
value and differs between individuals due to the varying avidities of ADA immune responses. An 
ADA sampling strategy of collecting samples at times when the least drug concentration is antic-
ipated (trough concentrations) can increase the likelihood of accurate ADA detection.
It is useful to present ADA results from clinical studies as (a) characteristics of the ADA immune
response, (b) relationship of ADA with pharmacokinetics (PK) and, when relevant, pharmacody-
namics (PD) biomarkers, and (c) relationship of ADA with clinical safety and efficacy.
Clinical consequences of ADA can range from no apparent clinical effect to lack of efficacy (pri-
mary treatment failure), loss of efficacy (secondary treatment failure) or heightened effect due to 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
60
altered exposure to the biologic drug, adverse drug reactions (administration-related systemic or 
site reactions), and severe adverse drug reactions (anaphylaxis and unique clinical problems asso-
ciated with cross-reactivity and neutralization of endogenous molecules). Thus it becomes im-
portant to examine any associations between ADA or any of its attributes with the various clinical 
sequelae. The presence of ADA may or may not preclude the administration of drug to ADA-
positive subjects because the outcome is dependent upon the magnitude of the impact of ADA on 
PK and PD. Hence, the relationship of ADA with PK/PD is an important additional consideration, 
but does not necessarily result in a clinically impactful consequence per se.
Immunogenicity Endpoints
A fundamental metric that informs clinical immunogenicity interpretation is the incidence of ADA 
in a study or across comparable studies. ADA incidence is defined as the proportion of the study 
population found to have seroconverted or boosted their pre-existing ADA during the study period.
Terms and Definitions
Validated ADA test methods enable characterization of samples into ADA-positive vs. ADA-neg-
ative. To classify the ADA status of a subject using data from an in vitro test method, each sample 
from the subject is categorized based on the following definitions:
Sample ADA Status:
•
Baseline ADA-positive sample: ADA is detected in the last sample before initiation of
treatment
•
Baseline ADA-negative sample: ADA is not detected in the last sample before initiation of 
treatment
•
ADA-positive sample: After initiation of treatment, (1) an ADA detected (positive 
seroconversion) sample in a subject for whom ADA is not detected at baseline, or (2) an ADA 
detected sample with ADA titer to be at least 4-fold or greater (≥) than baseline positive titer
•
ADA-negative sample: After initiation of treatment, ADA not positive sample relative to
baseline
Next, using the sample ADA status, subject ADA status is defined as follows:
Subject ADA Status:
•
Baseline ADA-positive subject: A subject with baseline ADA-positive sample
•
ADA-positive subject: A subject with at least one ADA positive-sample relative to baseline 
at any time after initiation of treatment
1) Persistent Positive (PP): ADA-positive sample at 2 or more consecutive time points, where 
the first and last ADA-positive samples are at least 16 weeks apart
2) Not PP-Last Sample Positive: Not persistent positive with ADA-positive sample at the last 
sampling time point
1) Other Positive: Not persistent positive but some ADA-positive samples with the last sam-
ple being negative
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
61
2) Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies de-
tected
•
ADA-negative subject: A subject with no ADA-positive sample after the initiation of 
treatment.
(Note: 16 weeks was chosen based on a long half-life of IgG4.)
Population for Analyses
Analysis of immunogenicity data will be based on ADA evaluable subjects defined as all treated
subjects with baseline and at least 1 post-baseline immunogenicity assessment. Analysis dataset
and data listing will include all available ADA samples. However, subject-level ADA status will
be defined based on only adequate samples (e.g., excluding 1-hour post-infusion samples when
clearly indicated).
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
62
APPENDIX 4
SEQUENTIALLY REJECTIVE PROCEDURE
Section 7.5.6 of this SAP specifies the multiple testing procedure that controls family-wise type I 
error rate of 5% in the strong sense across primary and secondary endpoints. After rejecting an 
individual hypothesis, the local significance levels and the transition weights of the edges are up-
dated: the rules for that update are determined by Algorithm 1 in Maurer and Bretz (2013)20. The 
resulting sequentially rejective testing procedure is uniquely determined by the graph in Figure 
7.5.6-1. Below example illustrates the principles of this iterative procedure.
In this study, two primary endpoints (OS in all randomized subjects and OS in subjects with PD-
L1 CPS ≥ 20) and one secondary endpoint (OS in subjects with PD-L1 CPS ≥ 1) will be tested at 
the interim analysis (Time 1) and final analysis (Time 2) as described in Section 5. 
Step 1: At Time 1, OS in all randomized subjects and OS in subjects with PD-L1 CPS ≥ 20 will 
be respectively tested in nominal alpha 0.01 (obtained from O’Brien and Fleming α-spending func-
tion given information fraction of 80% and initial overall alpha is equally split for the two end-
points). Assuming only OS in subjects with PD-L1 CPS ≥ 20 is rejected, it will be removed from 
the graph and the entire nominal alpha (0.025) for this endpoint will be passed to the secondary 
endpoint OS in subjects with PD-L1 CPS ≥ 1. The below figure illustrates the update of the graph
before (part A) and after (part B) Step 1.
Step 2: At Time 1, OS in subjects with PD-L1 CPS ≥ 1 will be tested at 0.01 (the nominal alpha is 
determined by the actual information fraction for this population and can vary from 0.01). If it is 
not significant, graph will not change and continue to Step 3.
Step 3: At Time 2 (final analysis), OS in all subjects and in subjects with PD-L1 CPS ≥ 1 will each 
be tested at 0.022.  Assuming only OS in subjects with PD-L1 CPS ≥ 1 is rejected, it will be 
removed from the graph and the entire nominal alpha (0.025) for this endpoint will be passed to 
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
63
the endpoint OS in all randomized subjects. The below figure illustrates the update of the graph
before and after Step 3.
Step 4: The overall alpha for OS in all randomized subjects becomes 0.05 and this endpoint can 
be retested with nominal alpha of 0.043 at Time 2 (final analysis).
Similarly, if OS in all randomized subjects is significant in any of the 2 time points but OS in 
subjects with PDL1 CPS ≥ 20 is not, the latter will be re-tested with updated nominal alpha ob-
tained from O’Brien and Fleming α-spending function using an overall alpha of 0.05. Subse-
quently, if OS in subjects with PD-L1 CPS ≥ 20 is significant, the OS in subjects with PD-L1 CPS 
≥ 1 will also be tested with nominal alpha obtained from O’Brien and Fleming α-spending function
using an overall alpha of 0.05.
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
64
11
REFERENCES
1
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer 
J Clin 2011 ; 6(2):69-90
2
NCI SEER Statistics Review http://seer.cancer.gov/statfacts/html/oralcav.htmlaccessed March 
5,2016
3
Leemans CR, Braakhuis B, Brakenhoff R. Molecular biology of head and neck cancer. Nature 
Reviews Cancer Vol 11 Jan 2011
4
NCCN Guidlines Version 2.2014 Head and Neck Cancers
5
Vermoken et al Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl 
J Med 2008;359:1116-27
6
Ferris et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell 
carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with 
analyses by tumor PD-L1 expression. Oral Oncology 81 (2018) 45–51
7
Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.
PNAS 2010; 107: 4275-80.
8
The EuroQol Group: EuroQol: A new facility for the measurement of health-related quality of 
life—The EuroQol Group. Health Policy 16:199-208, 1990.
9
Dolan P. Modeling valuations for EuroQol health states. Medical Care 1997;35: 1095-1108
10 Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D 
utility and VAS scores in cancer. Health Qual Life Outcomes 2007;5:70
11 Yount S, List M, Du H et al. A randomized validation study comparing embedded versus 
extracted FACT Head and Neck Symptom Index scores. Qual Life Res. 2007; 16: 1615-1626.
12 Robert L. Ferris, George Blumenschein Jr, Jerome Fayettec, Joel Guigay et al.Nivolumab for 
Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016; 375:1856-
1867
13 Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus 
cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head 
and neck (KEYNOTE-048): a randomized, open-label, phase 3 study. Lancet. 2019;394:1915-
1928.
14 Brookmeyer R. and Crowley J. A confidence interval for the median survival time. Biometrics 
38:29-41, 1982
15 Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored and 
Truncated Data, New York: Springer-Verlag
Approved
2.0
v
Approved
1.0
v


STATISTICAL ANALYSIS PLAN
CA209651
BMS-936558
nivolumab
65
16 Global Biometric Sciences, SAS Analysis Dataset Specification, Unique Adverse Events. 
Version 2.0, April 22, 2015
17 Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 26: 404–413
18 Greenwood, M. The errors of sampling of the survivorship tables, Reports on Public Health 
and Statistical Subjects, 33, Appendix 1, HMSO, London, 1926
19 Kalbfleisch, J. D. and Prentice, R. L. (1980), The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons.
20 W Maurer, and F Bretz (2013). Multiple testing in group sequential trials using graphical ap-
proaches. Statistics in Biopharmaceutical Research. Vol 5, 2013.
21 Adverse Event Domain Requirements Specification Bristol Myers Squibb Co. PRI. Version 
2.3.0 April 23, 2018
22 Non-Study Medication Domain Requirements Specification Bristol Myers Squibb Co. PRI. 
Version 2.10.0 April 23, 2018
Approved
2.0
v
Approved
1.0
v