Conditions: Various Advanced Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 578
Healthy volunteers: no

Brief summary:
The purpose of this study to investigate the safety and effectiveness of nivolumab, and nivolumab combination therapy, to treat patients who have virus-associated tumors. Certain viruses have been known to play a role in tumor formation and growth. This study will investigate the effects of the study drugs, in patients who have the following types of tumors:

* Anal canal cancer-No longer enrolling this tumor type
* Cervical cancer
* Epstein Barr Virus (EBV) positive gastric cancer-No longer enrolling this tumor type
* Merkel Cell Cancer
* Penile cancer-No longer enrolling this tumor type
* Vaginal and vulvar cancer-No longer enrolling this tumor type
* Nasopharyngeal Cancer - No longer enrolling this tumor type
* Head and Neck Cancer - No longer enrolling this tumor type

Detailed description:

Arms:
arm 1: Nivolumab intravenous infusion as specified

\*\*Not participating: Japan, Korea, and Taiwan arm 2: Nivolumab intravenous infusion as specified arm 3: Nivolumab intravenous infusion as specified with Ipilimumab intravenous infusion as specified

\*\*Not participating: Belgium, France and Germany

Cohort expansion participating countries: Spain, US, UK, Netherlands, Japan and Mexico

\*\*Not participating in cohort expansion: France, Germany, Korea and Taiwan arm 4: Nivolumab intravenous infusion as specified with Relatlimab intravenous infusion as specified

\*\* Not Participating: Belgium, Germany, France, Japan, Korea, Taiwan, UK, and Netherlands

Enrollment is closed for this cohort arm 5: Nivolumab intravenous infusion as specified with Daratumumab intravenous infusion as specified

\*\*Not Participating: Belgium, Germany, France, Japan, Korea, Taiwan, UK, and Netherlands

Enrollment is closed for this cohort

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Relatlimab intervention 4: Daratumumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
Non-Comparative, Open-Label, Multiple Cohort, Phase 1/2 Study of Nivolumab Monotherapy and 
Nivolumab Combination Therapy in Subjects With Virus-Positive and Virus-Negative Solid Tumors 
 
NCT Number: NCT02488759 
Document Date (Date in which document was last revised): May 7, 2019 


Page:
1
Protocol Number:
CA209358
IND Number:
129,947
EUDRACT Number
2015-000230-29
Date:
22-Apr-2015
Revised Date:
07-May-2019
Clinical Protocol CA209358
Non-Comparative, Open-Label, Multiple Cohort, Phase 1/2 Study of Nivolumab Monotherapy 
and Nivolumab Combination Therapy in Subjects with Virus-Positive and Virus-Negative Solid 
Tumors
Revised Protocol Number: 07
Incorporates Administrative Letter 02
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ08543
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 
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 
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
2
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Revised 
Protocol 07
07-May-2019
•
Incorporates Administrative Letter 02.
•
Changed exploratory objective and endpoint of progression-free 
survival to recurrence-free survival.
•
Updated inclusion/exclusion criteria from bulleted lists back to letters.
•
Updated language for EQ-5D-3L and EORTC-QLQ-C30.
•
Added missing footnote identifier to Table 5.1-3.
Administrative 
Letter 01
05-Mar-2019
Revised 
Protocol 06
18-Jul-2018
•
Terminated enrollment and treatment of daratumumab combination 
cohorts.
•
Added a Combination B cohort expansion for SCC of the cervix.
•
Changed the neoadjuvant secondary endpoint to an exploratory 
endpoint.
•
Closed enrollment in the combination cohorts for anogenital HPV 
associated tumor types.
Revised 
Protocol 05
18-Apr-2018
•
Added 24-month maximum treatment duration for nivolumab.
•
Clarified sample sizes for neoadjuvant tumor types.
•
Allow concurrent enrollment for Combination Cohorts A, B, and D.
•
Removed gastric cancer from Combination Cohorts.
•
Enrollment to Combination C is closed (including to crossovers).
•
Added new safety data from BMS-986016 and daratumumab.
•
Changed order of nivolumab and daratumumab administration so that 
nivolumab is now administered before daratumumab.
•
Removed oxygen saturation testing from vital signs collection in all on-
treatment groups.
•
Clarified imaging duration to be consistently starting at week 8.
•
Added 400-mg vials for daratumumab.
•
Updated naming of tumor types from “HPV associated tumors” to 
“Anogenital Cancers.”
In addition to the above changes, other minor changes have been made, 
including correction of typographical errors, and administrative updates.
Revised 
Protocol 04
28-Oct-2016
Incorporates Amendment 13
Amendment 
13
28-Oct-2016
This global amendment was written primarily to address the following:
•
Addition of two treatment arms, consisting of nivolumab combined 
with an anti-LAG3 agent (BMS-986016) and nivolumab combined 
with daratumumab to the metastatic combination cohort.
•
Updates to the sample sizes for various tumor types in the metastatic 
monotherapy and metastatic combination therapy cohorts for 
combinations A and B
•
Addition of HPV positive anal canal and penile cancers to the 
metastatic combination cohort
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
4
Document
Date of Issue
Summary of Changes
•
Clarification that results of Day 29 tumor biopsy for neoadjuvant 
cohort must be reviewed by pathologist and a copy of the pathology 
report must be sent to BMS
•
Nivolumab program level revisions, including algorithm update and 
contraception requirements.
•
Updates to references in Section 12 in accordance with information 
added to the protocol 
In addition to the above changes, other minor changes have been made, 
including correction of typographical errors, and administrative updates.
Revised 
Protocol 03
16-Mar-2016
Incorporates Amendment 09 and Administrative Letter 01
Amendment 
09
16-Mar-2016
This global amendment was written primarily to address the following:
•
Addition of a metastatic combination cohort that will investigate the 
safety and efficacy of nivolumab in combination with ipilimumab in 
virus-positive and virus-negative solid tumors.
o
Updated the dose delay, resume and discontinuation criteria to 
include ipilimumab
o
Updated the sample size, interim analysis, and analysis 
populations to include the metastatic combination cohort
•
Clarified collection of tumor tissue samples
•
Provided specificity and updates related to biomarker sample 
requirements and biomarker testing methodologies
In addition to the above changes, other minor changes have been made, 
including the following:
•
Clarified dose delay, resume and discontinuation criteria
•
Clarified that the analysis will be performed by tumor type in each 
cohort
•
Omitted protocol content to reduce redundancy between sections 
explaining protocol discontinuation
•
Corrected typographical errors, and made administrative updates
Administrative 
Letter 01
18-Dec-2015
Revised 
Protocol 02
16-Oct-2015
Incorporates Amendment 07
Amendment 
07
16-Oct-2015
This global amendment was written primarily to address the following:
•
Removed an exclusion criterion regarding prior surgeries that 
require general anesthesia and surgeries requiring local/epidural 
anesthesia. This change was made based on feedback provided by 
disease experts working on this trial
In addition to the above changes, other minor changes have been made, 
including the following
•
Provided viral status determination clarifications
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
5
Document
Date of Issue
Summary of Changes
•
Removed a smoking history requirement for neoadjuvant cohort 
HPV positive SCCHN subjects
•
Edited the allowable window for safety lab testing prior to dosing
•
Omitted protocol content to reduce redundancy between sections 
explaining protocol discontinuation
•
Provided updates regarding dose delays in the neoadjuvant cohort
•
Added four month post-surgery follow-up assessments for 
neoadjuvant cohort subjects
•
Made updates regarding tumor scan assessment timing during 
follow-up period for neoadjuvant cohort
•
Corrected discrepant information regarding windows for protocol-
specified cycles
•
Removed the requirement to discontinue tumor assessments one 
year after a complete response is determined 
•
Added a description regarding research related to ex vivo 
functional assays
•
Corrected typographical errors, and made administrative updates
Revised 
Protocol 01
23-Jul-2015
Incorporates Amendment 03
Amendment 
03
23-Jul-2015
This global amendment was written primarily to address the following:
•
Addressed feedback 
 regarding 
contraceptive language
In addition to the above changes, other minor changes have been made, 
including the following:
•
Corrected discrepancy in the protocol schema regarding the 
screening period duration
•
Clarified, updated, and corrected discrepancies pertaining to, 
information regarding virus testing throughout the protocol
•
Provided clarification regarding entry criteria related to specific 
tumor types
•
Provided specificity for entry criteria related to prior therapies
•
Provided specificity and updates related to biomarker sample 
requirements and biomarker testing methodologies
•
Corrected discrepancies regarding oxygen saturation testing
•
Updated safety laboratory testing requirements pertaining to  
bicarbonate or total CO2 testing
•
Provided information regarding clinical interest related to 
objective response rate.
•
Corrected typographical and spelling errors throughout the 
document
Original 
Protocol
22-Apr-2015
Not applicable
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 07:
Based on discussion with medical team and key investigators, the newly proposed endpoint of 
recurrence-free survival (RFS) is more clinical meaningful and suitable than the previous endpoint 
of progression-free survival (PFS) in terms of reflecting the efficacy of nivolumab as neoadjuvant 
therapy.
During Protocol Revision 06, the inclusion/exclusion criteria sequencing was inadvertently 
changed from a lettering scheme to bullets. Per Protocol Revision 07, this has been corrected and 
the inclusion/exclusion criteria are again sequenced with letters.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Exploratory Objectives
Revised progression-free survival after 
1 year objective to recurrence-free 
survival after surgery.
More clinically meaningful.
Synopsis, Exploratory Objectives
Clarified the EQ-5D to EQ-5D-3L;
added “questionnaire” to each.
Clarification.
Synopsis, Exploratory Endpoints
Revised progression-free survival to 
recurrence-free survival.
More clinically meaningful.
Synopsis, Outcomes Research 
Assessments
Revised language describing the EQ-
5D-3L and EORTC-QLQ-C30.
Clarification.
Synopsis, Sample Size
Deleted Table 6.
Not referenced in synopsis 
text.
1.3.3, Exploratory Objective(s)
Revised progression-free survival after 
1 year objective to recurrence-free 
survival after surgery.
More clinically meaningful.
1.3.3, Exploratory Objective(s)
Clarified the EQ-5D to EQ-5D-3L;
added “questionnaire” to each.
Clarification.
3.3.1, Inclusion Criteria
3.3.2, Exclusion Criteria
Reformatted lists from bullets to letters.
Reverted to original letter 
sequencing to align with 
CRFs.
5, Study Assessments and Procedures
Table 5.1-3: On-Treatment 
Assessments Metastatic Combination 
Therapy Cohorts (CA209358)
Added missing footnote identifier to 
study drug administration for Cohorts 
A and B.
Footnote identifier was 
inadvertently missing from 
previous version (though 
footnote was in place).
5.7, Outcomes Research Assessments
Revised language describing the EQ-
5D-3L and EORTC-QLQ-C30.
To bring in line with current 
standards.
8.3.3, Exploratory Endpoint(s)
Revised progression-free survival 
description to recurrence-free survival.
More clinically meaningful.
8.4.6.1, EQ-5D
Revised language.
Clarification.
Revised Protocol No.: 07
Date: 07-May-2019
6
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07
Section Number & Title
Description of Change
Brief Rationale
8.4.6.2, EORTC QLQ-C30
Revised language.
Clarification.
11, List of Abbreviations
Added definitions for EQ-5D-3L and 
EORTC-QLQ-C30.
Clarification.
Revised Protocol No.: 07
Date: 07-May-2019
7
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
SYNOPSIS
Clinical Protocol CA209358
Protocol Title: Non-Comparative, Open-Label, Multiple Cohort, Phase 1/2 Study of Nivolumab Monotherapy 
and Nivolumab Combination Therapy in Subjects with Virus-Positive and Virus-Negative Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 
On the basis of eligibility and tumor type (Epstein Barr Virus [EBV] positive gastric cancer, EBV positive 
nasopharyngeal cancer [NPC], cervical cancer, HPV positive and negative squamous cell cancer of the head and neck 
[SCCHN], anogenital HPV associated cancers [vaginal, vulvar, anal canal, penile], and Polyomavirus positive Merkel 
cell cancer [pMCC]), the study will enroll or randomize subjects into neoadjuvant treatment or recurrent/metastatic 
monotherapy, or assign or randomize into the recurrent/metastatic combination therapies cohorts (A, B, C or D). 
Treatments for each cohort are as follows:
Neoadjuvant cohort:
•
Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15
Metastatic Monotherapy Cohorts:
•
Nivolumab administered IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until 
disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first.
Metastatic Combination Cohorts (Combinations A, B, C, and D):
•
Combo Arm A: Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks plus Ipilimumab 1 mg/kg IV over 30 
minutes every 6 weeks  for a maximum of 24 months or until disease progression, unacceptable toxicity, or 
withdrawal of consent, whichever comes first.
•
Combo Arm B: Nivolumab 1 mg/kg IV over 30 minutes plus Ipilimumab 3 mg/kg IV over 30 minutes every 
3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 
24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes 
first.
•
Combo Arm C: Nivolumab 240 mg IV over 30 minutes plus BMS-986016 (relatlimab) 80 mg IV over 60 
minutes administered every 2 weeks for a maximum of 24 month, or until disease  progression,  unacceptable 
toxicity, or withdrawal of consent, whichever comes first. As of Revised Protocol 05, enrollment will be 
closed in Combination C. 
•
Combo Arm D: Daratumumab 16 mg/kg IV administered weekly for the first 8 weeks. Starting at Week 3, 
nivolumab 240 mg IV over 30 minutes will be administered every 2 weeks. Nivolumab will be administered 
before the daratumumab infusion on study days when both study drugs are administered on the same day.  
Daratumumab 16 mg/kg will be administered every 2 weeks from Weeks 9-24. Starting at Week 25, 
nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a 
maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever 
comes first. The infusion rates for the first, second, and subsequent daratumumab infusions should closely 
follow the specifications of the currently approved (USPI)/pharmacy reference manual. As of Revised 
Protocol 05, enrollment will be closed in Combination C.
Revised Protocol No.: 07
Date: 07-May-2019
8
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Study Phase: 1/2
Research Hypothesis (A):  Nivolumab, in the neoadjuvant setting, will be safe and tolerable in subjects with select 
virus positive and virus-negative tumors.
Research Hypothesis (B):  Treatment with nivolumab alone or in combination with either ipilimumab, BMS-986016
(relatlimab), or daratumumab will lead to clinically meaningful tumor reductions, as measured by objective response 
rate and duration of response, in subjects with metastatic or unresectable tumors.
Primary Objectives  
•
In the neoadjuvant cohort, to investigate the safety and tolerability of neoadjuvant nivolumab administration in 
the following tumor types:
−
HPV-positive SCCHN
−
HPV-negative SCCHN
−
Merkel Cell Carcinoma 
−
Cervical, vaginal, or vulvar cancers
•
In the metastatic cohort (nivolumab monotherapy), to evaluate the investigator-assessed objective response rate 
(ORR) in subjects with the following diseases:
−
Metastatic or recurrent nasopharyngeal carcinoma (NPC) 
−
Metastatic or Recurrent EBV related gastric cancer
−
Metastatic or Recurrent Merkel Cell Carcinoma
−
Metastatic or Recurrent cervical, vaginal, or vulvar cancers
−
Metastatic or recurrent HPV positive cell cancer of the head and neck (SCCHN)
•
In the metastatic cohort combination therapies (nivolumab combined with either ipilimumab or BMS-986016), 
to evaluate the investigator-assessed ORR in subjects with the following diseases:
−
Metastatic or recurrent NPC
−
Metastatic or recurrent Merkel Cell Carcinoma
−
Metastatic or recurrent cervical cancer
−
Metastatic or recurrent HPV positive SCCHN (with prior exposure to anti-PD-1;  anti-PD-L1 antibody or 
anti-CTLA-4 therapy [Combination C])
−
Other metastatic or recurrent anogenital HPV associated tumors (vulvar, vaginal, anal canal, penile)
•
In the metastatic cohort combination therapy (nivolumab combined with daratumumab), to evaluate the 
investigator-assessed ORR in subjects with the following diseases:
−
Metastatic or recurrent HPV positive or negative or unknown SCCHN (without prior I-O therapy exposure)
Secondary Objectives
•
Metastatic cohort (monotherapy and combination therapies): To evaluate the duration of response, progression-
free survival and overall survival.
Exploratory Objectives
Neoadjuvant Cohort
•
To determine the percent change from baseline of select immune cells and the percent change from baseline of 
select immune activation/inhibitory molecules of viral specific T cells in tumor specific subsets of nivolumab 
treated subjects.
•
To evaluate the recurrence-free survival after neoadjuvant administration of nivolumab and surgery
•
To determine the percent change from baseline in tumor volume after two doses of neoadjuvant nivolumab.
Revised Protocol No.: 07
Date: 07-May-2019
9
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
To determine pathologic complete response of tumors in subjects who receive surgical resection after two doses 
of neoadjuvant nivolumab in SCCHN, resectable Merkel Cell Carcinoma, and cervical, vaginal, or vulvar cancer.
•
To evaluate changes in anti-viral and anti-tumor immune responses at the tumor site, using proliferative and/or 
functional assays.
•
To investigate the potential association between selected biomarker measures in peripheral blood and tumor 
tissue, including PD-L1, with safety and clinical efficacy measures. 
•
To investigate the pharmacodynamic activity of nivolumab in the peripheral blood and tumor tissue as measured 
by gene expression, flow cytometry, immunohistochemistry and soluble factor assays. 
•
To study the effect of nivolumab on the viral antigen specific T cell responsiveness in the peripheral blood. 
•
To evaluate the potential association between the number of tumor mutations and neoantigens with clinical 
efficacy measures and determine if tumor antigen-specific T cells are present in the periphery.
•
To assess the subject’s overall health status as assessed by the EQ-5D-3L questionnaire. 
•
To evaluate cancer specific health related quality of life as assessed by EORTC QLQ-C30 questionnaire.
•
To characterize pharmacokinetics of nivolumab and explore exposure-response relationships.
•
To characterize the immunogenicity of nivolumab.
Metastatic Cohort (Monotherapy and Combination Therapies)
•
To determine the safety and tolerability [defined as toxicity rates (worst CTC grade per subject) of adverse events 
and specific laboratory tests] of nivolumab monotherapy and combination therapy (ipilimumab, BMS-986016, or 
daratumumab) in subjects with metastatic or recurrent viral-mediated tumors.
•
To evaluate the pre and post treatment EBV DNA levels in subjects with EBV positive gastric cancer 
(monotherapy only) and nasopharyngeal carcinoma.
•
To investigate the potential association between selected biomarker measures in peripheral blood and tumor 
tissue, including PD-L1, with safety and clinical efficacy measures. 
•
To investigate the pharmacodynamic activity of nivolumab monotherapy and combination therapy (ipilimumab, 
BMS-986016, or daratumumab) in the peripheral blood and tumor tissue as measured by gene expression, flow 
cytometry, immunohistochemistry and soluble factor assays. 
•
To study the effect of nivolumab monotherapy and combination therapy (ipilimumab, BMS-986016, or 
daratumumab) on the viral antigen specific T cell responsiveness in the peripheral blood. 
•
To evaluate the potential association between the number of tumor mutations and neoantigens with clinical 
efficacy measures and determine if tumor antigen-specific T cells are present in the periphery.
•
To assess the subject’s overall health status as assessed by the EQ-5D. 
•
To evaluate cancer specific health related quality of life as assessed by EORTC QLQ-C30.
•
To characterize pharmacokinetics of nivolumab monotherapy and combination therapy (ipilimumab, 
BMS-986016, or daratumumab) and explore exposure-response relationships.
•
To characterize the immunogenicity of nivolumab monotherapy and combination therapy (ipilimumab, 
BMS-986016, or daratumumab).
Study Design:  This is an open label, multi-center, phase 1/2 trial to investigate the safety and efficacy of nivolumab 
as a single agent or in combination with either ipilimumab, BMS-986016 (relatlimab, anti-LAG3 antibody), or 
daratumumab in viral positive and viral negative tumor types of the following tumor types: EBV positive gastric 
cancer, EBV positive NPC, cervical cancer, HPV positive and negative SCCHN, anogenital HPV associated cancers 
(vaginal, vulvar, anal canal, penile), and pMCC.
On the basis of eligibility and tumor type, patients will be enrolled into the neoadjuvant or recurrent/metastatic 
monotherapy, or assigned or randomized into the recurrent/metastatic combination therapies cohorts (A, B, C or D). 
Revised Protocol No.: 07
Date: 07-May-2019
10
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Upon approval of Revised Protocol 05, all Metastatic Combination Cohorts A, B, and D will enroll patients 
concurrently and enrollment will be closed for Combination Cohort C.
Combination B squamous cell cancer (SCC) of the cervix cohort is being expanded to add approximately 70 patients 
to further confirm the efficacy signal. Approximately 50 patients will be added to receive Combination B study drug 
as first-line treatment of their recurrent/metastatic disease if unfit or unsuitable to receive platinum-based therapy; and 
approximately 20 patients will be added to receive study drug as second-line treatment of their recurrent/metastatic 
SCC of the cervix.
Treatments for each cohort are as presented above. 
Study Design Schematic for the Neoadjuvant Cohort
The tumor types for the neoadjuvant cohort and the study design schematic for the neoadjuvant cohort are presented 
below:
•
HPV positive SCCHN and HPV negative SCCHN
•
Cervical, Vaginal, Vulvar carcinoma
•
Merkel Cell Carcinoma
The diseases or tumor types for the recurrent/metastatic monotherapy cohort and the study design schematic for the 
recurrent/metastatic monotherapy cohort are presented below: 
•
EBV positive Gastric cancer, 
•
HPV positive SCCHN
•
GYN (Cervical, vaginal, and vulvar carcinoma)
•
Merkel Cell carcinoma 
•
Nasopharyngeal Carcinoma (NPC) 
Neoadjuvant
Nivo 240 mg
(2 doses)
1) Day 1
2) Day 15
Biopsy
Prior to 1st
dose
Biopsy or 
Surgical 
resection
(Day 29)
Investigator’s choice 
Standard of Care 
(SOC)
Nivo 240 mg Q2 weeks
Until 24 months maximum 
duration, PD, or Toxicity
Treatment
Follow-Up
Screening
Subsequent Treatment
Up to 5 weeks
TUMORS:
• GYN (cervical, vaginal, 
vulvar) - N = 21 
evaluable subjects
• MCC – N = 21 
evaluable subjects
• HPV (+) SCCHN – N = 
21 evaluable subjects
• HPV (-) SCCHN – N = 
21 evaluable subjects
•
F/U  visit 1+2
•
F/U post 
surgery (month 
4, 8, and 12)
•
Survival F/U
For Subjects with HPV: 
Virus selection required 
If unresectab erecurrent or 
metastatic disease within 1 
year after end of SOC 
If eligible
Min 12 weeks
10 subjects enrolled in each tumor - PAUSE –
Safety analyses
Additional 11 subjects enrolled if  ≤ 2/10 have 
surgery delayed > 4 weeks (due to nivo AE’s as 
specified in the label)
Revised Protocol No.: 07
Date: 07-May-2019
11
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Study Design Schematic for the Metastatic Monotherapy Cohort 
The diseases or tumor types for the recurrent/metastatic combination therapy cohorts (Combo A, B and C) and the 
study design schematics for the recurrent/metastatic combination therapies A, B, and C are presented below.
•
HPV positive SCCHN
−
Immuno-Oncology naive (anti-tumor vaccine and any T cell co-stimulation or checkpoint pathways therapy) 
(Combo A)
−
Prior PD-1/PD-L1 experienced (Combo C)
•
Cervical cancer
•
Anogenital HPV associated tumors (vaginal, vulvar, anal canal, penile)
•
Merkel Cell Carcinoma
•
Nasopharyngeal Carcinoma (NPC)
Study Design Schematic for the Metastatic Cohort Combination Therapies A and B and Combo B SCC of the 
Cervix Expansion
Metastatic 
Monotherapy 
Nivo monotherapy 240 mg
Q2 weeks
Until disease progression, toxicity, 
withdrawal of consent, or a maximum 
of 24 months
TUMORS:
• EBV (+) Gastric - N=12
• HPV(+) SCCHN - N=23
• GYN (cervical, vaginal, 
vulvar) - N=23
• MCC - N=23
• NPC  - N=23
Up to 5 weeks
Up to 2 priortreatments
≥ 1 target lesion
ECOG status: 0 or 1
• Imaging every 8 weeks starting at 
Week 8 for the first year of treatment
• Imaging every 12 weeks starting at 
year 2 and beyond
Min 12 weeks
survival
For Subjects with HPV (+) and 
EBV (+):  virus selection required
Revised Protocol No.: 07
Date: 07-May-2019
12
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Study Design Schematic for the Metastatic Cohort Combination Therapy C
The disease or tumor type for the recurrent/metastatic combination D therapy cohort and the study design schematic 
for the recurrent/metastatic combination cohort for combination therapy D are presented below: 
•
HPV positive or HPV negative or HPV unknown SCCHN 
−
Immuno-Oncology therapy naive (anti-tumor vaccine and any T cell co-stimulation or checkpoint pathways 
therapy)
Treatment
Follow-Up
Screening
Subsequent Treatment
Combo B Cervical Cancer 
expansion  
• Up to 2 prior treatments
• > 1 target lesion
• ECOG PS: 0-1
SCC OF THE CERVIX
• First-line treatment – 50 patients
• Second-line treatment – 20 
patients
Nivo + Ipi Combo
Combo B
Nivo-1mg/kg + Ipi-3mg/kg 
q3w x 4 followed by Nivo 
240mg q2w until disease 
progression, toxicity, 
withdrawal of consent, or a 
maximum of 24 months
• Imaging every 8 weeks 
starting at Week 8 for 
the first year of 
treatment
• Imaging every 12 weeks 
starting at year 2 and 
beyond
Min 12 
weeks
Survival
N = approx. 70 will be added to combo B to 
recieve treatment as first-line or second-line 
treatment
Relatlimab(Anti-Lag-3) 80 
mg +
Nivolumab 240 mg q2W 
until, disease progression, 
toxicity, withdrawal of 
consent, or a maximum of 
24 months
• Imaging every 8 
weeks starting at 
Week 8 for the first 
year of treatment
• Imaging every 12 
weeks starting at 
year 2 and beyond
Treatment
Follow-Up
Screening
Subsequent Treatment
• Up to 2 prior treatments*
• > 1 target lesion
• ECOG PS: 0-1
TUMOR TYPE:
•HPV+ SCCHN (I-O experienced)**
Min 12 weeks
Survival
Combo C (Nivo + Relat) 
N = approx. 40
*Prior I-O therapy is permitted and is not counted toward the number of prior systemic treatment
**Include subjects that have had prior exposure to anti-PD-1, anti-PD-L1  or anti-CTLA-4 antibodies monotherapy or combination 
therapy
Revised Protocol No.: 07
Date: 07-May-2019
13
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Study Design Schematic for the Metastatic Cohort Combination Therapy D: Tumor Type SCCHN HPV 
positive, negative or unknown I-O naive.
All subjects will complete 3 periods of the study: Screening, Treatment, Follow-up, including survival follow-up. 
Duration of Study: The last visit will be defined as the latest survival visit included in the final analysis of OS (ie, 
the latest subject death, loss to follow up, or withdrawal of consent) for a tumor type within each cohort.  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 collection has concluded.
Study Population:
Inclusion Criteria:
a)
Histopathologic confirmation of the following tumor types
i)
Merkel Cell Carcinoma 
(1). MCPyV status will be determined after enrollment
ii)
EBV-Positive Gastric or Gastro-Esophageal junction carcinoma (including adenocarcinoma arising from 
the lower esophagus) 
(1). For subjects in the metastatic cohorts (monotherapy only) with gastric tumor types, EBV positivity 
is defined by EBER in situ hybridization. Testing for EBV positivity will be performed prior to 
study drug assignment using the EBER1 DNP probe from Ventana in a properly certified lab. 
Samples interpreted as (+) if nuclear staining of any intensity above the background in tumor cells, 
provided the negative internal controls (adjacent normal tissue) are negative.
iii) Nasopharyngeal Carcinoma 
(1). For subjects in the metastatic cohorts (monotherapy and combination) with nasopharyngeal 
carcinoma tumor types, EBV positivity is as defined by EBER in situ hybridization as specified 
above. Virus testing will be performed retrospectively only if results from prior accepted testing are 
not available. 
iv) Squamous cell carcinoma of the cervix, vagina, vulva, anal canal, and penile (Note: anal canal and 
penile for metastatic combination cohorts only)
(1). For subjects in the neoadjuvant and metastatic (monotherapy and combination) cohorts with 
gynecological tumors, HPV positivity is defined by FDA approved tests (Cobas HPV Test; Digene 
Hybrid Capture 2 High-Risk HPV DNA Test; Cervista™ HPV HR and Genfind™ DNA Extraction 
Kit; Cervista™ HPV 16/18; APTIMA® HPV Assay) or other well validated commercially available 
tests (such as Ventana Inform HPV ISH test) comprising in situ hybridization, real-time PCR, or 
immunohistochemistry (IHC). High-risk HPV positivity includes the following subtypes:  16, 18, 
• Imaging every 8 weeks 
starting at Week 8 for the 
first year of treatment
• Imaging every 12 weeks 
starting at year 2 and 
beyond
Treatment
Follow-Up
Screening
Subsequent Treatment
• Up to 2 prior 
treatments
• > 1 target lesion
• ECOG PS: 0-1
TUMOR TYPES:
•SCCHN – HPV 
+/HPV – or HPV 
unknown
•I-O naïve
Min 12 weeks
Survival
N = approx. 40
Combo D
• Daratumumab 16 mg/kg q1W 
– Week 1 to 8; q2W –Week 9  
to 24 and q4W starting on 
Week 25 until toxicity, 
withdrawal of consent, or a 
maximum of 24 months
• Nivolumab 240 mg q2W –
starting on Week 3  and 480 
mg q4W starting  from Week 
25 until toxicity, withdrawal of 
consent, or a maximum of 24 
months
Revised Protocol No.: 07
Date: 07-May-2019
14
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Virus testing will be performed retrospectively 
only if results from prior accepted testing are not available.  
v)
Squamous cell carcinoma of the Head and Neck
(1). For subjects in the neoadjuvant and metastatic (monotherapy and combination) cohorts HPV 
positivity is defined by p16INK4a (p16) IHC employing clone E6H4 form MTM (Roche). HPV p16 
IHC should be interpreted as positive if > 70% strong and diffuse nuclear and cytoplasmic staining 
is specific to tumor cells. Testing for HPV 16 will be performed prior to study drug assignment 
using an appropriately validated test.
(2). HPV positive status can be obtained from either the primary tumor or metastatic lymph node.
(3). For subjects in the virus negative neoadjuvant cohort, HPV status should be documented as defined 
above. The p16 IHC should be interpreted as negative if < 70% strong and diffuse nuclear and 
cytoplasmic staining is specific to tumor cells.
b)
For subjects in the neoadjuvant cohort 
i)
Squamous cell carcinoma of the Head and Neck for whom surgical resection is planned. 
(1). Subjects must have newly diagnosed, histologically or cytologically confirmed squamous cell 
carcinoma or undifferentiated carcinoma of the oral cavity, pharynx and larynx. Subjects must have 
been determined to have resectable disease. 
(2). Subjects must have tumor amenable to pre-treatment biopsy. Post-treatment biopsy will consist of 
the operative specimen. Excisional, incisional or core needle samples are acceptable. Fine needle 
aspirates are prohibited. See Section 5.6.9 for further details. The biopsy may have been obtained 
from the primary tumor or metastatic lymph node. 
(3). Subjects must have both of the following:  
a.
T1 or greater primary lesions, 
b.
N1 or greater nodal disease,
ii)
Squamous cell cervical, vulvar, or vaginal cancer
(1). Stage II to IVA cervical cancer who have planned surgical staging or chemotherapy/radiation 
treatment
(2). Stage II to IVA vulvar or vaginal cancer who have planned curative intent surgery or 
chemotherapy/radiation treatment
(3). Subjects must have tumor amenable to pre-treatment biopsy. Post-treatment biopsy will consist of 
the operative specimen. Excisional, incisional or core needle samples are acceptable. Fine needle 
aspirates are prohibited. See Section 5.6.9 for further details.
iii) Merkel Cell Carcinoma: 
(1). Subjects must have tumor amenable to pre-treatment biopsy (core needle); post-treatment biopsy 
will consist of the operative specimen. Excisional, incisional or core needle samples are acceptable. 
Fine needle aspirates are prohibited. See section 5.6.9 for further details.
(2). Resectable disease of the following tumor types. Subjects must have one of the following Stages of 
disease
a.
Stage II A-IIIB: 
i.
Primary tumor ≥2 cm, or 
ii.
Primary tumor of any size with palpable regional lymph node 
metastases or resectable in-transit metastases.  
b.
Stage IV disease with resectable limited metastasis
c.
Local/Regional recurrent disease as defined as total burden ≥1 cm 
diameter with resectable disease defined by local or institutional surgical 
practices 
Revised Protocol No.: 07
Date: 07-May-2019
15
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
c)
For subjects in the metastatic (monotherapy and combination) cohorts
i)
Progressive metastatic or recurrent disease treated with no more than 2 prior systemic therapies or 
regimens in the metastatic setting. (In combo C, prior I-O therapy is not included in the number of prior 
systemic therapies)
ii)
Measurable disease by CT or MRI per RECIST 1.1 criteria (radiographic tumor assessment must be 
performed within 35 days prior to first dose).
iii) Subjects who actively refuse chemotherapy or other standard therapies for the treatment of unresectable 
or metastatic disease (advanced Stage III or Stage IV), despite being informed by the investigator about 
the treatment options may enroll. The subject’s refusal must be thoroughly documented. The investigator 
will discuss each individual subject refusing chemotherapy with the sponsor’s medical monitor or study 
director to confirm eligibility. Written approval from the sponsor’s medical monitor is required for 
eligibility.
iv) The following tumor types
(1). Histologically confirmed Gastric or Gastro-Esophageal Junction Carcinoma
(including 
adenocarcinoma arising from the lower esophagus) who are EBV positive, as defined above 
(monotherapy only). 
(2). Histologically confirmed HPV positive (monotherapy and Cohorts A and C or HPV negative or 
unknown (Combo D only) as defined above, Squamous Cell Carcinoma of the Head and Neck (oral 
cavity, pharynx, larynx) not amenable to local therapy with curative intent (surgery or radiation 
therapy with or without chemotherapy).
a.
Histologically confirmed HPV-positive or HPV-negative or unknown 
subjects naive to I-O
i.
Subjects cannot have had prior exposure to I-O therapies such 
as, but not limited to, anti-CTLA-4, anti-PD-1, combination of 
PD-1/CTLA-4 antibody, anti-PD-L1, anti-PD-L2, anti-KIR, 
anti-CD137, or anti-OX40 antibodies.
b.
Histologically confirmed HPV positive subjects progressing while on or 
after therapy with anti-PD-1 or anti-PD-L1 as most recent therapy, 
defined as Squamous Cell Carcinoma of the Head and Neck (oral cavity, 
pharynx, larynx) not amenable to local therapy with curative intent 
(surgery or radiation therapy with or without chemotherapy).(Combo C 
only)
i.
Cannot have had therapy discontinued due to serious and/or 
life-threatening anti-PD-1 or anti-PD-L1 antibody-related 
toxicity (e.g., dose-limiting toxicity in prior study) per 
Investigator’s assessment in consultation with the BMS 
Medical Monitor.
ii.
Last dose of antibody therapy must have been received ≥ 30 
days of first dose of study medication
iii.
Cannot have had prior exposure to other I-Os, such as, but not 
limited to, anti-CTLA-4, anti-PD-L2, anti-KIR, anti-CD137, or 
anti OX40 antibodies.
iv.
anti-PD-1/PD-L1/CTLA-4 does not need to be considered a one
of the previous lines of therapy. 
(3). Histologically confirmed cervical, vulvar, or vaginal cancer, as defined above. If the viral results 
are known prior to enrollment, and they are viral negative, the patient would be ineligible.
(4). Histologically confirmed Merkel Cell Carcinoma
a. Subjects with no prior systemic treatment will be allowed to enroll
Revised Protocol No.: 07
Date: 07-May-2019
16
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
(5). Histologically confirmed Nasopharyngeal Carcinoma, as defined above. If the viral results are 
known prior to enrollment, and they are viral negative, the patient would be ineligible.
a. HPV associated NPC is excluded in this cohort
b. Keratinizing squamous cell carcinoma (WHO Type I) is excluded in this cohort due to the 
low prevalence of EBV infection in this population.
(6). Histologically confirmed anal canal or penile carcinoma. If the viral results are known prior to 
enrollment, and they are viral negative, the patient would be ineligible (Metastatic Combination 
Cohorts only).
(7). Recurrent/metastatic SCC of the cervix patients not amenable to curative treatment with surgery 
and/or radiation therapy who are unsuitable for platinum-based therapy (ie, creatinine clearance of 
less than 60 mL/min or have experienced toxicity from prior platinum-based therapy) may enroll in 
the cervical cancer Combination B expansion cohort.
d)
For both neoadjuvant and metastatic (monotherapy and combination) cohorts
i)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
ii)
Men and women of age 18 or older.
iii) Subject willing to comply to provide tumor tissue for PD-L1 expression analysis and other biomarker 
correlative studies. Biopsy should be excisional, incisional or core needle. Fine needle aspirates are 
prohibited.
Exclusion Criteria:
1.
Target Disease Exceptions
a)
Active brain metastases or leptomeningeal metastases. Exception: Subjects with brain metastases are eligible 
if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at 
least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. 
There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration.
2.
Medical History and Concurrent Diseases
a)
Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk 
associated with study participation or study drug administration, impair the ability of the subject to receive 
protocol therapy, or interfere with the interpretation of study results.
b)
Prior malignancy active within the previous 3 years except for locally curable cancers that have been 
apparently cured or successfully resected, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or gastric cancer, or carcinoma in situ of the prostate, cervix, or breast.
c)
Subjects with active, known or suspected autoimmune disease. Subjects with skin disorders (such as vitiligo, 
psoriasis, or alopecia), type I diabetes mellitus, residual hypothyroidism only requiring hormone replacement, 
or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
d)
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled 
or topical steroids, and adrenal replacement doses are permitted in the absence of active autoimmune disease.
e)
Subjects with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine.
f)
Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or checkpoint pathways, such 
as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including ipilimumab; or other 
medicines specifically targeting T cell co-stimulation or checkpoint pathways is also prohibited. Exception: 
Combo C SCCHN prior exposure to anti PD-1/PD-L1/CTLA-4 therapy
g)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to 
Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. Subjects with toxicities 
attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, 
such as neuropathy after platinum based therapy, are permitted to enroll.
Revised Protocol No.: 07
Date: 07-May-2019
17
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
h)
Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 
28 days of first administration of study treatment (subjects with prior cytotoxic or investigational products 
< 4 weeks prior to treatment might be eligible after discussion between investigator and sponsor, if toxicities 
from the prior treatment have been resolved to Grade 1 (NCI CTCAE version 4).
i)
Active neurological disease or confirmed history of encephalitis, meningitis, or uncontrolled seizures in the 
year prior to informed consent for Combo C only
j)
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following (Combo 
C only):
i)
Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent
ii)
Uncontrolled angina within the 3 months prior to consent
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, 
or torsades de pointes)
iv) QTc prolongation > 480 msec
v)
History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart 
failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, 
significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc.)
vi) Cardiovascular disease-related requirement for daily supplemental oxygen
vii) History of two or more MIs OR two or more coronary revascularization procedures
viii)Subjects with history of myocarditis, regardless of etiology
k)
For Combo D only
i)
Known history of stage 3-or 4 chronic obstructive pulmonary disease (COPD). 
ii)
Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any 
classification. Note that subjects who currently have controlled intermittent asthma or controlled mild 
persistent asthma are allowed to participate in the study.
iii) Screening 12-lead ECG showing a baseline QT interval as corrected (QTc) >480 msec
l)
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.
m) For the expansion cohort for subjects with SCC of the cervix and for patients eligible to receive study drug 
(Combo B) as first-line treatment for their recurrent/metastatic disease, must not have been treated previously 
with chemotherapy except when used concurrently with radiation therapy.
3.
Physical and Laboratory Test Findings
a)
Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or 
detectable presence of virus, e.g. 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). NOTE: Testing for HIV must be performed at sites where mandated 
locally.
4.
Allergies and Adverse Drug Reaction
a)
History of allergy to study drug components.
b)
History of severe hypersensitivity reaction to any monoclonal antibody.
5.
Sex and Reproductive Status
a)
WOCBP who are pregnant or breastfeeding
b)
Women with a positive pregnancy test at enrollment or prior to administration of study medication
Revised Protocol No.: 07
Date: 07-May-2019
18
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug Dosing
Cohort
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Neoadjuvant
Nivolumab
240 mg flat 
dose
Day 1,
Day 15a
30 minute 
Intravenous 
(IV) infusion
Two doses
Metastatic
Monotherapy
Nivolumab
240 mg flat 
dose
every 2 weeks
30 minute 
Intravenous 
(IV) infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
Neoadjuvant 
Subjects Treated 
with Study Drug 
Post-Standard of 
Care
Nivolumab
240 mg flat 
dose
every 2 weeks
30 minute 
Intravenous 
(IV) infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
Metastatic 
Combination 
Cohort 
Combo A
Nivolumab
3 mg/kg
every 2weeks 
30 minute 
Intravenous 
(IV) infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
Ipilimumab
1 mg/kg 
every 6week
30 minute 
Intravenous 
(IV) infusion
Metastatic 
Combination 
Cohort Combo B
(Cervical cancer 
and anogenital 
HPV associated 
tumors only)
Nivolumab
1 mg/kg
every 3 weeks 
for 4 doses
30 minute 
Intravenous 
(IV) infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
240 mg flat 
dose
then every 2 
weeks
Ipilimumab
3 mg/kg 
every 3weeks 
for 4 doses
30 minute 
Intravenous 
(IV) infusion
Revised Protocol No.: 07
Date: 07-May-2019
19
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Study Drug Dosing
Cohort
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Metastatic 
Combination 
Cohort
Combo C
Nivolumab
240 mg
every 
2 weeks
30 minute 
Intravenous 
(IV) infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first 
discontinuation 
from study
BMS-986016
(relatlimab)
80 mg
every 2 weeks
60 minute 
Intravenous 
(IV) infusion
Metastatic 
Combination 
Cohort
Combo D
Nivolumab
240 mg flat 
dose
Every 2 weeks 
starting at Week 
3
30 minute 
Intravenous 
(IV) infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
480 mg flat 
dose
then every 4 
weeks starting 
at Week 25
Nivolumab will be administered 
before daratumumab when both 
study drugs are administered on 
the same day.
Daratumumab
16 mg/kg
Every week 
(Wks 1-8) then 
every 2 weeks 
(Wks 9-24), 
then every 4 
weeks starting 
at Week 25
Intravenous 
(IV) infusion
See Section 4.3
a A delay of the 2nd dose of nivolumab is acceptable for up to 1 week (up to Day 22); however, the 2nd dose of 
nivolumab should not be administered after Day 22 in order to avoid postponing surgery/biopsy beyond Day 29 
and subsequent standard of care.
Study Assessments: 
Safety: 
Safety assessments at baseline will include a medical history to be obtained to capture relevant underlying conditions. 
Baseline examinations should include signs and symptoms, weight, height, ECOG Performance Status, BP, HR, 
temperature, and respiratory rate should be performed within 14 days prior to first dose. Concomitant medications 
will also be collected from within 14 days prior to first dose and through the study treatment. Baseline safety laboratory 
assessments should be done within 14 days prior to the first dose. 
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments will be performed
continuously during the treatment phase. On-study assessments including weight, height, ECOG Performance Status, 
BP, HR, temperature, respiratory rate, and oxygen saturation by pulse oximetry at rest and after exertion will be 
performed. On-study safety laboratory assessments will also be performed. 
Revised Protocol No.: 07
Date: 07-May-2019
20
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Efficacy: 
Tumor imaging assessments for ongoing study treatment decisions will be completed by the investigator using 
RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria.
Statistical Considerations:
Sample Size: Sample size determination is not based on statistical power calculation.
1)
Neoadjuvant cohort: 
The SCCHN tumor types will contain 21 HPV-positive and 21 HPV-negative evaluable subjects. MCC and cervical, 
vaginal, or vulvar cancers tumor types will contain 21 evaluable subjects each. A sample size of 21 subjects can detect, 
with more than 66% and 89% probability, a safety event that occurs at an incident rate of 5% and 10%, respectively. 
Assuming 10%, 15%, and 20% for pathologic complete response rate, a sample size of 21 can detect, more than 89%, 
97% and 99% probability, at least one pathologic complete response respectively.
2)
Recurrent/metastatic monotherapy cohort:
HPV+ SCCHN, GYN, MCC and NPC tumor types in the recurrent/metastatic cohort will contain 23 subjects. Table 1 
shows the probabilities of observing 0, 1 or 2 responders and ≥3 responders assuming 5%, 20% and 30% true response 
rate of ORR. Table 2 shows two-sided 95% exact CI using Clopper-Pearson methods based on observed 3, 4, and 
5 responders out of 23 subjects.
EBV+ Gastric tumor type will contain 12 subjects, due to the low prevalence. Table 3 shows the precision of the 
estimation of ORR based on the two sided 95% exact CI using Clopper-Pearson methods based on 1, 2, 3, 4, and 
5 responders out of 12 subjects. 
Table 1
Probability of Observing Responses Given True ORR for Sample Size 
of 23 Subjects
True response rate of 
ORR
Probability of observing 0, 1 or 2 
responses
Probability of observing 
≥3 responses
5%
89.5%
10.5%
20%
13.3%
86.7%
30%
1.6%
98.4%
Table 2
Two-sided 95% exact CI Using Clopper-Pearson Method 
Based on Number of Observed Responses out of 23 Subjects
The number of observed 
responses
3
4
5
Observed Response Rate
3/23 (13.0%)
4/23 (17.4%)
5/23 (21.7%)
95% exact CI
(2.8%, 33.6%)
(5.0%, 38.8%)
(7.5%, 43.7%)
Revised Protocol No.: 07
Date: 07-May-2019
21
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 3
Two-sided 95% Exact CI Using Clopper-Pearson Method 
Based on the Number of Observed Responses out of 12 
Subjects
The number of 
observed responses
1
2
3
4
5
Observed Response 
Rate
1/12 
(8.3%)
2/12 
(16.7%)
3/12 
(25.0%)
4/12 
(33.3%)
5/12 
(41.7%)
95% exact CI
(0.2%, 
38.5%)
(2.1%, 
48.4%)
(5.5%, 
57.2%)
(9.9%, 
65.1%)
(15.2%, 
72.3%)
3)
Recurrent/metastatic combination cohort:
The HPV+ SCCHN, MCC, and NPC tumor types in the recurrent/metastatic cohort will each contain approximately 
40 subjects that will be enrolled to the Combo A treatment arm. Patients with cervical cancer and anogenital HPV 
associated tumors (vulvar/vaginal/anal canal/penile) tumor types will be randomized in a 1:1 ratio to one of two dosing 
schema (Combo A or Combo B). Each dosing schema will contain approximately 40 subjects.
Subjects with HPV+ SCCHN with prior anti PD-1/PD-L1/CTLA-4 treatment will be enrolled in Metastatic 
Combination Cohort (Combo C). Combo C will contain approximately 40 subjects.
Additionally, the metastatic cervical Combination B cohort will be expanded to treat approximately 50 subjects as 
first-line treatment for their recurrent/metastatic disease if unfit or unsuitable to receive platinum-based therapy and 
approximately 20 subjects as second-line treatment for their recurrent/metastatic SCC of the cervix to confirm the 
efficacy signal. With Combo B and the Combo B expansion, there should be a total of approximately 75 subjects with 
first-line treatment and approximately 35 subjects with second-line treatment of cervical cancer (approximately 110
cervical subjects total).
Approximately 40 I-O naive HPV-negative, -indeterminate, and -positive SCCHN subjects will be enrolled to the 
Combo D treatment arm. In this study, an ORR in excess of 10% will be considered of clinical interest. Assuming the 
true ORR is 25%, 40 subjects in each tumor type can provide approximately 79.8% power to reject the null hypothesis 
that the true ORR is 10%, considering a 2-sided alpha of 5%. In addition Table 5 shows the precision of the estimation 
of ORR based on the two sided 95% exact CI using Clopper Pearson methods based on 8, 9, 12, 16 and 20 responders 
out of 40 subjects. At observed more than or equal to 9 responders, i.e., ORR ≥22.5%, the lower bound of the 95% 
CI excludes 10%.
Due to the low prevalence of EBV+ Gastric tumor types and the current investigation of this tumor type in other 
BMS-sponsored studies, combination cohorts in this study will no longer include EBV+ Gastric tumor type. Sample 
sizes of each treatment arm in each tumor type are summarized in Table 4. 
Table 4
Sample Size in Recurrent/Metastatic Combination Cohort
Combo A
Nivo-3mg/kg q2w 
+ Ipi-1mg/kg q6w
Combo B
Nivo-1mg/kg + Ipi-
3mg/kg q3w x 4 
followed by Nivo 240mg 
q2w
Combo C
Nivo+
Anti-Lag-3
Combo D
Nivo+Dara
Cervical
40
110a
Anogenital HPV 
associated tumors
(vaginal/vulvar/
anal canal/penile)
40
40
Revised Protocol No.: 07
Date: 07-May-2019
22
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 4
Sample Size in Recurrent/Metastatic Combination Cohort
Combo A
Nivo-3mg/kg q2w 
+ Ipi-1mg/kg q6w
Combo B
Nivo-1mg/kg + Ipi-
3mg/kg q3w x 4 
followed by Nivo 240mg 
q2w
Combo C
Nivo+
Anti-Lag-3
Combo D
Nivo+Dara
MCC
40
NPC
40
HPV+ SCCHN
(I/O naive)
40 
HPV+ SCCHN (Prior 
PD-1/PD-L1)
40
I-O Naive SCCHN 
(HPV positive/negative/
unknown)
40
a Includes 40 from Combination B and 75 from Combination B expansion.
Table 5
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on the Number 
of Observed Responses out of 40 Subjects
The number of 
observed 
responses
8
9
12
16
20
Observed 
Response Rate
8/40 (20.0%)
9/40 (22.5%)
12/40 (30.0%)
16/40 (40.0%)
20/40 (50.0%)
95% exact CI
(9.1, 35.6)
(10.8. 38.5)
(16.6, 46.5)
(24.9, 56.7)
(33.8, 66.2)
Endpoints:
Primary Endpoints:
Neoadjuvant cohort: 
•
The safety and tolerability objective will be measured by the incidence of drug-related select AEs and drug-related 
SAEs.
•
Rate of surgery delay, which is defined as the proportion of subjects in the neoadjuvant cohort with surgery 
delayed > 4 weeks from the planned surgery date or planned start date for chemoradiation due to a drug-related 
AE will be reported for each tumor type.
Metastatic cohort (monotherapy and combination therapies): The objective response rate (ORR). ORR is defined 
as the number of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response 
(PR) divided by the number of treated subjects. BOR is defined as the best response designation recorded between the 
date of first dose and the date of the initial objectively documented tumor progression per investigator assessment 
using RECIST 1.1 criteria or the date of the last tumor assessment date prior to subsequent therapy. In this study, an 
ORR in excess of 10% will be considered of clinical interest, and an ORR of 25% or greater will be considered of 
strong clinical interest.
Revised Protocol No.: 07
Date: 07-May-2019
23
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Secondary Endpoints:
Metastatic cohort (monotherapy and combination therapies): 
•
Duration of response (DOR) is defined as the time from first confirmed response (CR or PR) to the date of the 
initial objectively documented tumor progression as determined per investigator assessment using RECIST 1.1 
criteria or death due to any cause, whichever occurs first. Subjects who did not start subsequent anti-cancer 
therapy and die without a reported prior progression will be considered to have progressed on the date of their 
death. Subjects who did not progress or die will be censored on the date of their last tumor assessment. Subjects 
who did not have any on study tumor assessments and did not die will be censored on the date they were treated. 
Subjects who started any subsequent anti-cancer therapy prior to death and without a prior reported progression 
will be censored at the last tumor assessment prior to or on the date of initiation of the subsequent anti-cancer 
therapy. DOR will only be evaluated in subjects with objective response of CR or PR
•
Overall survival (OS) is defined as the time from first dosing date to the date of death. A subject who has not died 
will be censored at last known date alive. 
•
Investigator-assessed progression free survival (PFS) is defined as the time from first dosing date to the date of 
the first documented tumor progression, as determined by investigators (per RECIST 1.1), or death due to any 
cause. Subjects who die without a reported prior progression will be considered to have progressed on the date of 
their death. Subjects who did not progress or die will be censored on the date of their last tumor assessment. 
Subjects who did not have any on study tumor assessments and did not die will be censored on the date they were 
treated. Subjects who started any subsequent anti-cancer therapy prior to death and without a prior reported 
progression will be censored at the last tumor assessment prior to or on the date of initiation of the subsequent 
anti-cancer therapy.
Exploratory Endpoints:
Neoadjuvant cohort: 
•
The percent change from baseline of immune cells and the percent change from baseline of select immune 
activation/inhibitory molecules of viral-specific T cells in tumor specific subsets of nivolumab treated subjects 
will be evaluated.  
•
Recurrence-free survival (RFS), which is defined in Section 8.3.3.
•
The percent change in tumor volume from baseline after two doses of neoadjuvant nivolumab is defined as the 
ratio of the change in tumor volume and the baseline tumor volume.
•
The proportion of treated subjects who experiences pathologic complete response will be used to determine 
pathologic response rate of tumors after two doses of neoadjuvant nivolumab in HPV positive and negative 
SCCHN, resectable Merkel Cell Carcinoma, and cervical, vaginal, or vulvar cancer. Pathological complete 
response (pCR) is defined as the absence of residual viable invasive cancer on hematoxylin and eosin evaluation 
of the complete resected tumor specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy.
Metastatic cohort (monotherapy and combination therapies): 
•
The safety and tolerability objective will be measured by the incidence of adverse events, serious adverse events, 
deaths and laboratory abnormalities.
•
Pre and post treatment EBV DNA levels will be collected in the subjects with EBV positive gastric cancer and 
nasopharyngeal carcinoma. The change in EBV DNA levels will be used to determine the effect of BMS-936558 
(nivolumab).
Revised Protocol No.: 07
Date: 07-May-2019
24
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Neoadjuvant and Metastatic cohort (monotherapy and combination therapies): 
•
The PK samples collected will be used to determine summary measures of nivolumab, ipilimumab, BMS-986016 
(relatlimab) and daratumumab exposure (see Section 8.4.4 in protocol).
•
Exploratory endpoints for pharmacodynamics, outcomes research and immunogenicity are discussed in detail in 
Sections 5.6, 5.7, and 5.8.
Other exploratory endpoints will be discussed in details in the statistical analysis plan.
Analyses:
Analyses for primary endpoints: 
Neoadjuvant cohort: 
•
Analyses of drug-related select AEs and drug-related SAEs are discussed in Section of safety analyses.
•
Rate of surgery delay will be summarized by binomial response rates and their corresponding two-sided 95% 
exact CIs using Clopper-Pearson method. 
Metastatic cohort (monotherapy and combination therapies): 
•
The investigator assessed ORR in the metastatic cohort will be summarized by binomial response rates and their 
corresponding two-sided 95% exact CIs using Clopper-Pearson method. 
Analyses for secondary endpoints: 
Metastatic cohort (monotherapy and combination therapies):
•
Time to event distribution will be estimated using Kaplan Meier techniques. This will be done for PFS (based on 
investigator assessments) and OS. Median PFS or OS along with 95% CI will be constructed based on a log-log 
transformed CI for the survivor function. Rates at some fixed time points will be derived from the Kaplan Meier 
estimate and corresponding confidence interval will be derived based on Greenwood formula for variance 
derivation and on log-log transformation applied on the survivor function. 
•
The DOR will be summarized for all treated subjects who achieve confirmed PR or CR using the Kaplan-Meier 
(KM) product-limit method. Median values of DOR, along with two-sided 95% CI using Brookmeyer and 
Crowley method, will also be calculated.
Analyses for exploratory endpoints: 
Methods for exploratory endpoints will be discussed in details in the statistical analysis plan.
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be presented using 
NCI CTCAE version 4. All on-study AEs, drug-related, AEs, SAEs and drug-related SAEs will be tabulated using 
worst grade per NCI CTCAE version 4 criteria by system organ class and MedDRA preferred term. On-study lab 
parameters including hematology, chemistry, liver function, thyroid function, and renal function will be summarized 
using worst grade per NCI CTCAE version 4 criteria.
The proportion of subjects in the neoadjuvant cohort with surgery delayed > 4 weeks due to a drug-related AE will be 
reported for each tumor type and the Clopper-Pearson method will be used to estimate the two-sided 95% confidence 
interval.
Pharmacokinetic Analyses
The nivolumab, ipilimumab, BMS-986016 (relatlimab), and daratumumab concentration data obtained in this study 
may be combined with data from other studies in any of the clinical development programs (nivolumab, ipilimumab, 
BMS-986016, and daratumumab) to develop or refine a population PK model. The models may be used to evaluate 
the effects of intrinsic and extrinsic covariates on the PK of nivolumab or other compounds and to determine measures 
of individual exposure (such as steady-state peak, trough, and time-averaged concentration). In addition, model 
Revised Protocol No.: 07
Date: 07-May-2019
25
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
determined exposures may be used for exposure-response analyses. If performed, results of population PK and 
exposure response-analyses will be reported separately.
Biomarker Analyses
The pharmacodynamic effects of nivolumab as monotherapy or in combination with ipilimumab, BMS-986016
(relatlimab) or daratumumab on selected biomarkers will be assessed by summary statistics and corresponding 
changes (or percent changes) from baseline tabulated by time and cohort. In addition, the time course of biomarker 
outcomes will be investigated graphically, by summary plots or individual subject plots. If there is an indication of a 
meaningful pharmacodynamic trend, methods such as linear mixed models may be used to characterize the pattern of 
change over time. The potential association between PD-L1 expression level (IHC) and clinical efficacy measures will 
be assessed using Fisher’s exact test or other methodology as appropriate.
Potential associations of various biomarker measures with pharmacokinetic exposure, safety and clinical efficacy 
measures will be investigated based on data availability. Methods such as, but not limited to, logistic regression and 
graphical summaries may be used to assess these associations.
The methodology for additional exploratory biomarker analyses will be described in the statistical analysis plan.
Outcomes Research Analyses
EQ-5D
Outcomes Research Subject’s overall health on the EQ-5D VAS at each assessment time point will be summarized 
using descriptive statistics (N, mean, standard deviation, median, first and third quartiles, minimum, maximum). 
Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment time point will be 
summarized by level of problem. Percentages will be based on the number subjects with EQ-5D data at each 
assessment time point.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression), health state (5 dimensions digits combined in a 5-digit number) 
and EQ-5D VAS will be provided.
EORTC QLQ-C30
The analysis of EORTC QLQ-C30 data will be performed in all Outcomes Research Subjects.
For each cohort, baseline scores and post-baseline score changes for all EORTC QLQ-C30 scales will be summarized 
using descriptive statistics (N, mean, standard deviation, median, first and third quartiles, minimum, maximum). 
Baseline and change from baseline in EORTC QLQ-C30 global health status/QoL composite scale data and the 
remaining EORTC QLQ-C30 scale data will be summarized by time point using descriptive statistics for each cohort 
(N, mean, standard deviation, median, first and third quartiles, minimum, maximum). In addition, the percentage of 
subjects demonstrating a clinically meaningful deterioration (defined as a 10 point change from baseline) will be 
presented for each scale at each assessment time point. Percentages will be based on the number of subjects with 
EORTC QLQ-C30 data at each assessment time point.
Immunogenicity Analyses
Immunogenicity may be reported for anti-drug antibody (ADA) positive status (such as persistent positive, 
neutralizing positive, only last sample positive, baseline positive and other positive) and ADA negative status, relative 
to baseline. Effect of immunogenicity on safety, efficacy, biomarkers and PK may be explored. Additional details will 
be described in the statistical analysis plan.
Revised Protocol No.: 07
Date: 07-May-2019
26
Approved
8.0
v
Approved
1.0
v


TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 07: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 07 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Disease Background ................................................................................ 
1.1.1.1 EBV Positive Tumors ...................................................................... 
1.1.1.2 HPV Positive Tumors ...................................................................... 
1.1.1.3 Polyomavirus Positive Merkel Cell Cancer (pMCC) ..................... 
1.1.2 Infection and Tumorigenesis .................................................................... 
1.1.2.1 HPV ................................................................................................. 
1.1.2.2 EBV ................................................................................................. 
1.1.2.3 Polyomavirus .................................................................................. 
1.1.3 Rationale for Nivolumab in the Neoadjuvant Setting .............................. 
1.1.4 Rationale for Immunotherapy in Virus-Associated Tumors .................... 
1.1.5 Rationale and Aims for Biomarker Assessments ..................................... 
1.1.6 Rationale for Dose Selection for Nivolumab ........................................... 
1.1.7 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab .... 
1.1.8 Rationale for Nivolumab plus Ipilimumab Combination Therapy .......... 
1.1.9 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab .................................................................................................. 
1.1.10 Rationale for Nivolumab plus Anti-LAG-3 Antibody (relatlimab, BMS-
986016) Combination Therapy ................................................................... 
1.1.11 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Relatlimab ................................................................................................... 
1.1.12 Rationale for Nivolumab plus Daratumumab Combination Therapy .... 
1.1.13 Rationale for Nivolumab Combined with Daratumumab in Patients with 
HPV Positive and Negative or Unknown SCCHN ...................................... 
1.1.14 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Daratumumab ............................................................................................. 
1.1.15 Duration of Treatment with Nivolumab Monotherapy or Combination 
Therapy ....................................................................................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objective(s) .......................................................................... 
1.4 Product Development Background ................................................................... 
1.4.1 Nivolumab ................................................................................................ 
1.4.1.1 Summary of Nivolumab Clinical Activity in the Metastatic Setting 
1.4.1.2 Summary of Nivolumab Safety in the Metastatic Setting ................ 
1
3
6
6
8
27
31
31
32
32
34
37
38
38
39
39
39
40
41
41
42
43
45
46
49
49
51
51
54
56
56
56
57
57
58
58
58
59
Clinical Protocol
BMS-936558
CA209358
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
27
Approved
8.0
v
Approved
1.0
v


1.4.2 Nivolumab Combined with Ipilimumab ................................................... 
1.4.2.1 Nivolumab and Ipilimumab Mechanism of Action ......................... 
1.4.2.2 Summary of Nivolumab plus Ipilimumab Safety Data .................... 
1.4.3 Nivolumab Combined with BMS-986016................................................. 
1.4.3.1 Nonclinical Pharmacology Studies Utilizing Murine Anti-PD-1 and 
Anti-LAG-3 Antibodies .......................................................................... 
1.4.3.2 Nonclinical Toxicology ................................................................... 
1.4.3.3 Nonclinical Pharmacokinetics ........................................................ 
1.4.3.4 Clinical Pharmacology ................................................................... 
1.4.3.5 Clinical Safety Combination Therapy (Nivolumab plus Relatlimab)
...............................................................................................................
1.4.4 Daratumumab .......................................................................................... 
1.4.4.1 Summary of Daratumumab Clinical Pharmacology ....................... 
1.4.4.2 Summary of Daratumumab Clinical Activity .................................. 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Viral Status Determination Prior to Entry............................................... 
3.1.2 Neoadjuvant Cohort ................................................................................. 
3.1.3 Subjects in the Metastatic Monotherapy Cohort ..................................... 
3.1.4 Subjects in the Metastatic Combination Cohorts ..................................... 
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................................................. 
3.4.1.1 Restricted Treatments ..................................................................... 
3.4.2 Permitted Therapy ................................................................................... 
3.4.3 Surgical Resection Following Initial Response ....................................... 
3.4.4 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow-up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-up ..................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
59
59
61
62
62
63
65
65
65
66
66
66
68
72
72
73
73
74
74
80
82
83
83
84
84
84
89
92
92
92
93
93
94
94
95
96
96
97
97
99
99
99
102
104
Clinical Protocol
BMS-936558
CA209358
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
28
Approved
8.0
v
Approved
1.0
v


4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.7.1 Premedications ........................................................................................ 
4.7.2 Management Algorithms for Immuno-oncology Agents .......................... 
4.7.3 Dose Delay Criteria ................................................................................. 
4.7.4 Dose Reductions....................................................................................... 
4.7.5 Criteria to Resume Dosing....................................................................... 
4.7.6 Discontinuation Criteria .......................................................................... 
4.7.7 Treatment of Study Drug-related Infusion Reactions .............................. 
4.7.8 Treatment Beyond Disease Progression .................................................. 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Imaging Assessments for the Study .......................................................... 
5.4.2 Primary Efficacy Assessment ................................................................... 
5.4.3 Secondary Efficacy Assessments .............................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetic Sample Analysis ........................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.6.1 Determination of Tumor’s Viral Positivity .............................................. 
5.6.2 Viral-related Assessments ........................................................................ 
5.6.3 HLA Genotyping ...................................................................................... 
5.6.4 Immunophenotyping ................................................................................. 
5.6.5 Ex Vivo Functional Assays ....................................................................... 
5.6.6 Peripheral Blood Gene Expression ......................................................... 
5.6.7 T Cell Repertoire Analysis ....................................................................... 
5.6.8 Single Nucleotide Polymorphism (SNP) Analysis .................................... 
5.6.9 Tumor Samples......................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Immunogenicity Assessments ........................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
106
106
106
107
107
109
109
110
112
115
117
117
118
118
146
146
146
147
147
149
149
149
155
155
156
157
157
157
157
157
157
158
158
166
166
167
167
168
169
169
170
170
171
171
171
Clinical Protocol
BMS-936558
CA209358
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
29
Approved
8.0
v
Approved
1.0
v


7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Endpoint Methods ............................................................. 
8.4.2.2 Secondary Endpoints Methods ........................................................ 
8.4.2.3 Exploratory Endpoints Methods ..................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.6.1 EQ-5D ............................................................................................. 
8.4.6.2 EORTC QLQ-C30 ........................................................................... 
8.4.7 Other Analyses ......................................................................................... 
8.4.7.1 Immunogenicity Analyses ................................................................ 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 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 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
171
171
171
175
176
176
176
177
178
178
178
178
178
179
179
179
179
180
180
180
180
180
180
181
181
181
181
182
182
182
182
182
183
183
185
186
193
207
208
216
224
227
Clinical Protocol
BMS-936558
CA209358
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
30
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
Programmed Cell Death-1 (PD-1; CD279) is a cell surface signaling molecule that delivers 
inhibitory signals that regulate the balance between T cell activation and tolerance by interacting 
with its ligands, PD-L1 (CD274; B7-H1) and PD-L2 (B7-DC/CD273). PD-1 is a 55 kD type I 
transmembrane protein that is a member of the CD28 family of T-cell regulatory receptors, which 
also includes CTLA-4, ICOS, and BTLA.1 PD-1 is primarily expressed on activated T cells, B 
cells, and myeloid cells.2 Its ligands, PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), have 
been shown to down-regulate T-cell activation upon binding to PD-1 in both murine and human 
systems.3,4 PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine inhibitory 
motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif (ITSM), that 
when phosphorylated, delivers a negative signal to the lymphocyte by the recruitment of SHP-2 to 
the phosphorylated tyrosine residue in the ITSM in its cytoplasmic region.5,6
Evidence for a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. PD-1-
deficient mice develop various autoimmune phenotypes, including dilated cardiomyopathy and a 
lupus-like syndrome with arthritis and nephritis.7,8,9 The emergence of these autoimmune 
phenotypes is dependent upon the genetic background of the mouse strain; many of these 
phenotypes emerge at different times and show variable penetrance. In addition to the phenotypes 
of null mutations, PD-1 inhibition by antibody-mediated blockade in several murine models has 
been found to play a role in the development of autoimmune diseases such as encephalomyelitis, 
graft-versus-host disease, and type I diabetes.10,11,12 Taken together, these results suggest that 
PD-1 blockade has the potential to activate anti-self T-cell responses, but these responses are 
variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is 
not accompanied by a universal loss of tolerance to self-antigens. 
Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. This suggests 
that host mechanisms limit the antitumor response.13,14,15,16,17,18
In humans, PD-L1 is constitutively expressed on macrophage-lineage cells, activated T cells, lung, 
vascular endothelial cells, and placental syncytiotrophoblasts.19 Aberrant expression of PD-L1 by 
tumor cells has been reported in a number of human malignancies.20,21,22,23,24,25,26 PD-L1 
expressed by tumor cells has been shown to enhance apoptosis of activated tumor-specific T cells 
in vitro.27 Moreover, the expression of PD-L1 may protect the tumor cells from the induction of 
apoptosis by effector T cells.28 Retrospective analyses of several human tumor types suggest that 
tumor over-expression (as measured by immunohistochemistry) of PD-L1 may permit immune 
evasion by tumors. In renal cell carcinoma, high surface expression levels of PD-L1 on tumor cells 
are related to tumor aggressiveness. Patients with high tumor and/or lymphocyte PD-L1 levels are 
4.5 times more likely to die from their cancer than patients exhibiting low levels of PD-L1 
expression.29
Revised Protocol No.: 07
Date: 07-May-2019
31
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds to PD-1. Blockade of the PD-1 
pathway by nivolumab was studied using the mixed lymphocyte reaction (MLR). PD-1 blockade 
resulted in a reproducible enhancement of both proliferation and IFN-γ release in the MLR.30 The 
effect of nivolumab on antigen-specific recall response was investigated using a CMV-
restimulation assay with human peripheral blood mononuclear cells (PBMCs) and was evaluated 
by ELISA. These data indicated that nivolumab, versus an isotype-matched control antibody, 
augmented IFN-g secretion from CMV-specific memory T cells in a dose-dependent manner. 
1.1.1
Disease Background
Study CA209358 is an open label, multicenter, Phase 1/2 trial to investigate the safety and efficacy 
of nivolumab as a single agent or in combination with either ipilimumab, relatlimab (anti-LAG3 
antibody), or daratumumab in viral positive and viral negative tumor types - Epstein Barr Virus 
(EBV) positive gastric cancer, EBV positive nasopharyngeal cancer (NPC), cervical cancer, HPV 
positive and negative squamous cell cancer (SCC) of the head and neck (SCCHN), anogenital 
HPV associated cancers (vaginal, vulvar, anal canal, penile), and Polyomavirus positive Merkel 
cell cancer (pMCC). 
1.1.1.1
EBV Positive Tumors
Gastric Cancer
As of 2012, gastric cancer is the fifth most common malignancy in the world with 952,000 cases 
globally and is the third leading cause of cancer death with 723,000 deaths.31 Gastric cancer often 
presents with advanced disease upon diagnosis (except in countries like Japan and Korea where 
early detection is common). In about 20-30% of cases, patients will present with resectable disease 
but in many of these, intraoperative discovery of lymph node metastasis is common and where 
curative surgery is possible, the recurrence rate after resection is high. For resectable disease, 
treatment options include neo and adjuvant chemotherapy with fluoropyrimidine, a platinum agent, 
and an anthracycline or a fluoropyrimidine in combination with radiation for adjuvant 
chemoradiotherapy. Despite these treatment options, the 5-year survival for Stage II-III gastric 
cancer remains 9-46%.32 For patients developing advanced and metastatic disease, the reported 1-
year survival is approximately 30% with a median survival of patients receiving treatment of 8 to 
14 months and those receiving best supportive care alone only 3 months.33
Recent analyses from The Cancer Genome Atlas (TCGA) project have proposed dividing gastric 
cancer into four subtypes, tumors positive for Epstein–Barr virus, which display recurrent PIK3CA 
mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as 
PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumors, which show 
elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling 
proteins; genomically stable tumors, which are enriched for the diffuse histological variant and 
mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumors 
with chromosomal instability, which show marked aneuploidy and focal amplification of receptor 
tyrosine kinases.34 TCGA classified 26 (8.8%) of the 295 gastric cancers samples evaluated as 
EBV positive, matching a larger meta-analysis which estimated the prevalence of EBV positive 
Revised Protocol No.: 07
Date: 07-May-2019
32
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
gastric cancers, as assessed by in situ hybridization for EBV-encoded small RNA, at 8.7% (95% 
CI: 7.5, 10.0) out of 70 trials and 15,952 cases.35 The EBV positive subtype demonstrated enriched 
amplifications at 9p24.1, a locus that contains JAK2, PD-L1, and PD-L2, which both bind PD-1, 
the target of nivolumab. Classification by molecular subtype would allow for selection of gastric 
subtypes that may be more likely to respond to targeted therapies compared to the WHO gastric 
cancer subsets of papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas.36 Clinical 
observations of EBV positive gastric cancer include distinct clinicopathologic characteristics, 
including male predominance, preferential location in the gastric cardia or postsurgical gastric 
stump, lymphocytic infiltration, a lower frequency of lymph node metastases, and a diffuse type 
of histology, as well as a more favorable prognosis.37,38
EBV Positive NPC
As of 2012, there were 86,691 cases of NPC with 50828 deaths.31 Several etiologic factors have 
been proposed including diet, genetic factors, chromosome loss, and HPV, but EBV appears to be 
the primary etiologic agent.39,40,41 The current WHO classification for NPC reflects the 
importance of EBV as it classifies NPC into the following histopathologic types:42
1) Keratinizing squamous cell carcinoma (WHO Type I):  The sporadic form of nasopharyngeal 
carcinoma most commonly is the keratinizing subtype (WHO Type I);
2) Nonkeratinizing carcinoma which is subdivided into the differentiated (Type II) and 
undifferentiated (Type III) forms. The endemic form of nasopharyngeal carcinoma, found in 
Southeast Asia, is commonly the undifferentiated, nonkeratinizing subtype (Type III). This is 
strongly associated with EBV and has a more favorable prognosis than other types. 
3) Basaloid squamous cell carcinoma: Basaloid squamous cell carcinoma was added to the WHO 
classification of head and neck tumors in 2005. 
Along with T and N stage, quantification of EBV DNA levels is a prognostic factor, with higher 
levels having a worse prognosis. Stage I-II with low DNA (< 4000 copies/mL) have a 5 year 
survival rate of 91 % whereas patients with the same stage but high DNA (> 4000 copies/mL) have 
a 5 year survival rate of 64%; for patients with Stage III-IV the rates are 66% and 54% 
respectively.43 The presence of detectable post-treatment EBV DNA, which may reflect 
microscopic residual tumor, appears to provide an even greater estimate of the risk of disease 
recurrence and death than pretreatment EBV DNA.44,45
Current treatment options include radiation for Stage I disease, combined chemotherapy, usually 
cisplatin, and radiation therapy for Stages II-IVB. The 5-year overall survival (OS) for 
nasopharyngeal carcinoma according to disease stage in a contemporary case series was 90%, 
84%, 75%, and 58% for stage I through IV, respectively.46 For recurrent disease, surgical resection 
can be an option. For non-surgical disease, chemotherapy doublets have produced response rates 
(between 60% and 74%) with no statistically significant differences in progression-free survival 
(PFS) (median 5.0 to 6.6 months) or overall survival (median 19 to 21 months and 3-year survival 
Revised Protocol No.: 07
Date: 07-May-2019
33
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
rates 19 to 21.5 months).47 For patients with recurrent or metastatic disease after one line of 
chemotherapy, there is no standard of care with several Phase 2 trials with single agents such as 
capecitabine48, irinotecan49, docetaxel50, gemcitabine51, and pemetrexed.52
1.1.1.2
HPV Positive Tumors
HPV Positive SCCHN
Head and neck carcinomas (HNC) are the fifth most common cancer in the world, with increasing 
incidence.53,54 In 2014 in the United States, the American Cancer Society estimates 55,000 new 
cases are diagnosed and approximately 12,000 deaths due to this cause occur yearly.55 HNCs 
describe malignancies of the upper aerodigestive tract which include squamous cell carcinomas 
(SCCHN) of the oral cavity, nasopharynx, pharynx and larynx. While tobacco and alcohol use are 
the most common risk factors for HNCs, Epstein-Barr virus and human papilloma virus (HPV) 
may also play a role in the development of carcinomas of the nasopharynx and squamous cell 
carcinomas of the oropharynx, respectively.53,54,56,57,58,59
A TNM-based classification is used to stage all SCCHN for treatment and outcome measures 
(American Joint Committee on Cancer [AJCC] Cancer Staging Manual 7th edition, 2010). At 
initial diagnosis, SCCHN can be of early stage (ES - 33%; Stage I/II), locally advanced 
(LA - 52 - 60%; stage III/IV-A/IV-B) or metastatic (met - ∼ 10%; Stage IV-C). With standard of 
care treatment, the 5-year survival for ES is 80%, for LA it is 50% and for metastatic disease, it is 
25%.60 Approximately 50% of the treated population returns with recurrent or refractory disease. 
For recurrent or refractory disease, the 1-year survival rate is 5% - 33% by various estimates with 
a median OS of 6 to 9 months.61,62 Metastatic and recurrent HNC that is no longer amenable to 
local surgical/radiation therapy causes substantial morbidity and high mortality, with a median 
PFS of ≤6 months due to the lack of effective therapeutic options.63,64,65
Treatment of recurrent or metastatic disease consists of cytotoxic chemotherapies such as 
methotrexate, organoplatinum compounds, fluorouracil (5-FU), or taxanes - either alone or in 
combination - and the biologic agent cetuximab. Patients whose disease progresses after platinum 
based therapy have a poor prognosis. In a retrospective analysis of 151 subjects with platinum-
refractory recurrent metastatic SCCHN, 68 patients (45%) receiving best supportive care had a 
median OS of 56 days (95% CI, 46 - 67 days) whereas in 43 subjects (28%), second line 
chemotherapy (platinum based or methotrexate) had no ORR and median OS was 107 days (95% 
CI, 83 - 135 days).66 In 2006, the US Food and Drug Administration (FDA) approved cetuximab 
(Erbitux®), for use as monotherapy in patients with recurrent or metastatic HNC who have 
progressed after platinum-based therapy based on a single-arm, multicenter clinical trial in 103 
patients with recurrent or metastatic SCCHN who had documented disease progression within 30 
days of a platinum-based chemotherapy regimen. The objective response rate (ORR) was 13% 
(95% confidence interval 7% - 21%) and the median duration of response was 5.8 months (range 
1.2 - 5.8 months).67 According to national guidelines, other single agents appropriate for this 
population include paclitaxel, docetaxel, and methotrexate, whose response rates range from 
Revised Protocol No.: 07
Date: 07-May-2019
34
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
15 - 40%.68,69 In a Phase 2 trial in subjects who progressed within 3 months since last platinum 
administration for the treatment of recurrent or metastatic HNC, the addition of docetaxel to 
cetuximab resulted in a partial response rate of 11% indicating that combination therapies with 
cetuximab in the platinum refractory setting have limited efficacy.70 In 2011, the FDA approved 
cetuximab in combination with platinum-based therapy with 5-FU in patients with recurrent or 
metastatic HNC based on an improvement of median OS from of 10.1 months compared to 7.4 
months for patients treated with platinum/5-FU alone.67
Despite the numerous treatment options, metastatic or recurrent HNC remains an area of high 
unmet medical need as patients who progress after treatment (refractory or platinum-resistant 
disease) have the worst prognosis with median OS of 3 - 4 months and 1 year survival rate of 
< 5%.71 In conclusion, there is no effective standard of care that provides survival benefits beyond 
4 - 6 months in second line platinum refractory recurrent or metastatic SCCHN.
HPV-associated head and neck cancer, largely presenting in the oropharynx has been increasing 
in incidence.61,63 In the US, some 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. HPV status is an independent prognostic factor for OS and PFS among patients with 
squamous-cell OPC.72 In this study, 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 p16 
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, and 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.63 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,64 concurrent chemoradiation,57,65 multi-drug induction chemotherapy,73
and targeted molecular therapies.58 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,74 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 HNC 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.
Revised Protocol No.: 07
Date: 07-May-2019
35
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Cervical, Vaginal, Vulvar, Anal Canal, and Penile Cancers
In the United States, almost 4900 cases of vulvar cancer are diagnosed each year, with over 1000 of 
those women expected to die from the disease; for cervical cancer in the US there are 12,000 new 
cases of invasive cervical cancer and approximately 4000 cancer-related deaths occur each year.56
HPV infection is associated with the development of cervical, vulvar, anal canal, and penile 
cancers.75 HPV 16 and 18 are the most common subtypes for vulvar, anal canal, and penile cancers; 
HPV 16, 18, 33, 6 and 31 are the 5 most frequently observed HPV types for cervical cancer. 
Whereas cervical cancer HPV infection occurs in nearly 100% of patients76, HPV associated 
squamous vulvar cancer affects younger women77 and is a warty squamous cell compared to 
keratinizing or differentiated. Only 70% of cases are associated with HPV infection.78
Treatment for vulvar or vaginal cancer is typically surgical resection, though chemoradiotherapy 
is another option.79 The 5-year survival for vulvar cancer depends on spread of disease, Local 
86%, Regional 54%, and Distant 16%.80 Treatment of recurrent disease includes surgical 
reexcision or resection and platinum based chemotherapy for metastatic disease. Recurrences are 
more likely local compared to distant (5.7%) and the 5-year survival rate was 60% for perineal 
recurrences, 27% for inguinal and pelvic recurrences, 15% for distant recurrences, and 14% for 
multiple recurrences.81
Treatment for cervical cancer is typically surgery for Stages IA - IIA1 and concurrent 
chemoradiation for Stages IB2 to IVA. The 5-year survival rate for cervical cancer depends on 
stage: IA 93%, IB 80%, IIA 63%, IIB58%, IIIA 35%, IIIB 32%, IVA 16%, and IVB 15%.82
Treatment of recurrent disease is typically with surgery for resectable disease or chemotherapy 
plus bevacizumab, which improved ORR (48% vs 36%) and mOS (17 vs 13.3 months) compared 
to chemotherapy alone.83 After first line chemotherapy, there is no standard of care that has 
demonstrated improved benefit over best supportive care.  
Anal cancer comprises 2.5% of all digestive system malignancies in the United States; 8080 new 
cases are diagnosed annually, with 1080 deaths.84 The incidence of anal cancer in the general 
population has increased over the last 30 years. A higher incidence has been associated with female 
gender, infection with human papillomavirus (HPV), lifetime number of sexual partners, genital 
warts, cigarette smoking, receptive anal intercourse, and infection with human immunodeficiency 
virus (HIV).85
Anal squamous cell cancer is believed to be directly linked to the presence of a complex 
inflammatory process most commonly caused by HPV infection (particularly with serotypes 16 
and 18) in the histologically unique area of the anal squamocolumnar epithelium.86
United States Surveillance, Epidemiology and End Results (SEER) data reveal approximately 
7000 to 8000 new anal cancer cases (64% female) and 1000 deaths recorded annually.87 About 
91% are believed to be caused by HPV. With anal cancer presentations at all stages, 5-year survival 
is 66.4%. Approximately 48% of patients have localized disease at presentation, and 5-year 
Revised Protocol No.: 07
Date: 07-May-2019
36
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
survival in this group is 80.7%, whereas in those who present with metastatic disease, 5-year 
survival is 30.4%.87
Consensus-based guidelines from NCCN and ESMO88 recommend cisplatin plus FU as a first-line 
regimen. If this regimen fails, no other regimens have been shown to be effective for metastatic 
disease.
Penile cancer is rare in Western countries. The American Cancer Society estimated that in 2016, 
2,030 penile cancers would be diagnosed in the United States, with 340 deaths.84 This death rate 
of 17% underscores the seriousness of this cancer; for comparison, only 3% of men with prostate 
cancer die from this disease. About 63% of cases of penile cancer are believed to be caused by 
HPV.
The prognosis of penile cancer is primarily related to the presence or absence of inguinal node 
metastasis. Untreated patients with inguinal metastases rarely survive 2 years. Of those with 
clinically palpable adenopathy and histologically proven metastases, 20 to 50% are alive at 5 years 
following inguinal lymphadenectomy. The results are even better when the extent of the nodal 
involvement is considered. An 82 to 88% 5-year survival rate has been reported when only 1 to 3 
lymph nodes are involved.89
Men with a history of penile cancer are at risk for both localized recurrence and distant metastases, 
and up to 30% of all patients will subsequently recur.90 Partial or total penile amputation is 
preferred for men with a local recurrence, whereas individualized chemotherapy treatment based 
on the patient’s performance status and symptoms91 is preferred for patients presenting with or 
who develop metastatic disease. Platinum based chemotherapies results in overall response rates 
of up to 30 to 38% in patients with distant metastatic penile carcinoma.92,93,94,95 For patients who 
progress after their initial chemotherapy, the prognosis is poor with a median survival of less than 
six months.96
1.1.1.3
Polyomavirus Positive Merkel Cell Cancer (pMCC)
According to a review of the SEER database, there were 3,870 cases of Merkel cell carcinoma 
(MCC) between 1973 and 2006.97 The review concluded that stage of disease was the best 
predictor of survival and the 10-year relative survival rate was higher in women than men (64.8% 
vs 50.5%, p < 0.001). For advanced disease, however, the 2-year survival rate for patients with 
American Joint Committee on Cancer (AJCC) stage IV disease is estimated to be 26%.98
Clinical observations have linked UV exposure and immune status to merkel cell carcinoma based 
on the observations that diagnosis occurs in the sun-exposed areas of skin in older individuals as 
well as in patients with immunocompromised states.99,100,101 Another etiologic factor is Merkel 
Cell Polyomavirus (MCPyV) which can integrate into tumor genome prior to the clonal expansion 
of tumor cells.102,103
Treatment of resectable disease involves surgery, wide local excision, and assessment of lymph 
nodes by sentinel node biopsy. A retrospective analysis of 1187 cases in the SEER database 
Revised Protocol No.: 07
Date: 07-May-2019
37
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
demonstrated a longer overall survival for patients who received adjuvant radiation compared to 
those who did not with a median survival of 63 months vs 45 months with pronounced 
improvement for patients with tumors lager than 2 cm (median survival 50 months vs
21 months)104 which led to the recommendation by the NCCN to offer adjuvant radiation to all 
patients with resected MCC.105 For metastatic disease, the NCCN recommends cisplatin or 
carboplatin with or without etoposide, topotecan, or the combination of cyclophosphamide, 
doxorubicin/epirubicin, and vincristine. Metastatic disease is incurable with chemotherapy and 
overall survival estimates for patients with metastatic disease come from single institution 
publications with small sample sizes, often less than 10106,107,108, highlighting an unmet medical 
need. 
Overall, this trial will examine the activity of nivolumab, alone or in combination with either 
ipilimumab, relatlimab, or daratumumab in viral positive and viral negative tumor types including: 
EBV positive gastric cancer, EBV positive NPC, HPV positive and negative SCCHN, HPV 
associated cervical cancer, anogenital HPV associated cancers (vaginal, vulvar, anal, penile, rectal)
and Polyomavirus positive Merkel cell carcinoma (pMCC). These tumor types may be more likely 
to respond to nivolumab which blocks the interaction of PDL-1/PD-L2 and PD-1, in two settings, 
a neoadjuvant or window of opportunity cohort in patients with resectable disease and a cohort of 
patients with metastatic disease who have progressed after one line of therapy or refused standard 
of care. 
1.1.2
Infection and Tumorigenesis
The establishment of a virus as the inducer of cellular transformation109 by Petyon Rous in the 
early 20th century paved the way for modern tumor biology. Since Rous’ observation, many 
cancers of different origins have been linked to chronic viral infections that are partly responsible 
for driving tumorigenesis through several mechanisms, including the disruption of tumor
suppressor proteins such as p53 and Rb, activation of cellular proliferation pathways, and 
inhibiting the apoptotic machinery.110 Two major classes of virus, Human Papilloma virus (HPV) 
and Epstein-Barr virus (EBV), are associated with ∼670,000 oncological cases per year, 
worldwide.110
1.1.2.1
HPV
Promotion of tumorigenesis by HPV is mediated by two key viral proteins, E6 and E7, both of 
which target cell cycle regulation, proliferation, and apoptosis pathways that drive cells toward 
transformation. The viral E6 protein binds to E6-AP, an ubiquitin ligase, resulting in degradation 
of p53 protein.111 In addition, E6, binds to histone acetyltransferases p300, ADA3, and CREB 
binding protein (CBP) preventing acetylation of p53 and inhibiting the transcription of 
p53-responsive genes. E6 has also been shown to inhibit apoptotic signaling by binding tumor 
necrosis factor (TNF)-α receptor (TNFR1), FAS-associated protein with death domain (FADD) 
and caspase 8, and through the degradation of pro-apoptotic BAX and BAK. Direct killing of cells 
through IFN is inhibited by E6 through inhibition of IRF3.112
Revised Protocol No.: 07
Date: 07-May-2019
38
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
The HPV protein E7 also targets a tumor suppressor, retinoblastoma (Rb), leading to its 
inactivation and resulting in constitutive activation of E2F-responsive genes. Further disruption of 
cell cycle control by E7 is achieved by inhibition of cyclin-dependent kinase inhibitors. Similar to 
E6, E7 results in cellular immune escape by inhibiting IFN signaling.112
1.1.2.2
EBV
Similar to HPV, infection of host cells with EBV may lead to their immortalization through 
multiple mechanisms of dysregulated cellular proliferation and apoptosis. The EBV-encoded 
protein EBNA-3C binds to several cell-cycle regulatory proteins, including cyclin D1, cyclin D2, 
cyclin D3, cyclin A, and CtBP. In addition, EBNA-3C negatively regulates cyclinB1 activity 
through a p53-dependent mechanism. The cumulative effects of EBNA-3C drive the infected cell 
into an uncontrolled proliferative state.113 In addition, the LMP1 viral protein has transformational 
properties through its activation of the NF-kB pathway.114
1.1.2.3
Polyomavirus
Three proteins encoded by the polyomavirus, large T, middle T, and small T, have roles in inducing 
transformation of virally infected cells. Large T antigen binds to the tumor suppressor Rb inducing 
a block in apoptosis.115 Middle T antigen induces cellular transformation in conjunction with large 
and small T through activation of cellular kinases, such as PI3K and PLCg.116 Small T antigen 
binds to the translational repressor 4E-BP1, resulting in dysregulated cap-dependent translation 
through activation of eIF4e.117
Many viral proteins, including HPV E6, E7 and EBV and polyoma virus proteins, EBNA-1, 
EBNA-3A, are immunogenic proteins and T cells that recognize viral protein epitopes can be 
found in the circulation of infected patients.118,119 The existence of viral-reactive T cells in cancer 
patients with viral-positive tumors is important, as anti-tumor immunity may be driven by these T 
cells, in addition to T cells that are specific to tumor-associated antigens.
The mechanisms of tolerance found in tumor-specific T cells, including expression of PD-1, have 
been shown to be similar to viral-specific T cells.120 However, the ability of viral antigen-specific 
T cells to mediate anti-tumor immunity leading to tumor burden reduction is unknown in human 
tumors. The rationale for targeting virally-infected tumors is described below.
1.1.3
Rationale for Nivolumab in the Neoadjuvant Setting
One of the primary objectives of this protocol is to assess the safety and tolerability of 
administering 2 doses of nivolumab in the neoadjuvant setting, prior to surgical resection of 
disease. Additional objectives are to evaluate the biological responses of the tumor 
microenvironment and periphery after nivolumab therapy. The surgically resected tumor will 
provide adequate sample to perform an in-depth analysis of the tumor and immune system. 
CA209-358 will provide preliminary safety and biomarker data utilizing nivolumab in the 
neoadjuvant setting prior to surgery.
Previous data indicate that short term doses of immune checkpoint inhibitors can be safely 
administered in the preoperative setting. In a 12 patient bladder cancer Phase 1 trial 6 subjects 
Revised Protocol No.: 07
Date: 07-May-2019
39
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
received two doses of 3 mg/kg and 6 patients received 10 mg/kg ipilimumab monotherapy with a 
3-week interval between doses prior to surgery of the urothelial tumor.121 Surgical delay was noted 
in 3 patients. Of note, at the approve dose of ipilimumab (3 mg/kg), none of the subjects had a 
delay in surgery due to a drug-related adverse event, and preoperative ipilimumab was safe and 
well tolerated. Two patients at the 10 mg/kg dose had delay due to irAE (Grade 2 and 3 diarrhea). 
An additional patient developed Grade 3 diarrhea and delayed surgical planning, but surgery was 
cancelled due to disease progression. 
Based on the safety/tolerability profile as described in Section 1.4.1.2, it is unlikely that subjects 
in the neoadjuvant cohort receiving 2 doses of nivolumab will experience a significant delay in 
surgery. In addition, as of 10-Mar-2015, there have been approximately 3289 subjects treated with 
nivolumab monotherapy in BMS sponsored clinical trials. Overall, there has been an approximate 
3% frequency of any grade, drug-related serious adverse events within the first 4 weeks of 
treatment, with the most frequent being pneumonitis (0.33%), pyrexia (0.3%), infusion-related 
reaction (0.24%), and hypersensitivity reaction (0.12%). All other drug-related serious adverse 
events have occurred at a frequency of < 0.1%. Given the low frequency of SAEs and a 
manageable toxicity profile of nivolumab, BMS anticipates a favorable benefit-risk profile with 
short term administration of nivolumab in the neoadjuvant setting. 
1.1.4
Rationale for Immunotherapy in Virus-Associated Tumors
As described above, the adaptive T cell response largely depends upon presentation of antigens by 
MHC in the context of an immune-stimulatory environment. Viral proteins, mutated proteins 
(neoantigens), and spatio-temporally dysregulated self-proteins represent targets of the T cell 
response that have potential to result in tumor-cell clearance. As evidence, T cell responses to viral 
antigens in patients with EBV+ or polyomavirus+ tumors can be identified and T cells against 
tumor neoantigens and self-antigens have been widely reported in the literature.122 Further, overall 
survival of both gastric and Merkel cell carcinoma patients is prognostically associated with the 
presence of tumor infiltrating T cells, suggesting immunosurveillance of tumor growth is taking 
place.123,124
Nonetheless, endogenous immune responses do not cause all tumors to regress. One plausible 
explanation, which has direct therapeutic consequences, is that virus associated tumors express 
PD-1 ligands as an adaptive response to virus antigen-specific cytokine-secreting T cells in the 
tumor microenvironment. Recently published results on HPV+ SCCHN and MCC support this 
notion. A recent review of MCC specimens for PD-L1 expression by tumor cells and tumor 
infiltrating lymphocytes (TILs) found that PD-L1 expression was present in 49% and 55% of 
samples, respectively, and specimens with PD-L1+ tumor cells, 97% (28/29) showed a geographic 
association with immune infiltrates.125 Among specimens with moderate-severe TIL intensities, 
100% (29/29) showed PD-L1 expression by tumor cells, but MCPyV(-) tumor cells were 
uniformly PD-L1(-).
Revised Protocol No.: 07
Date: 07-May-2019
40
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
These results demonstrated that virtually all HPV+ SCCHN and a majority of MCV+ MCC are 
PD-L1+ and, when positive, demonstrate focal PD-L1 expression associated with areas of 
lymphocyte infiltration. Conversely, among 8 MCV- MCCs, none expressed PD-L1. 
Taken together, these data suggest that virus associated cancers have distinct patterns of immune 
responses and a distinct tumor immune microenvironment.
1.1.5
Rationale and Aims for Biomarker Assessments
The biological basis of nivolumab, ipilimumab, relatlimab, and daratumumab in the treatment of 
oncological disease is to modulate the immune system to both generate and restore a durable anti-
tumor response leading to clearance of tumor. Clinical data supports the hypothesis that inhibition 
of the PD-1 pathway results in rejection of tumor by the host immune system.
The precise mechanisms by which nivolumab, ipilimumab, relatlimab, and daratumumab exert 
their immune-modulatory and anti-tumor activities is unclear; however, particular cell types, such 
as effector T cells and regulatory T cells, are critical for the anti-tumor response. 
Therefore, the major questions that will be addressed through the conduct of this study are:
•
Are tumor and/or viral-specific T cells present at the tumor site prior to nivolumab
monotherapy and in combination with ipilimumab, relatlimab, or daratumumab therapy?
•
Do nivolumab monotherapy and in combination with ipilimumab, relatlimab, or daratumumab
alter the frequency and activation state of tumor and/or viral-specific tumor infiltrating T cells?
•
Does expression of PD-L1 or PD-L2 on tumor cells prior to therapy correlate with clinical 
efficacy to monotherapy and combination therapies?
•
Does the mutational status of tumor cells correlate with clinical efficacy to monotherapy and 
combination therapies?
•
Can we define distinct pharmacodynamic markers of monotherapy and combination therapies
in the peripheral compartment?
•
How do nivolumab monotherapy and combination with ipilimumab, relatlimab, or 
daratumumab alter the activating and negative costimulatory molecules on immune cells in the 
periphery and at the tumor site? 
•
Do non-responding subjects have distinct mechanisms of resistance to study drugs (such as an 
increase in additional negative regulatory proteins, an increase in MDSC or Treg, or loss of 
tumor-associated antigens in the tumor)?
•
Is the intratumoral or peripheral T cell repertoire predictive of response to study drugs?
•
Does the composition and phenotype of the tumor microenvironment, at baseline, or on 
treatment, correlate with clinical efficacy?
1.1.6
Rationale for Dose Selection for Nivolumab 
Nivolumab is currently approved for the treatment of various tumors, including melanoma, 
adjuvant treatment of melanoma, NSCLC, RCC, classical Hodgkin Lymphoma, SCCHN,
hepatocellular carcinoma, and urothelial carcinoma, using a regimen of either nivolumab 240 
mg Q2W or nivolumab 3 mg/kg Q2W.
Revised Protocol No.: 07
Date: 07-May-2019
41
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
The nivolumab dose of 240 mg Q2W or 480 mg Q4W was selected for this study based on clinical 
data and modeling and simulation approaches using PPK and exposure-response analyses 
examining relationships between nivolumab exposures and efficacy and safety responses, using 
data from studies in multiple tumor types with body weight-normalized dosing (mg/kg). Flat 
dosing is expected to reduce prescription dosing errors, shorten pharmacy preparation time, and 
improve ease of administration. Additionally, in case of 480 mg Q4W, extending the dosing 
interval to 4 weeks provided numerous benefits to participants as they would have increased 
flexibility between clinical visits.
Using the PPK and exposure-response models, nivolumab exposures and probabilities of efficacy 
responses and risks of AEs were predicted following nivolumab 480 mg Q4W administration and 
compared to those following nivolumab 3 mg/kg Q2W administration. The overall distributions 
of average nivolumab steady-state exposures (Cav,ss) are comparable following administration with 
either nivolumab 3 mg/kg Q2W or nivolumab 480 mg Q4W over a wide range of body weights. 
Nivolumab 480 mg Q4W administration is predicted to result in approximately 43% greater 
steady-state peak concentrations (Cmax,ss) compared to nivolumab 3 mg/kg Q2W. Although the 
Cmax,ss of nivolumab is expected to be greater following nivolumab 480 mg Q4W compared to 
nivolumab 3 mg/kg Q2W, the predicted Cmax,ss following nivolumab 480 mg Q4W is well below 
the median Cmax,ss achieved following administration of nivolumab 10 mg/kg Q2W, a safe and 
tolerable dose level across a wide body range (35 to 160 kg).
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W, and the predicted risks of AEs due to discontinuation or death, 
≥Grade 3 AEs, and ≥Grade 2 immunotherapy-mediated AEs (IMAEs) are predicted to be similar 
following administration of nivolumab 480 mg Q4W relative to nivolumab 3 mg/kg Q2W across 
tumor types. Safety analyses using available data following nivolumab 3 mg/kg Q2W and 
10 mg/kg Q2W administration indicated there were no differences in AE profiles across body-
weight groups. Finally, initial clinical evidence demonstrates that, following administration of 
nivolumab 480 mg Q4W, nivolumab is well tolerated.
Nivolumab 480 mg Q4W is predicted to have approximately 16% lower steady-state trough 
concentrations (Cmin,ss) compared to nivolumab 3 mg/kg Q2W. While these exposures are 
predicted to be lower, they are on the flat part of the exposure-response curves and are not predicted 
to affect efficacy. Exposure-efficacy analyses of multiple PK measures and efficacy endpoints 
indicated that following administration of nivolumab 480 mg Q4W, efficacy is predicted to be 
similar to that following administration of nivolumab 3 mg/kg Q2W across multiple tumor types. 
Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and safety 
profiles to nivolumab 240 mgQ2W or nivolumab 3 mg/kg Q2W.
1.1.7
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes duration in 
subjects 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 
Revised Protocol No.: 07
Date: 07-May-2019
42
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
ipilimumab have used a 60 minute infusion duration for nivolumab and 90-minute infusion 
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 subjects 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%) subject in the 0.3 mg/kg 
and in 2 (2.8%) subjects 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 subjects. 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 metastatic 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.
1.1.8
Rationale for Nivolumab plus Ipilimumab Combination Therapy
Ipilimumab is a 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 interaction. 
Ipilimumab has been approved for use in over 40 countries including the United States in March 
2011 and the European Union in July 2011. The safety profile is detailed in the Investigator 
Brochure.126
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of immuno-
oncology and treatment with investigational agents targeting this mechanism has induced 
regressions in several types of cancer. Programmed death 1 (PD-1) receptor and cytotoxic T-
lymphocyte–associated antigen 4 (CTLA-4) are two important cellular targets that play 
Revised Protocol No.: 07
Date: 07-May-2019
43
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell 
exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation. 
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve 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.14,127
Multiple studies suggest a higher response rate and antitumor activity with the combination of 
nivolumab plus ipilimumab. The combination of nivolumab and ipilimumab was evaluated in 
CA209004 (MDX1106-04), a Phase 1b multiple ascending dose study in subjects with 
treatment-naive and previously treated advanced melanoma. Results showed promising activity 
with higher, but tolerable toxicity than ipilimumab alone.128 Based on these data, CA209069, a 
phase 2 study, compared the combination to ipilimumab alone in treatment-naïve patients with 
advanced melanoma: nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks x4 followed by 
nivolumab 3 mg/kg every 2 weeks versus ipilimumab 3 mg/kg every 3 weeks x 4.129 In patients 
with BRAF wild type tumors, the ORR was 61% (44/72), including 22% (16/72) complete 
responses (CR) in the group treated with the combination, 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). Recently, a phase 3 study (CA209067, n= 945) 
reported significantly improved PFS and ORR with the combination of nivolumab and ipilimumab 
versus ipilimumab alone in previously untreated melanoma. The median progression-free survival 
was 6.9 months (95% confidence interval [CI], 4.3 to 9.5) in the nivolumab group, 11.5 months 
(95% CI, 8.9 to 16.7) in the nivolumab-plus-ipilimumab group, and 2.9 months (95% CI, 2.8 to 
3.4) in the ipilimumab group. Significantly longer progression-free survival 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 (hazard ratio, 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). Deep and durable responses were observed in previously treated, extensive 
stage SCLC, with a response rate of 31.1% with the combination of nivolumab and ipilimumab.130
Given the increased efficacy observed with combination approaches in other tumor types, 
nivolumab plus ipilimumab may offer subjects with metastatic or recurrent cancers, who have been 
previously treated with up to 2 prior therapies and have no other approved treatment options, the 
potential for benefit.
Revised Protocol No.: 07
Date: 07-May-2019
44
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1.1.9
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab
Rationale for Combo A: nivolumab 3 mg/kg q 2weeks + ipilimumab 1 mg/kg q 6weeks
The combination of nivolumab and ipilimumab was evaluated in CA209004 (MDX1106-04), a 
Phase 1b multiple ascending dose study in subjects with treatment-naive and previously treated 
advanced melanoma. Antitumor activity was observed in 5 different combination cohorts: 
•
nivolumab 0.3 mg/kg and ipilimumab 3 mg/kg (Cohort 1, n = 14)
•
nivolumab 1 mg/kg and ipilimumab 3 mg/kg (Cohort 2, n = 17)
•
nivolumab 3 mg/kg and ipilimumab 1 mg/kg (Cohort 2a, n = 16)
•
nivolumab 3 mg/kg and ipilimumab 3 mg/kg (Cohort 3, n = 6)
•
nivolumab 1 mg/kg and ipilimumab 3 mg/kg (Cohort 8, n = 41)
From this study, it has been found that the 3 mg/kg nivolumab and 3 mg/kg ipilimumab 
combination regimen exceeded the maximum tolerated dose. Even though the drug-related 
discontinuation rates in combination cohorts were approximately 26 - 27%, the ORR in these 
cohorts were still higher compared to nivolumab monotherapy (42% - 44% versus 36%).
Additional studies have demonstrated the potential for IO combinations to improve antitumor 
responses across the nivolumab program.131 An ORR of 62 - 65% has been observed in advanced 
melanoma (CA209067 and CA209069, N = 407) with a combination regimen of nivolumab 
1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses. In RCC patients (CA209016), both 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 21) and nivolumab 1 mg/kg plus ipilimumab 
3 mg/kg (n = 23) showed antitumor activity with an ORR of 38% - 40%. 
Activity was observed in all cohorts, with response rates greater than 30% in the 2 cohorts in which 
nivolumab was dosed as 3 mg/kg. Follow-up time is limited, but PFS and OS was also encouraging 
in the nivolumab 3 mg/kg cohorts.
In summary, nivolumab and ipilimumab combinations have shown additive or synergistic 
activities across the tumor types investigated. To further improve the tolerability profile, other 
combination dosing regimens were also explored in the nivolumab development program. Less 
frequent dosing of ipilimumab at 1 mg/kg q6week when given with nivolumab 3 mg/kg q2week 
was found to have a similar discontinuation rate to that observed in nivolumab monotherapy (11% 
vs 10%) in preliminary data from CA209012.
Rationale for Combo B: nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q3 weeks x4, followed by 
nivolumab 240 mg q2 weeks
In CA209004, the 3 mg/kg nivolumab and 3 mg/kg ipilimumab cohort exceeded the maximum 
tolerated dose per protocol. In CA209004, while both Cohort 2 (1 mg/kg nivolumab + 3 mg/kg 
ipilimumab) and Cohort 2a (3 mg/kg nivolumab + 1 mg/kg ipilimumab) had similar clinical 
activity, a dose of 3 mg/kg of ipilimumab every 3 weeks for a total of four doses and 1 mg/kg 
nivolumab every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks until 
progression was chosen. Exposure-response analysis of nivolumab monotherapy across dose 
Revised Protocol No.: 07
Date: 07-May-2019
45
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
ranges of 1 mg/kg to 10 mg/kg reveals similar clinical activity while exposure-response analysis 
of 0.3 mg/kg, 3 mg/kg, and 10 mg/kg of ipilimumab monotherapy have demonstrated increasing 
activity with increase in dose in the phase 2 study CA184022. Therefore, theoretically the selection 
of 3 mg/kg of ipilimumab (Cohort 2) may be more clinically impactful than selection of 3 mg/kg 
of nivolumab (Cohort 2a). The combination arm has a similar dose and schedule as that in 
CA209004 for the first 12 weeks, increasing the likelihood of replicating the clinical activity seen 
in the CA209004 study. Based on the clinical activity in CA209004, the majority of responses to 
the combination of nivolumab and ipilimumab occur in the first 12 weeks. Given the uncertainty 
of whether the ipilimumab administered past week 12 contributes to the clinical benefit and the 
fact that the approved schedule for ipilimumab is every 3 weeks for a total of four doses in the 
FDA and EMA approved label dosing section, ipilimumab will administered every 3 weeks for a 
total of 4 doses. Nivolumab monotherapy treatment every two weeks until progression was studied 
in CA209003 and has been studied across the nivolumab monotherapy Phase 3 registrational trials. 
Thus starting at week 12, which is after the completion of the four doses of combined nivolumab 
and ipilimumab, nivolumab would continue to be administered every two weeks until progression.
Based on these data, the following two dosing schema will be evaluated in the metastatic 
combination treatment arms for CA209358:
•
Combo A: nivolumab 3 mg/kg q 2weeks + ipilimumab 1 mg/kg q 6weeks
•
Combo B: nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q3 weeks x4, followed by nivolumab 
240 mg q2 weeks
In view of the safety and efficacy data seen with Combo A in patients with NSCLC, Combo A 
will be investigated in the EBV positive NPC, cervical, vaginal, vulvar, anal canal and penile
cancer, HPV positive SCCHN and polyomavirus positive MCC tumor types.  
In addition, Combo B will be investigated in patients with cervical, vaginal, vulvar, anal canal,
and penile cancer tumor types in order to understand the effects of the higher dose of ipilimumab 
in viral positive tumor types. In addition, given the limited information on the optimal 
dose/regimen for these cancers, two doses are being proposed.
1.1.10
Rationale for Nivolumab plus Anti-LAG-3 Antibody (relatlimab, BMS-
986016) Combination Therapy
Like PD-1, lymphocyte activation gene-3 (LAG-3; CD223) is also a type I transmembrane protein 
that is expressed on the cell surface of activated CD4+ and CD8+ T cells and subsets of NK and 
dendritic cells.132,133 LAG-3 is closely related to CD4, which is a co-receptor for T helper cell 
activation. Both molecules have 4 extracellular Ig-like domains and require binding to their ligand, 
major histocompatibility complex (MHC) class II, for their functional activity. In contrast to CD4, 
LAG-3 is only expressed on the cell surface of activated T cells and its cleavage from the cell 
surface terminates LAG-3 signaling. LAG-3 can also be found as a soluble protein but it does not 
bind to MHC class II and its function is unknown.
Revised Protocol No.: 07
Date: 07-May-2019
46
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
It has been reported that LAG-3 plays an important role in promoting regulatory T cell (Treg) 
activity and in negatively regulating T cell activation and proliferation.134 Both natural and induced 
Treg express increased LAG-3, which is required for their maximal suppressive function.135,136
Furthermore, ectopic expression of LAG-3 on CD4+ effector T cells reduced their proliferative 
capacity and conferred on them regulatory potential against third party T cells.136 Recent studies 
have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus 
(LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell 
antitumor responses.120,137 In fact, LAG-3 maintained tolerance to self and tumor antigens via 
direct effects on CD8+ T cells in 2 murine models.
Immune tolerance observed in the setting of tumor development and tumor recurrence, however, 
seems to be mediated by the co-expression of various T cell negative regulatory receptors, not 
solely from LAG-3. Data from chronic viral infection models,120,136,138 knock-out mice,139,140,141
tumor recurrence models,142 and, to a more limited extent, human cancer patients,142,143,144 support 
a model wherein T cells that are continuously exposed to antigen become progressively inactivated 
through a process termed “exhaustion.” Exhausted T cells are characterized by the expression of 
T cell negative regulatory receptors, predominantly CTLA-4, PD-1, and LAG-3, whose action is 
to limit the cell’s ability to proliferate, produce cytokines, and kill target cells and/or to increase 
Treg activity. However, the timing and sequence of expression of these molecules in the 
development and recurrence of tumors have not been fully characterized.
It is hypothesized that CTLA-4 acts as the dominant off-switch for tolerance, but it is the strong 
synergy between the PD-1 and LAG-3 inhibitory pathways that seems to mediate tolerance to both 
self and tumor antigens.139,140,142 Whereas CTLA-4 knockout (KO) mice die prematurely from 
multiorgan inflammation,145
PD-1 and LAG-3 single knockout mice present minimal 
immunopathologic sequelae.140 In contrast, dual knock-out mice (LAG3-/-PD1-/-) abrogates self-
tolerance with resultant autoimmune infiltrates in multiple organs and even lethality.139,140 These 
dual knock-out mice also show markedly increased survival from and clearance of multiple 
transplantable tumors.139
Conversely, extensive co-expression of PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ 
T cells has been shown in distinct transplantable tumors and samples from melanoma, RCC, head 
and neck, NSCLC and ovarian cancer patients.142,146,147,148,149,150,151 Blockade of PD-1/PD-L1 
interactions has been successfully used to restore antitumor immunity in preclinical and clinical 
studies. But the simultaneous blockade of PD-1 and LAG-3 pathways on T cells may exert an even 
more robust antitumoral immunity in naive as well as in recurrent tumors due to the possibility of 
reversing LAG-3–mediated T cell exhaustion. In 2 syngeneic mice models, for example, dual anti–
LAG-3/anti–PD-1 antibody therapy is able to cure most mice of established tumors that are largely 
resistant to single antibody treatment.139 Furthermore, recurrent tumors from a melanoma mouse 
model with increased Treg cell numbers and increased expression of checkpoint inhibitors PD-1, 
LAG-3, TIGIT, and TIM-3, can be controlled by depletion of Tregs (via FoxP3-DTR) plus the 
administration of anti–PD-L1 antibody. But more importantly, tumor regression of these recurrent 
Revised Protocol No.: 07
Date: 07-May-2019
47
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
tumors can also be accomplished with the combination of anti-PD-L1 plus anti-LAG-3 antibodies 
(C9B7W mAb) which also increases T cell activity.142
Given the literature supporting synergistic activity of nivolumab and anti–LAG-3 antibody in viral 
models, it is hypothesized that this combination could have antitumor effects in virally-related 
cancers, including human papilloma virus (HPV)-related tumors such as HPV+ head and neck 
cancer (HNC). Recent evidence has shown a role of immune inhibitory receptors (e.g., PD-1/PD-
L1) in the adaptive immune resistance seen in HNCs associated with HPV. In these cancers with 
high lymphocytic infiltration, there is PD-1 expression on the majority of CD8+ tumor infiltrating 
lymphocytes (TILs) and PD-L1 expression on both tumor cells and tumor-associated 
macrophages.138 In a recent analysis, 33% to 47% of head and neck tumors showed a T cell-
inflamed phenotype (TCIP) similar to melanoma, based on a gene expression signature. 
Interestingly, 75% of HPV (+) tumors showed a TCIP compared to 23% of HPV(-) tumors. 
Furthermore, various checkpoint molecules were universally co-expressed in these TCIP tumors 
including PD1, CTLA4, LAG3, PDL-2, and IDO, as shown in gene expression analysis.147
Altogether these data support a role for the PD-1:PD-L1 pathway in T cell exhaustion leading to 
both persistence of HPV infection and malignant progression in HNC patients. It is then possible 
that LAG-3 may also play a role in virally induced T cell exhaustion in these patients. Gastric 
cancer is another exploratory tumor suitable for T cell-directed therapy based on preliminary 
objective responses observed in patients treated with anti-PD-L1 antibody therapy.152 In addition, 
LAG-3 expression ≥ 1% by immunohistochemistry has been documented in ~35% of gastric 
cancer samples (BMS-986016 Investigator Brochure v03. Document Control No. 930071620). A 
subtype of gastric cancer is also associated with Epstein-Barr virus (EBV) infection.148 This 
subtype is characterized by massive lymphocyte infiltration, better prognosis than EBV-negative 
tumors, and worldwide distribution, particularly in Asia. So, similar to HNC, the expression of 
checkpoint inhibitors may be leading to the persistence of EBV infection and/or malignant 
progression of these tumors which could be halted by T cell-directed therapy.
These data argue strongly that dual blockade of the PD-1 and LAG-3 pathways could be a 
promising combinatorial strategy for viral positive tumors.
Relatlimab is a fully human antibody specific for human LAG-3 that was isolated from immunized 
transgenic mice expressing human immunoglobulin genes. It is expressed as an IgG4 isotype 
antibody that includes a stabilizing hinge mutation (S228P) for attenuated Fc receptor binding in 
order to reduce or eliminate the possibility of antibody- or complement-mediated target cell killing. 
Relatlimab binds to a defined epitope on LAG-3 with high affinity (Kd, 0.25-0.5 nM) and 
specificity and potently blocks the interaction of LAG-3 with its ligand, MHC class II (IC50, 0.7 
nM). The antibody exhibits potent in vitro functional activity in reversing LAG-3-mediated 
inhibition of an antigen-specific murine T cell hybridoma overexpressing human LAG-3 (IC50, 1 
nM). In addition, Relatlimab enhances activation of human T cells in superantigen stimulation 
assays when added alone or in combination with nivolumab (anti-PD-1 antibody).
Revised Protocol No.: 07
Date: 07-May-2019
48
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1.1.11
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Relatlimab
Based on the available nonclinical combination data and the preliminary clinical data from study 
CA224-020, a combined dosing regimen of nivolumab 240 mg Q2W and BMS-986016 80 mg 
Q2W (Combo C) is selected for the metastatic cohort nivolumab plus BMS-986016 combination.
Overall, the safety profile of BMS-986016 in combination with nivolumab is manageable, with no 
MDT reached at the tested doses up to 80 mg BMS-986016 and 240 mg nivolumab (flat dose, 
2qw), and with evaluation of 240 mg BMS-986016 and 240 mg nivolumab combination dose based 
on clinical cut-off of 29-Jun-2016.153 Important examples of durable tumor regressions, as well as 
manageable immune-mediated adverse events provide evidence of immune activation in the 
subjects treated up to 80 mg BMS-986016/240 mg nivolumab. The clinical findings are supported 
by the preliminary pharmacokinetic (PK) and receptor occupancy (RO) findings. Peripheral CD8+ 
T-cell RO data measured at trough monotherapy BMS-986016 treatment shows a linear increase 
with dose: 74% RO at 20 mg, 84% RO at 80 mg, and 94% RO at 240 mg. A preliminary PK 
analysis indicates that BMS-986016 exposure parameters are generally proportional across the 
dose range evaluated (20 to 800 mg) and were not altered by combination with nivolumab.
Taken together, the preliminary data suggest that 80 mg BMS-986016 in combination with 240 mg 
nivolumab is safe and well tolerated, and there will be no drug-drug interaction expected from this 
combination. Therefore, a combined dosing regimen of nivolumab 240 mg Q2W and BMS-986016 
80 mg Q2W is recommended for investigation in this study. 
Additional details are provided in the current version of the BMS-986016 IB.154
Relatlimab Adverse Event Management Guidelines
In order to standardize the management of IO AEs across all novel IO treatment combinations and 
given that nivolumab is the backbone of therapy, nivolumab AE algorithms are recommended for 
AE management (see Appendix 2 for Nivolumab Adverse Event Management Guidelines for 
details).
1.1.12
Rationale for Nivolumab plus Daratumumab Combination Therapy
The tumor microenvironment is believed to be important in determining whether a patient can 
make an effective immune response to his/her tumor. Tumor cells can induce an 
immunosuppressive microenvironment through multiple tolerogenic factors and expression of 
inhibitory surface receptors that create a shield around the tumor, resulting in evasion of the 
immune response. Two such mechanisms include (1) expression of PD-L1 in tumor or infiltrating 
cells, which triggers PD-1 on T cells, inhibiting T cell activation and expansion of previously 
activated T cells; and (2) recruitment of immunosuppressive cell types such as regulatory T cells 
(Tregs) and myeloid-derived suppressor cells (MDSCs) into the tumor. Individual tumors may use 
more than one means to evade the immune system. Therefore using more than one method to 
unleash the immune response may show synergistic effects.
Revised Protocol No.: 07
Date: 07-May-2019
49
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Nivolumab, which blocks the PD-1 pathway, has demonstrated single agent clinical efficacy 
resulting in a survival benefit in patients with metastatic melanoma, squamous and non-squamous 
NSCLC, advanced RCC and has an approved label in these indications. Nivolumab has also 
demonstrated significant response rates in other solid tumor malignancies including small-cell lung 
cancer, head and neck cancer, bladder cancer. The combination of nivolumab with other therapies, 
such as ipilimumab, has also demonstrated meaningful response rates and progression-free 
survival in multiple solid tumor indications and is approved for metastatic melanoma in the US.  
Daratumumab is a human immunoglobulin G1 (IgG1) monoclonal antibody that targets CD38, 
inducing tumor cell death through multiple mechanisms, including antibody-dependent cell-
mediated cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody dependent 
cellular phagocytosis (ADCP).155,156 Daratumumab has shown promising anti-myeloma activity 
in 2 clinical studies (GEN501 and SIRIUS) in patients with relapsed and refractory MM, resulting 
in remarkable response rates that include stringent complete responses (sCRs) and prolonged 
clinical responses in heavily pretreated patients.157,158 Based on these data, daratumumab was 
approved by the US Food and Drug Administration for patients with MM who have received ≥3
prior lines of therapy.159 The target of daratumumab is CD38, which is highly and uniformly 
expressed on all malignant MM cells and expressed at relatively low levels on lymphoid or 
myeloid cells and in some tissues of non-hematopoietic origin.160 CD38 is a type II transmembrane 
glycoprotein with ectoenzymatic activity involved in the catabolism of extracellular nucleotides.
160,161 Other functions ascribed to CD38 include receptor-mediated adhesion by interacting with 
CD31 or hyaluronic acid, regulation of migration, and signaling events160,161,162 Daratumumab 
induces killing of MM cells and other CD38+ expressing cell types via the activation of potent 
cytotoxic immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC), 
antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity 
(CDC)155,163 Another mechanism of action is induction of apoptosis upon secondary 
crosslinking.164 In addition, during daratumumab therapy, an increase in CD4+ T cells and CD8+ 
T cells has been demonstrated. These T cells are possibly involved in a host-anti-MM immune 
response. This increase can be related to cross presentation of tumor antigens by antigen-
presenting cells after phagocytosis of daratumumab-coated MM cells in combination with killing 
of CD38-positive suppressor cells such Tregs, Bregs, and myeloid-derived suppressor cells 
(MDSCs)165
In the current study, the combination of daratumumab to nivolumab is expected to deplete CD38+ 
immunosuppressive 
cells 
from 
the 
tumor 
microenvironment, 
thus 
alleviating 
the 
immunosuppression so that the nivolumab activated T cells can mount an effective immune 
response to the tumor. This trial will test whether simultaneous blockade of PD-1 with nivolumab 
and the immunoregulatory effects with daratumumab will result in enhanced anti-tumor responses 
in patients with solid tumors.
Following a full review of all available relevant data for daratumumab in combination with 
nivolumab, a safety signal that would cause a significant risk for patients was not validated based 
Revised Protocol No.: 07
Date: 07-May-2019
50
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
on the absence of a pattern of severe AEs that could not be accounted for by underlying disease or 
prior therapy.
The cumulative efficacy data in more than 100 patients in different solid tumor cohorts does not 
demonstrate an efficacy signal that would warrant continuation of the combination treatment in 
these solid tumor trials. Therefore, additional enrollment and continued treatment in this cohort 
have been discontinued. At the discretion of the principal investigator, alternative treatment 
options will be considered and/or subject(s) may continue treatment with nivolumab monotherapy.
1.1.13
Rationale for Nivolumab Combined with Daratumumab in Patients with 
HPV Positive and Negative or Unknown SCCHN
Per Revised Protocol 06, enrollment and treatment in this cohort have been terminated. This study 
will investigate the combination of daratumumab and nivolumab in patients with HPV positive,
negative, or unknown SCCHN. Nivolumab, which blocks the PD-1 pathway, has demonstrated 
single agent clinical efficacy in numerous tumor types. However, there are still a significant 
number of patients that do not respond to single-agent checkpoint inhibition possibly due to other 
immunosuppressive mechanisms present in the tumor microenvironment. This presence of 
immunosuppressive cell types such as Tregs and MDSCs in the tumor microenvironment actively 
dampen the anti-tumor response.  
Daratumumab a human immunoglobulin G1 (IgG1) monoclonal antibody that targets CD38 has 
shown promising anti-myeloma activity in 2 clinical studies (GEN501 and SIRIUS) in patients 
with relapsed and refractory MM. Responding patients also demonstrated increased T-cell 
responses to viral- and alloantigens, suggesting a revival of anti-tumor immune response from an 
immune suppressive state.165 The fact that CD38 is expressed on Treg and suppressive cells of 
myeloid lineage, plus the observed immune stimulatory activity of daratumumab in the clinic, 
suggest that daratumumab may exhibit immune-stimulatory activities by targeting CD38+ Treg. 
Data mining of TCGA data indicates that CD38 mRNA expression is present in tumor biopsies 
from SCCHN subjects and these biopsies have also shown to have all Treg gene based signature. 
This supports the hypothesis of targeting CD38+ Treg populations in SCCHN to reverse 
immunosuppression and up regulate anti-tumor immunity. Such immunity will be further 
enhanced through the combination treatment with nivolumab, by co-targeting CD38+ Treg and 
PD-1 immune checkpoint. This immuno-modulatory role of daratumumab for reversing the 
immunosuppressive tumor microenvironment has prompted a clinical evaluation of the 
combination of daratumumab with the immune checkpoint inhibitor, nivolumab in patient with 
HPV positive, negative or unknown SCCHN.
1.1.14
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Daratumumab
Per Revised Protocol 06, enrollment and treatment in this cohort have been terminated. For the 
nivolumab/daratumumab combination cohort, nivolumab will be administered at 240 mg Q2W, an 
approved nivolumab dosing regimen for NSCLC and RCC indications. Daratumumab will be 
administered at 16 mg/kg QW from Week 1 to 8, Q2W from Week 9 to 24, and Q4W from Week 
25 and for a maximum of 24 months, or until disease progression, unacceptable toxicity, or 
Revised Protocol No.: 07
Date: 07-May-2019
51
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
withdrawal of consent, whichever comes first. As nivolumab 480 mg Q4W dosing regimen would 
produce similar exposures to that of 240 mg Q2W dosing regimen based on PPK modeling and 
simulation, nivolumab will be administered at 480 mg Q4W starting from Week 25 for the 
convenience to patients.
Dosing of daratumumab in subjects with multiple myeloma is recommended at 16 mg/kg (weekly 
for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter) administered via IV 
until disease progression or unacceptable toxicity. The dose selection was based on an acceptable 
safety profile, maximal clinical activity, and pharmacokinetics consistent with saturation of the 
target. The data supporting the selection of a 16 mg/kg dose for the treatment of multiple myeloma 
are as follows:
•
Safety: Clinical safety data demonstrated that daratumumab is well-tolerated, with 
clinically manageable side effects, highlighted by the fact that no subject treated with 
16 mg/kg daratumumab monotherapy discontinued treatment as a result of a 
daratumumab related adverse event.
−
For doses above 4 mg/kg, there was no dose dependent toxicity pattern observed.
•
Clinical efficacy: Clinical response data derived from Study GEN501 and Study 
MMY2002 show robust activity among subjects treated at 16 mg/kg with ORRs of 
36% and 29%, respectively.
−
The response rates were consistently and significantly higher and deeper at the 16 mg/kg dose 
level as compared to various schedules at the 8 mg/kg dose level.
•
Pharmacokinetics: Daratumumab exhibits target-mediated drug disposition. 
Daratumumab binds to CD38 receptors in the body and the complex with 
daratumumab is rapidly cleared. As the dose is increased or after repeated 
administration, CD38 becomes saturated, and the impact of target binding clearance is 
minimized and PK data can indicate target saturation.
−
Population pharmacokinetic and exposure-response analyses suggested that 16 mg/kg is the 
lowest tested dose at which the majority (approximately 80%) of subjects achieved serum 
concentrations above the model-predicted 99% target saturation threshold and 90% of the 
maximum effect on ORR threshold.
−
Lowering the dose would likely result in reduced efficacy, whereas increasing the dose may 
not provide further improvement of the benefit-risk profile.
−
The initial weekly dosing schedule rapidly established efficacious concentrations. The every 2 
week and every 4 week dosing frequencies were sufficient to produce serum concentration 
levels that maintained target saturation; thus reducing the risk of disease progression.
Daratumumab is associated with high infusion-related reactions requiring treatment with steroid. 
In GEN501 study, a phase 1/2 study of daratumumab in relapsed/refractory MM subjects, infusion-
related reactions were the most frequent adverse events, occurred in 71% of patients. The majority 
of these reactions included grade 1 and 2, and characterized by rhinitis, cough, headache, pyrexia, 
and dyspnea. Most infusion-related reactions occurred during the first daratumumab infusion and 
only few patients (<10%) had infusion-related reactions with more than one infusion. The SIRIUS 
(MMY2002) study confirmed the results from GEN501 study that demonstrated single agent 
Revised Protocol No.: 07
Date: 07-May-2019
52
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
activity of daratumumab with a favorable toxicity profile.157,158 Among one hundred six patients 
who had a median of 5 prior lines of therapy (95% refractory to lenalidomide and bortezomib) and 
received daratumumab monotherapy at a dose of 16 mg/kg, 43% of the patients experience 
infusion-related reactions, which were predominantly grade 1 and 2, and could be managed with 
interruption of the infusion or extra corticosteroids and antihistamines. Therefore, to mitigate the 
increased risk of infusion-related reactions for nivolumab/daratumumab combination cohort, 
nivolumab 240 mg Q2W administration will start with the third daratumumab infusion and 
corticosteroids will be administered before and after treatment. 
Historically, clinical trials with nivolumab have prohibited the use of high dose steroids before and 
during the study due to the potential interference with the immune activation mechanism of 
checkpoint inhibition. Specifically, in the nivolumab registrational trials, patients requiring 
treatment with systemic corticosteroids (greater than 10 mg daily prednisone equivalents) within 
14 days of study drug administration were excluded. However, there have been exceptions to 
eligibility criteria for certain subjects which have not appeared to impact the efficacy of the therapy 
including prophylactic high dose steroids for contrast dye allergy and non-autoimmune conditions 
such as delayed-type hypersensitivity reaction. Furthermore, high dose systemic corticosteroids 
and other immunosuppressants are commonly used to treat immune-related adverse reactions. This 
concomitant steroid use to manage immune related AEs does not appear to impair the efficacy of 
nivolumab and these conclusions have been shared with the regulatory authorities. Pre-treatment 
with steroids has also been allowed in nivolumab trials where corticosteroids are part of standard 
of care. High doses of dexamethasone have been administered with nivolumab therapy for patients 
with hematological malignancies where both lenalidomide and bortezomib require administration 
with standard doses of dexamethasone. In 1L NSCLC studies with nivolumab and pembrolizumab, 
steroid pre-medication is mandated with some chemotherapies and this has not appeared to impact 
overall response rates (reference KN-021 study, CM 012 CSR). In GBM studies, corticosteroid 
treatment for symptomatic brain lesions is considered standard of care and therefore allowed in 
these trials. Furthermore, the inclusion of steroid treatment in the clinical trials with daratumumab 
did not impact the pharmacodynamic effect of expansion of activated T cells that was observed, 
suggesting that T cell activation and expansion still occurs in the presence of systemic steroid 
treatment. Taken together, the low likelihood that steroid premedication would compromised 
safety with, and the evidence that efficacy is not impacted by steroid premedication, support 
evaluation of nivolumab in combination with daratumumab given with appropriate steroid 
premedication.
Based on the well-established safety profiles of daratumumab and nivolumab, it is not anticipated 
that the combination treatment will result in overlapping toxicities. The clinical experience of the 
combination treatment is being investigated in patients enrolled in the CA209-039 study (Multiple 
Phase 1 Safety Cohorts of Nivolumab Monotherapy or Nivolumab Combination Regimens Across 
Relapsed/Refractory Hematologic Malignancies), that were treated with nivolumab and 
daratumumab at the doses that will be administered in this study. As of the database lock of 15-
May-2017, 7 patients have been dosed in CA209039: 3 in the nivolumab and daratumumab (ND)
arm and 4 in the nivolumab and daratumumab with pomalidomide (ND-Pd) arm. The first study 
Revised Protocol No.: 07
Date: 07-May-2019
53
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
drug dose was given on 30 Dec 2016; 2 subjects received 4 cycles of therapy, 1 subject received 
3 cycles of therapy, 2 subjects received 2 cycles of therapy, and 2 subjects received 1 cycle of 
therapy. One patient was discontinued from the study due to disease progression, after completing 
3 cycles of therapy. 
Related cytopenias were reported in the ND-Pd arm, which aligns with the expected safety profiles 
of daratumumab and pomalidomide and the underlying disease. The daratumumab and 
pomalidomide dosing was held for the Grade 3-4 neutropenia events, and treatment was resumed 
upon recovery to the protocol defined blood counts.  
There were 2 daratumumab related infusion related reactions, one in each treatment arm, which 
resolved and the full dose was administered in both cases (after the infusion was interrupted and 
appropriate medication was administered). 
Three related SAEs were reported. A Grade 4 blood bilirubin increase in the ND arm was 
reconsidered by the investigator as an unrelated event, indicative of disease progression. This SAE 
was revised after the database lock. The Grade 1 pneumonitis SAE in the ND arm was related to 
nivolumab, and resolved in 8 days after treatment was held, per the nivolumab management 
algorithm. The Grade 3 respiratory syncytial virus bronchitis in the ND-Pd arm was related to 
daratumumab and pomalidomide, and at the time of onset (C1D8) the patient had not started 
nivolumab dosing yet.
All safety data from the daratumumab/nivolumab cohort in the current study will be regularly 
monitored by the study physician, the protocol study team, and the BMS medical safety teams.
Starting from Week 25, subjects in the present study will be switched from nivolumab 240 mg 
Q2W to nivolumab 480 mg Q4W, which provides a more convenient dosing regimen for subjects. 
Based on PK modeling and simulations, nivolumab 480 mg Q4W is predicted to provide Cavgss 
similar to 240 mg Q2W. While 480 mg Q4W is predicted to provide greater (approximately 20%) 
maximum steady state concentrations and lower (approximately 10%) steady state trough 
concentrations, these exposures are predicted to be within the exposure ranges observed at doses 
up to 10 mg/kg Q2W used in the nivolumab clinical program, and are not considered to put subjects 
at increased risk. Similar to the nivolumab 240 mg Q2W dosing regimen, the exposures predicted 
following administration of nivolumab 480 mg Q4W, are on the flat part of the exposure-response 
curves for previously investigated tumors in melanoma and NSCLC, and are not predicted to affect 
efficacy. Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and 
safety profiles to nivolumab 240 mg Q2W. 
1.1.15
Duration of Treatment with Nivolumab Monotherapy or Combination 
Therapy
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 2-4 
months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. A recent analysis in a melanoma study suggests the majority of patients who discontinue 
Revised Protocol No.: 07
Date: 07-May-2019
54
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
treatment.166 Furthermore, a limited duration of ipilimumab, including only 4 induction doses, 
resulted in long term survival in patients with metastatic melanoma, with a sustained plateau in 
survival starting around 2 years after the start of treatment.167
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive >5 years and remained progression-free 
without any subsequent therapy (2) In the CA209003 NSCLC cohort, the overall survival (OS) 
curve begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.168
These survival outcomes are similar to phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2 year OS rates of 
23% and 29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC 
respectively).169
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a  maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, p = 0.00017) and pembrolizumab 
10 mg/kg (HR 0.60, p < 0.00001) compared to docetaxel, with an OS plateau developing beyond 
2 years in both pembrolizumab arms. Among 690 patients who received pembrolizumab, 47 
patients completed 2 years of pembrolizumab and stopped treatment. Most were able to maintain 
their response, including those with stable disease, with only 2 patients (4%) having confirmed 
progression after stopping at 2 years.170
Keynote-006 was a randomized phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.171
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 2 
years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
Revised Protocol No.: 07
Date: 07-May-2019
55
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note,  
the PFS curves in both groups plateau approximately 1 year after randomization (i.e., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.172
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
1.2
Research Hypothesis
Research Hypothesis (A): Nivolumab, in the neoadjuvant setting, will be safe and tolerable in 
subjects with select virus positive and virus-negative tumors.
Research Hypothesis (B): Treatment with nivolumab alone or in combination with either 
ipilimumab, BMS-986016 (relatlimab), or daratumumab will lead to clinically meaningful tumor 
reductions, as measured by objective response rate and duration of response, in subjects with 
metastatic or unresectable tumors.
1.3
Objectives(s)
1.3.1
Primary Objectives
•
In the neoadjuvant cohort, to investigate the safety and tolerability of neoadjuvant nivolumab 
administration in the following tumor types:
−
HPV-positive SCCHN
−
HPV-negative SCCHN
−
Merkel Cell Carcinoma 
−
Cervical, vaginal, or vulvar cancers
•
In the metastatic cohort (nivolumab monotherapy), to evaluate the investigator-assessed 
objective response rate (ORR) in subjects with the following diseases:
−
Metastatic or recurrent nasopharyngeal carcinoma (NPC) 
−
Metastatic or recurrent EBV related gastric cancer
−
Metastatic or recurrent Merkel Cell Carcinoma
−
Metastatic or recurrent cervical, vaginal, or vulvar cancers
−
Metastatic or recurrent HPV positive squamous cell cancer of the head and neck (SCCHN)
•
In the metastatic cohort combination therapy (nivolumab combined with either ipilimumab
[Combo A or B], or BMS-986016 (relatlimab) [Combo C]), to evaluate the investigator-
assessed objective response rate (ORR) in subjects with the following diseases:
−
Metastatic or recurrent nasopharyngeal carcinoma (NPC) 
−
Metastatic or recurrent Merkel Cell Carcinoma
−
Metastatic or recurrent cervical cancers
Revised Protocol No.: 07
Date: 07-May-2019
56
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
−
Metastatic or recurrent HPV positive squamous cell cancer of the head and neck (SCCHN) 
(with prior exposure to anti-PD-1; anti-PD-L1 or anti-CTLA-4 antibody therapy [Combination
C])
−
Other metastatic or recurrent anogenital HPV associated tumors (vulvar, vaginal, anal canal, 
penile)
•
In the metastatic cohort nivolumab combined with daratumumab (Combo D) to evaluate the 
investigator-assessed objective response rate (ORR) in subjects with:
−
Metastatic or recurrent HPV positive, negative, or unknown squamous cell cancer of the head 
and neck (SCCHN) (without prior I-O therapy exposure)
1.3.2
Secondary Objectives
•
Metastatic cohort (monotherapy and combination therapy): To evaluate the duration of 
response, progression-free survival and overall survival.
1.3.3
Exploratory Objective(s)
Neoadjuvant Cohort
•
To determine the percent change from baseline of select immune cells and the percent change 
from baseline of select immune activation/inhibitory molecules of viral-specific T cells in 
tumor specific subsets of nivolumab treated subjects
•
To evaluate the recurrence-free survival after neoadjuvant administration of nivolumab and 
surgery
•
To determine the percent change from baseline in tumor volume after two doses of 
neoadjuvant nivolumab.
•
To determine pathologic complete response of tumors in subjects who receive surgical 
resection after two doses of neoadjuvant nivolumab in SCCHN, resectable Merkel Cell 
Carcinoma, and cervical, vaginal, or vulvar cancer.
•
To evaluate changes in anti-viral and anti-tumor immune responses at the tumor site, using 
proliferative and/or functional assays.
•
To investigate the potential association between selected biomarker measures in peripheral 
blood and tumor tissue, including PD-L1, with safety and clinical efficacy measures. 
•
To investigate the pharmacodynamic activity of nivolumab in the peripheral blood and tumor 
tissue as measured by gene expression, flow cytometry, immunohistochemistry and soluble 
factor assays. 
•
To study the effect of nivolumab on the viral antigen specific T cell responsiveness in the 
peripheral blood. 
•
To evaluate the potential association between the number of tumor mutations and 
neoantigens with clinical efficacy measures and determine if tumor antigen-specific T cells 
are present in the periphery.
•
To assess the subject’s overall health status as assessed by the EQ-5D-3L questionnaire.
•
To evaluate cancer specific health related quality of life as assessed by EORTC QLQ-C30
questionnaire.
•
To characterize pharmacokinetics of nivolumab and explore exposure-response relationships.
•
To characterize the immunogenicity of nivolumab.
Revised Protocol No.: 07
Date: 07-May-2019
57
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
Metastatic Cohort (Monotherapy and Combination Therapy)
•
To determine the safety and tolerability [defined as toxicity rates (worst CTC grade per 
subject) of adverse events and specific laboratory tests] of nivolumab monotherapy and 
combination therapy (ipilimumab, daratumumab, or BMS-986016) in subjects with 
metastatic or recurrent viral-mediated tumors.
•
To evaluate the pre and post treatment EBV DNA levels in subjects with EBV positive 
gastric cancer (recurrent/metastatic monotherapy only) and nasopharyngeal carcinoma.44,45
•
To investigate the potential association between selected biomarker measures in peripheral 
blood and tumor tissue, including PD-L1, with safety and clinical efficacy measures. 
•
To investigate the pharmacodynamic activity of nivolumab monotherapy and combination 
therapy (ipilimumab, daratumumab, or BMS-986016) in the peripheral blood and tumor 
tissue as measured by gene expression, flow cytometry, immunohistochemistry and soluble 
factor assays. 
•
To study the effect of nivolumab monotherapy and combination therapy (ipilimumab, 
daratumumab, or BMS-986016) on the viral antigen specific T cell responsiveness in the 
peripheral blood. 
•
To evaluate the potential association between the number of tumor mutations and 
neoantigens with clinical efficacy measures and determine if tumor antigen-specific T cells 
are present in the periphery.
•
To assess the subject’s overall health status as assessed by the EQ-5D. 
•
To evaluate cancer specific health related quality of life as assessed by EORTC QLQ-C30.
•
To characterize pharmacokinetics of nivolumab monotherapy and combination therapy 
(ipilimumab, daratumumab, or BMS-986016,) and explore exposure-response relationships.
•
To characterize the immunogenicity of nivolumab monotherapy and combination therapy 
(ipilimumab, daratumumab, or BMS-986016).
1.4
Product Development Background
Information for nivolumab (BMS-936558, anti-PD-1 antibody), ipilimumab (YERVOY®; anti-
CTLA antibody), daratumumab (anti-CD38 antibody) and BMS-986016 (relatlimab, anti-LAG-3 
antibody) is provided in the sections below; additional details are provided in the respective 
Investigator Brochures.
1.4.1
Nivolumab
1.4.1.1
Summary of Nivolumab Clinical Activity in the Metastatic Setting
The PK, clinical activity, and safety of nivolumab have been assessed in approximately 70 clinical 
studies sponsored by BMS, Ono Pharmaceutical Co., Ltd. (ONO), or other partners.
Approximately 12,300 subjects have received nivolumab in single- or multiple-dose Phase 1/2/3 
studies or studies with nivolumab in combination with other therapeutics (ipilimumab, cytotoxic 
chemotherapy, anti-angiogenics, and targeted therapies). 
Nivolumab monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and previously 
treated advanced RCC; it is also approved for the treatment of cHL in the US. In addition, 
Revised Protocol No.: 07
Date: 07-May-2019
58
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
nivolumab has been approved for use in combination with ipilimumab for unresectable melanoma 
in multiple countries, including the US and EU.
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, 
classical Hodgkin’s lymphoma (cHL), small cell lung cancer (SCLC), gastric cancer, urothelial 
cancer, hepatocellular carcinoma, and colorectal cancer. In confirmatory trials, nivolumab as 
monotherapy demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with advanced or metastatic NSCLC, unresectable or metastatic 
melanoma, advanced RCC, or SCCHN. Nivolumab in combination with ipilimumab improved 
PFS and ORR over ipilimumab alone in subjects with unresectable or metastatic melanoma. 
Additional details on the efficacy profile of nivolumab, including results from clinical studies, are 
available in the nivolumab IB.
1.4.1.2
Summary of Nivolumab Safety in the Metastatic Setting
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date.
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, the 
safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and manageable using established safety guidelines. A pattern of immune-related adverse 
events has been defined, for which management algorithms have been developed; these are 
provided in Appendix 2. Most high-grade events were manageable with the use of corticosteroids 
or hormone replacement therapy (endocrinopathies) as instructed in these algorithms. For 
additional material, see the nivolumab Investigator Brochure.
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
1.4.2
Nivolumab Combined with Ipilimumab
1.4.2.1
Nivolumab and Ipilimumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. The 
immune surveillance functions by limiting the emergence of tumors as they arise and/or causing 
tumor shrinkage. Tumor progression may depend upon acquisition of traits that allow cancer cells 
to evade immune surveillance and an effective immune response. This evasion may occur by 
exploiting any of the checkpoints that control the regulatory immune response, including display 
of antigens and control of co-stimulatory pathways that affect the proliferation of cells involved in 
immunity. Current immunotherapy efforts attempt to break the apparent tolerance of the immune 
system to tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination 
or by modulating regulatory checkpoints of the immune system, either directly by stimulation of 
Revised Protocol No.: 07
Date: 07-May-2019
59
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
immune cells by antibodies directed to receptors on T and B cells or indirectly by cytokine 
manipulation. T-cell stimulation is a complex process involving the integration of numerous 
positive, as well as negative, co-stimulatory signals in addition to antigen recognition by the T-
cell receptor (TCR). Collectively, these signals govern the balance between T-cell activation and 
tolerance to antigens.
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a member 
of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, CTLA-4, ICOS, 
and BTLA.2 PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine 
inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif 
(ITSM). Two ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 
(B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon 
binding to PD-1 in both murine and human systems. PD-1 delivers a negative signal by the 
recruitment of SHP-2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic region. 
PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells. Further evidence for 
a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. PD-1-deficient 
mice develop various autoimmune phenotypes, including dilated cardiomyopathy, a lupus-like 
syndrome with arthritis and nephritis, and accelerated diabetes mellitus. The emergence of these 
autoimmune phenotypes is dependent upon the genetic background of the mouse strain and many 
of these phenotypes emerge at different times and show variable penetrance. In addition to the 
phenotypes of null mutations, PD-1 inhibition by antibody-mediated blockade in several murine 
models has been found to play a role in the development of autoimmune diseases such as 
encephalomyelitis, graft-versus-host disease, and type I diabetes. Taken together, these results 
suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but these 
responses are variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or 
inhibition is not accompanied by a universal loss of tolerance to self-antigens.
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. Antitumor 
activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors that are 
negative for the expression of PD-L1. This suggests that host mechanisms (ie, expression of PD-
L1 in antigen-presenting cells) limit the antitumor response. Consequently, both PD-L1 positive 
and negative tumors may be targeted using this approach. In humans, constitutive PD-L1 
expression is normally limited to macrophage-lineage cells, although expression of PD-L1 can be 
induced on other hematologic cells as well, including activated T cells. However, aberrant 
expression of PD-L1 by tumor cells has been reported in a number of human malignancies. PD-L1 
expressed by tumor cells has been shown to enhance apoptosis of activated tumor-specific T cells 
in vitro. Moreover, the expression of PD-L1 may protect the tumor cells from the induction of 
apoptosis by effector T cells.
Nivolumab (BMS-936558; anti-PD-1 mAb) is a fully human monoclonal immunoglobulin (Ig)G4 
antibody that binds to the programmed death-1 (PD-1) cell surface membrane receptor, a negative 
regulatory molecule expressed by activated T and B lymphocytes. Blockade of the PD-1pathway 
by nivolumab was studied using the mixed lymphocyte reaction (MLR). PD-1 blockade resulted 
Revised Protocol No.: 07
Date: 07-May-2019
60
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
in a reproducible enhancement of both proliferation and interferon release in the MLR. The effect 
of nivolumab on antigen-specific recall response was investigated using a CMV-restimulation 
assay with human peripheral blood mononuclear cells (PBMCs), and was evaluated by ELISA.
Ipilimumab is a fully humanized IgG1 monoclonal antibody binding to the anti-cytotoxic T-cell
lymphoma-4 antigen (CTLA-4). Ipilimumab is an approved therapy for metastatic melanoma and 
has demonstrated improved overall survival as monotherapy and in combination with
dacarbazine.131,173 It has been studied in combination with multiple standards of care (SOC)
therapies including chemotherapy for squamous and non-squamous NSCLC and radiotherapy for 
hormone resistant prostate cancer.126 Phase III studies are ongoing in NSCLC, SCLC, and prostate
carcinoma.
1.4.2.2
Summary of Nivolumab plus Ipilimumab Safety Data
Several doses of nivolumab and ipilimumab are currently being explored in ongoing clinical trials. 
Although the optimal doses have not yet been defined across multiple tumor types, the largest 
studies to date have been done in melanoma at a dose of nivolumab 1 mg/kg combined with 
ipilimumab 3 mg/kg administered IV every 3 weeks for 4 doses followed by nivolumab 3 mg/kg 
IV every 2 weeks. These studies include subjects with previously untreated unresectable or 
metastatic melanoma in CA209067 (313 subjects) and CA209069 (94 subjects) (a total of 
407 subjects). Based on the pooled analyses, nivolumab 1 mg/kg combined with ipilimumab 
3 mg/kg administered IV every 3 weeks for 4 doses followed by nivolumab 3 mg/kg IV every 
2 weeks has an acceptable safety profile, as demonstrated by the frequency, severity, and types of 
AEs, drug-related deaths, SAEs, and AEs leading to discontinuation as described below. 
Additional details on safety and clinical activity of nivolumab plus ipilimumab combinations are 
described in the IB.131
The following were the key safety findings for these pooled subjects:
•
The most frequently reported drug-related AEs of any grade (≥15% of subjects) were 
diarrhea (43.0%), fatigue (35.4%), pruritus (33.4%), rash (31.0%), nausea (24.8%), pyrexia 
(18.7%), ALT increased (18.2%), AST increased (16.7%) and decreased appetite (16.2%). 
The most frequently reported drug-related Grade 3 - 4 AEs (≥5% of subjects) were colitis 
(9.6%), diarrhea (8.80%), ALT increased (8.4%), lipase increased (8.4%), and AST increased 
(5.9%).
•
The majority of drug-related SAEs were Grade 3 - 4 in severity. The most frequently 
reported drug-related SAEs of any grade (≥2% of subjects) were colitis (11.1%), diarrhea 
(8.8%), pyrexia (3.7%), pneumonitis (2.7%), hypophysitis (2.2%), transaminases increased 
(2.2%), and adrenal insufficiency (2.0%). The majority of drug-related SAEs were 
Grade 3 - 4. The most frequently reported drug-related Grade 3 - 4 SAEs (≥2% of subjects) 
were colitis (8.8%), diarrhea (5.7%), and transaminases increased (2.2%).
•
Drug-related AEs leading to discontinuation occurred in 36.4% of subjects. The majority of 
drug-related AEs leading to discontinuation of study drug were Grade 3 - 4 in severity. The 
most frequently reported drug-related AEs of any grade leading to discontinuation of study 
drug (≥2% of subjects) were colitis (10.1%), diarrhea (7.4%), ALT increased (4.7%), and 
Revised Protocol No.: 07
Date: 07-May-2019
61
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
AST increased (4.2%). These were also the most frequently reported drug-related Grade 3 - 4 
SAEs leading to discontinuation of study drug (≥2% of subjects).
•
The most frequently reported drug-related select AE categories with nivolumab + ipilimumab 
combination therapy were skin (61.9%), GI (46.4%), endocrine (29.7%), and hepatic 
(29.0%). The majority of select AEs were considered by the investigators to be related to 
study treatment.
•
Drug-related select AEs were mostly Grade 1 - 2 in all categories with the exception of 
hepatic select AEs where the majority were Grade 3 - 4.
•
Across categories, the majority of high-grade events subsequently resolved, including those 
for which immunosuppressive medication was not initiated.
•
The majority of deaths (80/105) were due to disease progression. Study drug toxicity was 
considered responsible for 2 deaths; 1 subject died of ventricular arrhythmia within 30 days 
of the last dose and the other died of pneumonitis between 31 and 100 days of the last dose.
•
Abnormalities in select hematology assessments and liver/kidney function tests were 
primarily Grade 1 - 2 in severity.
•
The immunogenicity of nivolumab was low and not clinically meaningful. 
In general, the frequency of adverse events was lowest across AE categories in the nivolumab 
monotherapy group and highest in the nivolumab + ipilimumab group. However, the types and 
frequency of AEs reported in the nivolumab + ipilimumab group were as expected based on the 
mechanism of action of the two agents and were consistent with previously reported data. 
Additional toxicity, including a higher frequency of Grade 3 - 4 AEs, was observed in the 
nivolumab+ipilimumab group relative to the ipilimumab group, leading to a higher frequency of 
discontinuation from study treatment. The most frequently reported select AE categories were 
skin, GI, endocrine, and hepatic. Select AEs belonging to these categories were reported more 
frequently in the nivolumab+ipilimumab group than the ipilimumab group. The majority of events 
were manageable. In summary, results to date suggest that the safety profile of 
nivolumab+ipilimumab combination therapy is consistent with the mechanisms of action of 
nivolumab and ipilimumab. The nature of the AEs is similar to that observed with either agent 
used as monotherapy; however, both frequency and severity of most AEs are increased with the 
combination.174
1.4.3
Nivolumab Combined with BMS-986016
1.4.3.1
Nonclinical Pharmacology Studies Utilizing Murine Anti-PD-1 and
Anti-LAG-3 Antibodies
The importance of LAG-3 as an immunotherapy target was validated in murine in vivo models 
using 2 surrogate antibodies specific for mouse LAG-3. These studies evaluated tumor growth 
inhibition in syngeneic tumor models (Sa1N fibrosarcoma and MC38 colon adenocarcinoma) and 
monitored acceleration of autoimmunity in the non-obese diabetic (NOD) model. Anti-LAG-3 
antibody administration resulted in both overall tumor growth inhibition and an increase in the 
number of tumor-free (TF) mice in those treatment groups (Figure 1.4.3.1-1).
Revised Protocol No.: 07
Date: 07-May-2019
62
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Anti-LAG-3 antibody administered in combination with anti-PD-1 antibody provided enhanced 
antitumor activity above the activity of either agent alone. For example, in multiple Sa1N tumor 
models, anti-LAG-3 antibody resulted in 20%-30% TF mice compared to control and 
anti−PD-1 antibody-treated mice (0%−10% TF mice), while the combination of anti−LAG-3 and 
anti−PD-1 antibodies resulted in 60%−90% TF mice. In the MC38 model, anti−LAG-3 antibody 
showed modest tumor growth inhibition alone but when administered in combination with 
anti-PD-1 antibody, resulted in enhanced antitumor activity above that observed for anti-PD-1 
antibody alone (80% vs. 40% TF mice, respectively).
Figure 1.4.3.1-1:
Antitumor Activity of Anti-LAG-3 and Anti-PD-1 Antibodies in 
Murine Models
1.4.3.2
Nonclinical Toxicology
The nonclinical toxicology package for relatlimab consists of the following studies:
•
Four-Week Intermittent (QW) Intravenous Exploratory Combination Pharmacodynamic and 
Toxicity Study in Cynomolgus Monkeys with Anti-LAG3.1 Antibody (a precursor of the anti-
LAG3.5 antibody) and Nivolumab.
•
GLP-Compliant Four-Week Intravenous Combination Toxicity Study in Cynomolgus 
Monkeys with a 6-Week Recovery with BMS-986016 and Nivolumab.
The key results were as follows:
−
Single-agent BMS-986016 administered at up to 100 mg/kg/week did not result in adverse 
changes.
−
Combined administration of BMS-986016 and nivolumab (100 and 50 mg/kg/week, 
respectively) resulted in moribundity of 1 male out of 9 monkeys on study Day 29. From 
Days 26 to 29, this monkey presented with elevated body temperature, shivers, red or clear 
nasal discharge, fecal changes (unformed, scant or absent feces), decreased feeding 
Revised Protocol No.: 07
Date: 07-May-2019
63
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
behavior, mild dehydration, sneezing, decreased activity, and hunched posture. After 2 
days of veterinary care and antibiotic treatment, this animal did not show any 
improvement and was euthanized on Day 29 for poor clinical condition. There were no 
remarkable gross necropsy findings. Histopathological findings in this monkey included: 
slight lymphoplasmacytic inflammation of the choroid plexus; minimal to moderate 
lymphohistocytic inflammation of the vasculature of the brain parenchyma, meninges, 
spinal cord (cervical and lumbar); and minimal to moderate mixed cell inflammation of 
the epididymes, seminal vesicles and testes. Clinical pathology changes indicated 
decreases in red blood cell count, hemoglobin concentration and hematocrit whose cause 
was unclear, and an increase in fibrinogen correlating with the inflammation observed in 
the central nervous system (CNS) and male reproductive tract.
−
Additional histopathological findings upon combination administration of BMS-986016 
and nivolumab (100 and 50 mg/kg/week, respectively) were limited to minimal to slight 
non-reversible lymphoplasmacytic inflammation of the choroid plexus in the brain in 7 of 
8 remaining monkeys, and minimal lymphohistiocytic inflammation of the vasculature of 
the brain parenchyma in 1 of 8 remaining monkeys, whose reversibility could not be 
assessed.
−
NOAEL for single-agent BMS-986016 was considered to be 100 mg/kg/week (mean 
AUC[0-168h] = 474,000 μg•h/mL); NOAEL for single-agent nivolumab was considered 
to be 50 mg/kg/week (mean AUC[0-168h] = 193,000 μg•h/mL); NOAEL for combination 
of BMS-986016 and nivolumab was not determined.
−
However, the combination therapy was generally well tolerated and clinical signs of 
toxicity were observed in only 1 of 9 monkeys (approximately 10%). Therefore, 100/50 
mg/kg/week 
BMS-986016/nivolumab 
(mean 
BMS-986016 
AUC[0-168h] 
= 
514,000 μg•h/mL; mean nivolumab AUC[0-168h] = 182,000 μg•h/mL) was considered 
the STD10.
−
The doses administered (100 mg/kg BMS-986016 and 50 mg/kg nivolumab) are ≥ 10 
times higher than the maximum doses proposed for the current study.
•
GLP-Compliant Tissue Cross Reactivity Study in Human and Select Cynomolgus Monkey 
Tissues with BMS-986016.
−
Positive staining with BMS-986016-FITC was observed in the plasma membrane or
plasma membrane granules of mononuclear leukocytes of most human tissues, including
lymphoid tissues and hematopoetic cells of the bone marrow. In addition, staining with
BMS-986016-FITC was observed in the cytoplasm of the human pituitary endocrine cell
epithelium. Although BMS-986016 is not expected to have access to the cytoplasmic
compartment in vivo and the repeat-dose toxicology studies in monkeys showed no effects 
on the pituitary gland, these findings may be of clinical significance and will be monitored.
−
In Vitro Cytokine Release and Lymphocyte Activation Assessment with BMS-986016
using Human Peripheral Blood Mononuclear Cells.
−
BMS-986016 did not induce cytokine release when presented to human PBMCs
regardless of concentration, donor, or incubation time. The levels of cytokines observed
were either at or near the assay lower limits of quantification with no evidence of dose-
dependence or pattern across donors (IL-1β, IL-2, IL-5, IL-10, IL-12p70, and IFN-γ) or 
were generally overlapping with cytokine levels from PBMCs incubated with negative 
controls (IL-6, IL-8, TNF-α).
Revised Protocol No.: 07
Date: 07-May-2019
64
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
−
Consistent with the lack of cytokine release, there was no evidence that BMS-986016 
induced T or NK cell activation, as measured by surface expression of CD25 and CD69. 
Expression levels of these markers on T and NK cells following stimulation with BMS-
986016 were similar to those observed upon stimulation with negative controls.
−
Overall, these data indicate that BMS-986016 does not possess agonistic potential to
induce either T or NK cellular activation or cytokine release.
1.4.3.3
Nonclinical Pharmacokinetics
Relatlimab demonstrated favorable PK properties in cynomolgus monkeys. From both single-dose 
and repeat-dose IV PK studies, relatlimab decayed bi-exponentially and the exposure was 
approximately dose-proportional. The systemic clearance (CLTp) ranges from 0.12 to 0.22 
mL/h/kg and a terminal half-life (T-HALF) 133 to 414 hours. Co-administration with nivolumab 
did not appear to affect exposure to relatlimab. The volume of distribution at steady state (Vss) 
was 62 to 72 mL/kg, suggesting limited distribution outside the plasma. Anti-BMS-986016 
antibodies were detected in some monkeys but the presence of anti-BMS-986016 antibodies 
appeared to have no impact on BMS-986016 exposure.
1.4.3.4
Clinical Pharmacology
The current Phase 1 clinical program is evaluating advanced solid tumors (special focus in non-
small cell lung cancer [NSCLC], renal cell carcinoma, and malignant melanoma) in Study CA224-
020 and relapsed refractory hematological malignancies (Hodgkin and non-Hodgkin lymphomas) 
in Study CA224-022. As of 29-Jun-2016, 89 subjects have been treated with relatlimab in these 2 
ongoing studies assessing PK, clinical activity, and safety. An interim determination of relatlimab
multiple dose PK was carried out using all available serum concentrations data from Studies 
CA224 020 and CA224 022. In general, the Cmax and area under the concentration versus time 
curve over the dosing interval (AUC[TAU]) values over the first dosing interval increased 
approximately equal to the increment in the relatlimab dose. The PK of BMS 986016 and 
nivolumab was not altered when given in combination. Relatlimab concentration time data were 
reasonably described by population PK model with linear, 2 compartment, zero-order IV infusion 
model with first order elimination. The model estimated mean T-HALF was 19 days, and the 
typical CLT was 13.7 mL/h. The population PK model will be used to understand the source of 
variability in relatlimab PK and effect of intrinsic and extrinsic factors.
Currently available data suggest that relatlimab monotherapy exhibits a low level of 
immunogenicity, with 6 out of 42 subjects having at least 1 post-baseline positive anti-drug 
antibody (ADA) samples. There are limited data available in combination cohort to make inference 
on immunogenicity rate.
1.4.3.5
Clinical Safety Combination Therapy (Nivolumab plus Relatlimab)
For details on clinical safety, see Section 1.1.11 and the BMS-986016 IB.
Revised Protocol No.: 07
Date: 07-May-2019
65
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1.4.4
Daratumumab
1.4.4.1
Summary of Daratumumab Clinical Pharmacology
Daratumumab is a first-in-class immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody 
(mAb) that specifically binds to the CD38 protein expressed on the surface of multiple myeloma 
tumor cells and other cell types at various levels. In vitro, daratumumab can induce tumor cell lysis 
through complement dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and 
antibody-dependent cellular phagocytosis in malignancies expressing CD38. 
The population pharmacokinetic (PK) analysis included patients with multiple myeloma who 
received daratumumab. Over the dose range from 1 to 24 mg/kg, AUC increases more than dose-
proportionally. Clearance decreases with increasing dose and repeated dosing, indicating target-
mediated pharmacokinetics. Following the recommended dose and schedule, the Cmax at the end 
of weekly dosing is 2.9-fold higher than following the first infusion. Daratumumab steady state is 
achieved approximately 5 months into the every 4-week dosing period and the Cmax at steady-
state to Cmax after the first dose is 1.6. The mean (SD) linear clearance and mean (SD) central 
volume of distribution are estimated to be 171.4 (95.3) mL/day and 4.7 (1.3) L, respectively. The 
mean (SD) estimated terminal half-life associated with linear clearance is approximately 18 (9) 
days. Population PK analyses indicated that the central volume of distribution and clearance of 
daratumumab increase with increasing body weight, supporting the body weight-based dosing 
regimen. Population PK analyses also show that age (31-84 years), gender, mild to severe renal 
impairment (15 to 89 mL/min) and mild hepatic impairment do not have clinically important 
effects on the pharmacokinetics of daratumumab. 
Exposure-response analyses for efficacy and safety were conducted using data from trials GEN501 
and MMY2002. The exposure-efficacy analysis shows that ORR increases with increasing 
daratumumab concentration, with a plateau achieved at daratumumab maximal pre-infusion 
concentrations (Cpre-infusion, max) ≥ 270 μg/mL. Furthermore, the median progression free 
survival (PFS) appears shorter in patients with daratumumab Cpre-infusion,max < 270 μg/mL (1.9 
month) and longer (6.6 months) in those with daratumumab concentrations > 270 μg/mL. 
However, this analysis was confounded by baseline risk factors such as disease severity. There 
was no exposure-safety relationship for infusion related reactions (IRR), thrombocytopenia, 
anemia, neutropenia and lymphopenia within the exposure range from 0.1 to 24 mg/kg studied in 
trials MMY2002 and GEN501.
1.4.4.2
Summary of Daratumumab Clinical Activity
Based on the preclinical activity of daratumumab, a phase 1/2 study was initiated in MM patients 
with relapsed/refractory disease (GEN501 study).157 In the first-in-human dose-escalation part of 
the study the maximum-tolerated dose was not reached with dose levels up to 24 mg/kg. In the 
phase 2 part of the study, patients with a median of 4 prior lines of therapy (majority refractory to 
lenalidomide and bortezomib) were treated with daratumumab at a dose of 8 mg/kg or 16 mg/kg. 
The overall response rate (at least PR) was 36% in the 16 mg/kg cohort and 10% in the 8 mg/kg 
group. Remarkably, in this extensively pretreated group of patients, 2 out of 42 patients treated 
with 16 mg/kg daratumumab achieved a first complete response. The median PFS in the 8 mg/kg 
Revised Protocol No.: 07
Date: 07-May-2019
66
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
and 16 mg/kg groups were 2.4 and 5.6 months, respectively. The 12-month survival was 77% for 
both groups. The most frequent adverse events were infusion-related reactions, which occurred in 
71% of patients. The majority of these reactions included grade 1 and 2, and characterized by 
rhinitis, cough, headache, pyrexia, and dyspnea. Most infusion-related reactions occurred during 
the first daratumumab infusion and only few patients (<10%) had infusion-related reactions with 
more than one infusion. 
The SIRIUS (MMY2002) study confirmed the results from GEN501 study that demonstrated 
single agent activity of daratumumab with a favorable toxicity profile.158 One hundred six patients, 
with a median of 5 prior lines of therapy (95% refractory to lenalidomide and bortezomib), 
received daratumumab monotherapy at a dose of 16 mg/kg. At least a PR was achieved in 29% of 
patients with stringent CR in 3%. The median duration of response was 7.4 months. The median 
progression-free survival was 3.7 months and 1-year overall survival was 65%. Notably, subgroup 
analysis showed that in the group of patients who were refractory to lenalidomide, pomalidomide, 
bortezomib and carfilzomib, PR or better was achieved in 21% of these patients. Infusion-related 
reactions were observed in 43% of the patients and were predominantly grade 1 and 2, and could 
be managed with interruption of the infusion or extra corticosteroids and antihistamines. In 
conclusion, results from these studies show that daratumumab is well tolerated and that in the 16 
mg/kg cohort at least a partial response can be achieved in 29-36% of the patients.157,175,176
Virtually all patients with PR or CR, achieved 50% reduction in tumor load within 3 months after 
start of therapy. 
Based on preclinical evidence showing potential benefit of combining daratumumab with 
lenalidomide.177,178,179 another phase 1/2 study is currently evaluating the combination of 
daratumumab plus lenalidomide and dexamethasone in relapsed/refractory MM (GEN503; 
NCT01615029). Preliminary safety data show a manageable toxicity profile and high efficacy of 
this three-drug regimen.180,181
Daratumumab has also been shown to be safe, tolerable and efficacious when combined with other 
immunomodulatory agents in two separate Phase 3 trials combining daratumumab with 1) 
lenalidomide and dexamethasone (POLLUX) and pomalidomide and dexamethasone (CASTOR). 
In the POLLUX trial, lenalidomide-dexamethasone was combined with or without daratumumab 
in patients with relapsed/refractory myeloma with 1-3 previous lines of therapy (patients with 
lenalidomide-refractory disease were excluded).182 In this study the daratumumab treated patients 
had a significantly higher CR rate and an unprecedented improvement in the PFS (HR: 0.37). 
There was no additional toxicity when daratumumab was added to lenalidomide-dexamethasone, 
except for infusion-related reactions, which occurred in approximately half of the patients mostly 
during the first infusion. Another phase 3 trial compared bortezomib-dexamethasone with or 
without daratumumab (CASTOR).183 Also in this study there was a significant improvement in 
CR rate, leading to a significant improvement of the PFS (HR: 0.39). Also in the CASTOR study 
daratumumab did not add toxicity to bortezomib-dexamethasone, except for infusion-related 
reactions occurring in approximately half of the patients, mostly during the first infusion of 
daratumumab.
Revised Protocol No.: 07
Date: 07-May-2019
67
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1.5
Overall Risk/Benefit Assessment
There is a significant unmet medical need for subjects with virus positive tumors including 
nasopharyngeal carcinoma, gastric, Merkel cell carcinoma, cervical/vulvar/vaginal/anal 
canal/penile, or SCCHN as outlined in Section 1.1. Virus positive tumors may have distinct 
patterns of immune responses and tumor immune microenvironments (Section 1.1.4); therefore, a 
strong rationale exists to support blocking the PD-1 signaling pathway with the goal of improving 
patient outcomes in the metastatic/recurrent settings. In the metastatic setting, subjects with virus-
positive tumors generally have limited treatment options with high mortality rates, and NCCN 
guidelines recommend clinical trials as an option for each of the tumor types in this trial.
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure, and 
will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 2. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
The combination of nivolumab plus relatlimab has the potential for increased benefit compared 
to monotherapy targeting the PD-1 pathway, ie, nivolumab monotherapy. In the nonclinical GLP 
toxicology study, lymphoplasmacytic infiltration in the choroid plexus (and spinal cord) was 
reported at the highest doses of anti-PD-1 antibody (3/6 animals) and the anti-LAG-3 + anti-PD-1 
antibody combination (5/6). Importantly, these findings were not reported with anti-LAG-3 
antibody alone either the 30 mg/kg or 100 mg/kg (highest dose).
These are nonspecific histopathology changes, without clinical manifestations in all but one of the 
animals treated with combination therapy, which have been observed in other studies with 
antibodies and small molecules in monkeys. Three subjects have experienced treatment related 
and immune mediated aseptic meningitis that have responded to immunosuppressive therapy. 
Vigilance regarding the communication and evaluation of potential neurologic toxicity remains an 
ongoing priority.
Therapy with relatlimab and nivolumab is investigational and it is possible that a higher incidence 
of immune mediated-adverse events may occur with the combination of 2 antibodies targeting T 
cells. The immune-related grade 5 myocarditis event prompted closer monitoring of subjects with 
ECGs and troponins, as well as tighter eligibility criteria regarding baseline ejection fraction and 
history of cardiovascular disease. Unanticipated side effects events may also occur, like the Grade 
Revised Protocol No.: 07
Date: 07-May-2019
68
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
4 VF that was also reported in combination therapy, Part B. There were several confounding 
factors in this case but, in the absence of a clear etiology, the event was considered treatment-
related. In the setting of troponin surveillance three cases of grade 1 myocarditis have been 
documented and managed without progression to subsequent cardiac dysfunction. Adverse events 
and SAEs will continue to be reviewed expeditiously by the Medical Monitor, investigators and 
the Pharmacovigilance group to monitor safety. With 243 subjects treated with combination 
therapy as of the clinical cut-off date, the overall safety profile of relatlimab + nivolumab currently 
appears similar to nivolumab monotherapy.
The potential direct benefit to subjects who participate in the CA224020 study is that both single-
agent and combined therapy with these investigational agents may result in a greater proportion of 
subjects with stabilization of disease, objective response, or increased duration of response than 
those observed with nivolumab monotherapy. It is also possible that combination therapy may 
reverse LAG-3-mediated T cell exhaustion and achieve responses in 1) tumor types known to be 
unresponsive to nivolumab; 2) tumors refractory to anti-CTLA4 and anti PD-1 or anti PD L1 
antibody therapy; and/or 3) virally-associated tumors. In fact, multiple RECIST1.1 defined partial 
responses have been observed with relatlimab monotherapy and in combination with nivolumab, 
both in the immunotherapy naive, as well as the anti-PD-1 resistant setting. More specifically, first 
disclosure of the initial efficacy at ASCO 2017 showed an ORR of 12.5% in advanced melanoma 
subjects that have progressed on prior anti-PD1/PDL1 with an even more encouraging ORR of 
20% in subjects with significant LAG-3 expression in tumor associated immune cells. Thus, the 
potential for direct benefit in subjects with few if any alternative treatment options has been 
initially demonstrated, warranting continued evaluation of the combination across tumor types 
while extending testing in the melanoma prior IO population.
Based on preliminary data as of the clinical cutoff date of 15-Jun-2017, the safety profile of 
relatlimab in combination with nivolumab is manageable, with no maximum tolerated dose (MTD) 
reached at the tested doses up to 160 mg relatlimab and 240 mg nivolumab (flat dose, every 2 
weeks [Q2W]), with evaluation of the 240 mg relatlimab/240 mg nivolumab combination dose-
level ongoing. At the time of the clinical cutoff date (15-Jun-2017) one dose-limiting toxicity 
(DLT) of Grade 5 myocarditis was observed at the 240 mg relatlimab/240 mg nivolumab 
combination dose level among five evaluable subjects. There was no dose relationship between 
the incidence, severity, or causality of adverse events (AEs) to combination therapy. In the nine 
expansion cohorts, a total of 262 subjects were treated with 80 mg relatlimab and 240 mg 
nivolumab Q2W. Most AEs were low grade (Grade 1 to Grade 2) with a total of 26 subjects 
experiencing a drug-related serious adverse event (SAE). All AEs, except for one Grade 5 
myocarditis and one Grade 4 drug-induced liver injury (DILI), were reversible and manageable by 
withholding study drug administration providing standard medical care, and/or following immune-
related AE algorithms. In summary the safety profile of the combination of relatlimab and 
nivolumab appears similar to nivolumab monotherapy in terms of both frequency and severity of 
AEs.
A pattern of immune-related adverse events has been defined for treatment with nivolumab 
monotherapy and nivolumab in combination with other immune-targeting agents such as 
Revised Protocol No.: 07
Date: 07-May-2019
69
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
relatlimab. Management algorithms have been developed for these events and are provided in 
Appendix 2. Most high-grade events are manageable with the use of corticosteroids or hormone 
replacement therapy (endocrinopathies) as instructed in these algorithms.
Myocarditis has been observed with nivolumab monotherapy treatment (see nivolumab IB Section 
5.6.2). Given the grade 5 myocarditis event in the CA224020 study, and the known nonclinical 
mouse double LAG-3/PD-1 knockout myocarditis phenotype, increased cardiac surveillance with 
troponin measurements were instituted. As of the clinical cutoff date of 15-Jun-2017 there have 
been four grade 1 myocarditis cases (asymptomatic troponin elevations with imaging correlate of 
myocardial inflammation but without evidence of cardiac dysfunction). Treatment was delayed in 
all cases, and precautionary steroid treatment was given without any of the participants developing 
evidence of cardiac dysfunction.
Additional safety measures for cardiovascular risks implemented for subjects receiving 
combination treatment with Combo C have been added to the protocol: 
•
Exclusion of subjects with history of myocarditis, regardless of etiology.
•
Exclusion Criteria under significant cardiac events: history of 2 or more myocardial infarctions 
(MIs) OR 2 or more coronary revascularization procedures.
•
Screening left ventricular ejection fraction (LVEF) assessment (if not performed in the last 6 
months) with documented LVEF ≥50% by either transthoracic echocardiogram or multiple 
gated acquisition scan (transthoracic echocardiogram being the preferred test) for subjects.
•
Increased emphasis in clinical monitoring of subjects for signs and symptoms of cardiovascular 
toxicities during training meetings and safety teleconferences.
•
Addition of pre-dose ECG testing.
•
Addition of troponin laboratory testing.
Daratumumab induces antimyeloma effects via multiple mechanisms of action. An additional 
mechanism of action has been proposed in which treatment with daratumumab eliminates a 
population of highly immunosuppressive CD38+ Tregs, T-cell MDSCs, and Bregs and thus 
stimulates T-cell effector functions.165 This immunomodulatory effects of daratumumab, 
specifically its ability to promote T-cell expansion and activation, are expected to potentiate the 
effect of anti-PD-1 antibody. The combination of nivolumab plus daratumumab is expected to 
potentiate the effect of nivolumab by sensitizing the bone marrow T cells to PD-1 blockade, which 
would translate in augmented clinical benefit.
Daratumumab is approved as monotherapy for third line treatment of MM patients who failed prior 
therapies.157,158 Recent reported results demonstrated safety and efficacy when combined with 
other immunomodulatory therapies in second line MM, including lenalidomide and 
dexamethasone.175
Daratumumab’s primary adverse events includes infusion reactions, which are reported to be 
uncommon with nivolumab alone (Nivolumab IB). However, infusion related reactions to 
daratumumab occur in close to 50% of the patients, largely with the first infusion. According to 
Revised Protocol No.: 07
Date: 07-May-2019
70
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
the currently approved United States Prescribing Information (USPI), daratumumab infusions 
should be interrupted for infusion reactions of any severity, and drug should be permanently 
discontinued in case of life-threatening infusion reactions. Pre-infusion and post-infusion 
medication should be administered to all patients, per the currently approved USPI. Severe
infusion related reactions have been reported in less than 1% of subjects in clinical trials with 
nivolumab, with overall rates of infusion related reactions of any grade ranging from 1% to 6%. 
The risk of infusion reactions is greater with the first and second infusions with daratumumab and 
decreases for subsequent doses. Therefore, to minimize the likelihood of infusion related reactions 
to the nivolumab and daratumumab combinations, the first nivolumab dose is administered at week 
3 (ie, after the first two doses of daratumumab at weeks 1 and 2). Further, on each dosing day when 
nivolumab is administered with daratumumab, the required pre-infusion medication for 
daratumumab is administered first, followed by infusion of nivolumab then infusion of 
daratumumab and then administration of daratumumab post-infusion medications.
Other AEs of any grade reported in a high frequency (>25%) of daratumumab treated subjects 
include low grade fatigue and nausea which have been associated with nivolumab treatment. Only 
one severe AEs (Grade 3/4) of pneumonia has been reported with daratumumab (>5% frequency). 
Pneumonia is considered uncommon with nivolumab as reported in the USPI; however, severe 
cases have been reported. The hematological AEs that have been reported following treatment with 
daratumumab (anemia, thrombocytopenia, neutropenia, lymphopenia), which are common in 
subjects with hematological malignancies, are not expected to be observed in subjects with solid 
tumors. In contrast to nivolumab, there have been no cases of immune related AEs, including 
pneumonitis, reported in the label for daratumumab. Based on the above assessment, the potential 
benefit of combining nivolumab and daratumumab appears to outweigh the potential risk. The 
overall risk/benefit assessment supports the evaluation of these combinations in this setting.
It is possible that unforeseen or unanticipated AEs may occur. In order to minimize the overall 
risks to participating subjects, the protocol has inclusion-exclusion criteria appropriate to the 
population, and specific follow-up safety assessments. Routine safety monitoring for all the AEs 
described above will be implemented in the protocol to ensure that we are monitoring the potential 
for overlapping toxicities.
Adverse events and SAEs will continue to be reviewed expeditiously by the Medical Monitor, 
investigators and the Pharmacovigilance group to monitor safety.
For subjects with local or locally advanced virus-positive tumors that are amenable to therapies 
with curative intent (neoadjuvant cohort of this study), there are multiple treatment options 
including perioperative chemotherapy, radiation, and/or observation post-resection depending on 
the disease stage and intraoperative findings. To minimize any delay to receiving treatment with 
curative intent, only two doses of nivolumab will be administered q2 week. This will coincide with 
the time when subjects are being scheduled for surgery and other perioperative treatments; 
therefore, minimal delays are expected. Furthermore, based on the known safety and tolerability 
profile of nivolumab, it is unlikely that adverse events from neoadjuvant administration will risk 
delaying surgery or receipt of standard of care. Prior precedent for the safety of perioperative 
Revised Protocol No.: 07
Date: 07-May-2019
71
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
checkpoint inhibition has been established in a Phase I bladder cancer study with ipilimumab (see 
Section 1.1.3). In addition, to minimize the risk of potential delays, a two stage approach will be 
taken to stop enrollment if there are delays to surgery or chemotherapy/radiation due to a 
nivolumab-related adverse event as specified in the label in the region of treatment in more than 2 
of the first 10 subjects treated within each tumor type. Lastly, although there are no efficacy data 
on neoadjuvant administration of nivolumab, there is potential for some clinical benefit as 
objective responses have been observed in clinical trials within weeks of initial treatment.  
There is risk associated with tumor biopsies, including bleeding, infection, and pain. While there 
is no direct benefit to subjects who undergo these procedures, there is a potential that data 
generated from these samples will guide the further development of these compounds and may be 
of direct benefit for others with advanced solid tumors. 
In summary, based on the manageable safety profile of nivolumab and nivolumab in combination 
with ipilimumab, the observed clinical activity of nivolumab and nivolumab in combination with 
ipilimumab across multiple tumor types, and the rationale for immune checkpoint inhibition for 
patients with virus-associated tumors, it is felt that the overall benefits to subjects outweigh the 
potential risks in the neoadjuvant or metastatic/recurrent settings. Furthermore, the potential direct 
benefit to subjects who participate in this study of combined therapy with nivolumab plus 
relatlimab may result in a greater proportion of subjects with stabilization of disease, objective 
response, or increased duration of response than those observed with nivolumab monotherapy. It 
is also possible that combination therapy may reverse LAG-3−mediated T cell exhaustion and 
achieve responses in virus-associated tumors.
Additionally, because nivolumab and daratumumab have some overlapping toxicity profiles (i.e. 
infusion related reaction, diarrhea), it is possible that a higher incidence of adverse events may 
occur with the combination of 2 drugs. Based on the above assessment, the potential benefit of 
combining nivolumab and daratumumab appears to outweigh the potential risk. The overall 
risk/benefit assessment supports the evaluation of these combinations in this setting. Per Revised 
Protocol 06, enrollment and treatment in this cohort have been terminated.
Depending on the clinical activity, results could form the basis for regulatory filings. Additional 
combination arms based on a nivolumab backbone, and/or expansion of existing cohorts, may be 
added in future amendments. 
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
Revised Protocol No.: 07
Date: 07-May-2019
72
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
Revised Protocol No.: 07
Date: 07-May-2019
73
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
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. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open label, multi-center, phase 1/2 trial to investigate the safety and efficacy of 
nivolumab as a single agent or in combination with either ipilimumab, BMS-986016 (relatlimab,
anti-LAG3 antibody), or daratumumab in viral positive and viral negative tumor types of the 
following tumor types: Epstein Barr Virus (EBV) positive gastric cancer, EBV positive 
nasopharyngeal cancer (NPC), cervical cancer, HPV positive and negative squamous cell cancer 
of the head and neck (SCCHN), anogenital HPV associated cancers (vaginal, vulvar, anal canal, 
penile), and Polyomavirus positive Merkel cell cancer (pMCC).
On the basis of eligibility and tumor type, patients will be enrolled into the neoadjuvant or 
recurrent/metastatic monotherapy, or assigned or randomized into the recurrent/metastatic 
combination therapies cohorts (A, B, and D). Upon approval of Revised Protocol 05, all Metastatic 
Combination Cohorts A, B, and D will enroll patients concurrently, and enrollment will be closed 
for Combination Cohort C.
Combination B SCC of the cervix cohort is being expanded to add approximately 70 patients to 
further confirm the efficacy signal. Approximately 50 patients will be added to receive 
Combination B study drug as first-line treatment of their recurrent/metastatic disease if unfit or 
unsuitable to receive platinum based therapy; and approximately 20 patients will be added to 
receive study drug as second-line treatment of their recurrent/metastatic SCC of the cervix.
Revised Protocol No.: 07
Date: 07-May-2019
74
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Treatments for each cohort are as follows:
Neoadjuvant cohort:
•
Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 
1 and Day 15
Metastatic Monotherapy Cohorts:
•
Nivolumab administered IV over 30 minutes at 240 mg every 2 weeks for a maximum of 
24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, 
whichever comes first.
Metastatic Combination Cohorts (Combinations A, B, C, and D):
•
Combo Arm A: Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks plus Ipilimumab 1
mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease
progression, unacceptable toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm B: Nivolumab 1 mg/kg IV over 30 minutes plus Ipilimumab 3 mg/kg IV over 
30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes 
every 2 weeks for a maximum of 24 months or until disease progression, unacceptable 
toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm C: Nivolumab 240 mg over 30 minutes every 2 weeks plus Anti-Lag3 (BMS-
986016) 80 mg for a maximum of 24 months or until disease progression, unacceptable 
toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm D: Daratumumab 16 mg/kg IV administered weekly for the first 8 weeks. 
Starting at Week 3, nivolumab 240 mg IV over 30 minutes will be administered every 2 
weeks. Nivolumab will be administered before the daratumumab infusion on study days 
when both study drugs are administered on the same day. Daratumumab 16 mg/kg will be 
administered every 2 weeks from Weeks 9-24. Starting at Week 25, nivolumab 480 mg IV 
flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a 
maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of 
consent, whichever comes first. The infusion rates for the first, second, and subsequent 
daratumumab infusions should closely follow the specifications of the currently approved 
(USPI)/pharmacy reference manual.184
The tumor types for the neoadjuvant cohort and the study design schematic for the neoadjuvant 
cohort (Figure 3.1-1) are presented below:
•
HPV positive SCCHN and HPV negative SCCHN
•
Cervical, Vaginal, Vulvar carcinoma
•
Merkel Cell Carcinoma
Revised Protocol No.: 07
Date: 07-May-2019
75
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Figure 3.1-1:
Study Design Schematic for the Neoadjuvant Cohort:
The diseases or tumor types for the recurrent/metastatic monotherapy cohort and the study design 
schematic for the recurrent/metastatic monotherapy cohort is presented in Figure 3.1-2 are
presented below:
•
EBV positive Gastric cancer, 
•
HPV positive SCCHN
•
Cervical, vaginal, and vulvar carcinoma
•
Merkel Cell carcinoma 
•
Nasopharyngeal Carcinoma (NPC) 
Figure 3.1-2:
Study Design Schematic for the Metastatic Monotherapy Cohort
The diseases or tumor types for the recurrent/metastatic combination therapy cohorts (Combo A,
B and C) are listed below and the study design schematics for the recurrent/metastatic combination 
therapies A, B, and C are presented in Figure 3.1-3 and Figure 3.1-4.
Neoadjuvant
Nivo 240 mg
(2 doses)
1) Day 1
2) Day 15
Biopsy
Prior to 1st
dose
Biopsy or 
Surgical 
resection
(Day 29)
Investigator’s choice 
Standard of Care 
(SOC)
Nivo 240 mg Q2 weeks
Until 24 months maximum 
duration, PD, or Toxicity
Treatment
Follow-Up
Screening
Subsequent Treatment
Up to 5 weeks
TUMORS:
• GYN (cervical, vaginal, 
vulvar) - N = 21 
evaluable subjects
• MCC – N = 21 
evaluable subjects
• HPV (+) SCCHN – N = 
21 evaluable subjects
• HPV (-) SCCHN – N = 
21 evaluable subjects
•
F/U  visit 1+2
•
F/U post 
surgery (month 
4, 8, and 12)
•
Survival F/U
For Subjects with HPV: 
Virus selection required 
If unresectab erecurrent or 
metastatic disease within 1 
year after end of SOC 
If eligible
Min 12 weeks
10 subjects enrolled in each tumor - PAUSE –
Safety analyses
Additional 11 subjects enrolled if  ≤ 2/10 have 
surgery delayed > 4 weeks (due to nivo AE’s as 
specified in the label)
Metastatic 
Monotherapy 
Nivo monotherapy 240 mg
Q2 weeks
Until disease progression, toxicity, 
withdrawal of consent, or a maximum 
of 24 months
TUMORS:
• EBV (+) Gastric - N=12
• HPV(+) SCCHN - N=23
• GYN (cervical, vaginal, 
vulvar) - N=23
• MCC - N=23
• NPC  - N=23
Up to 5 weeks
Up to 2 priortreatments
≥ 1 target lesion
ECOG status: 0 or 1
• Imaging every 8 weeks starting at 
Week 8 for the first year of treatment
• Imaging every 12 weeks starting at 
year 2 and beyond
Min 12 weeks
survival
For Subjects with HPV (+) and 
EBV (+):  virus selection required
Revised Protocol No.: 07
Date: 07-May-2019
76
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
HPV positive SCCHN
−
Immuno-Oncology naive (anti-tumor vaccine and any T cell co-stimulation or checkpoint 
pathways therapy) (Combo A)
−
Prior PD-1/PD-L1 (Combo C)
•
Cervical cancer (Combo A and B)
•
Anogenital HPV associated tumors (vaginal, vulvar, anal canal, penile) (Combo A and B)
•
Merkel Cell Carcinoma (Combo A)
•
Nasopharyngeal Carcinoma (NPC) (Combo A)
Figure 3.1-3:
Study Design Schematic for the Metastatic Cohort Combination 
Therapies A and B and Combo B SCC of the Cervix Expansion
Treatment
Follow-Up
Screening
Subsequent Treatment
Combo B Cervical Cancer 
expansion  
• Up to 2 prior treatments
• > 1 target lesion
• ECOG PS: 0-1
SCC OF THE CERVIX
• First-line treatment – 50 patients
• Second-line treatment – 20 
patients
Nivo + Ipi Combo
Combo B
Nivo-1mg/kg + Ipi-3mg/kg 
q3w x 4 followed by Nivo 
240mg q2w until disease 
progression, toxicity, 
withdrawal of consent, or a 
maximum of 24 months
• Imaging every 8 weeks 
starting at Week 8 for 
the first year of 
treatment
• Imaging every 12 weeks 
starting at year 2 and 
beyond
Min 12 
weeks
Survival
N = approx. 70 will be added to combo B to 
recieve treatment as first-line or second-line 
treatment
Revised Protocol No.: 07
Date: 07-May-2019
77
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Figure 3.1-4:
Study Design Schematic for the Metastatic Cohort Combination Arm 
C
The disease or tumor type for the recurrent/metastatic combination D therapy cohort are listed 
below and the study design schematic for the recurrent/metastatic combination cohort for 
combination therapy D is presented in Figure 3.1-5: HPV positive or HPV negative or unknown 
SCCHN 
−
Immuno-Oncology therapy naive (anti-tumor vaccine and any T cell co-stimulation or 
checkpoint pathways therapy)
Relatlimab(Anti-Lag-3) 80 
mg +
Nivolumab 240 mg q2W 
until, disease progression, 
toxicity, withdrawal of 
consent, or a maximum of 
24 months
• Imaging every 8 
weeks starting at 
Week 8 for the first 
year of treatment
• Imaging every 12 
weeks starting at 
year 2 and beyond
Treatment
Follow-Up
Screening
Subsequent Treatment
• Up to 2 prior treatments*
• > 1 target lesion
• ECOG PS: 0-1
TUMOR TYPE:
•HPV+ SCCHN (I-O experienced)**
Min 12 weeks
Survival
Combo C (Nivo + Relat) 
N = approx. 40
*Prior I-O therapy is permitted and is not counted toward the number of prior systemic treatment
**Include subjects that have had prior exposure to anti-PD-1, anti-PD-L1  or anti-CTLA-4 antibodies monotherapy or combination 
therapy
Revised Protocol No.: 07
Date: 07-May-2019
78
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Figure 3.1-5:
Study Design Schematic for the Metastatic Cohort Combination 
Therapy D: Tumor Type SCCHN HPV positive, negative or unknown 
I-O naive.
Table 3.1-1:
Tumor Types by Cohort
Tumor Type
Cohort
•
GYN (cervical, vaginal, vulvar) 
•
MCC 
•
HPV (+) SCCHN 
•
HPV (-) SCCHN 
Neoadjuvant Cohort 
•
EBV (+) Gastric 
•
HPV(+) SCCHN 
•
GYN (cervical, vaginal, vulvar) 
•
MCC 
•
NPC  
Metastatic Monotherapy Cohort
•
MCC
•
HPV+ SCCHN
•
NPC
•
Cervical cancer
•
Other anogenital cancers 
(vulvar/vaginal/anal/penile)
Metastatic Combination Cohort A
•
Cervical cancer
•
Other 
Anogenital 
Cancers 
(vulvar/vaginal/anal canal/penile)
Metastatic Combination Cohort B
•
HPV+ SCCHN (I-O experienced)
Metastatic Combination Cohort C
•
HPV +/HPV – or unknown SCCHN (I-O 
naïve)
Metastatic Combination Cohort D
All subjects will complete 3 periods of the study: Screening, Treatment, Follow-up, including
survival follow-up. 
• Imaging every 8 weeks 
starting at Week 8 for the 
first year of treatment
• Imaging every 12 weeks 
starting at year 2 and 
beyond
Treatment
Follow-Up
Screening
Subsequent Treatment
• Up to 2 prior 
treatments
• > 1 target lesion
• ECOG PS: 0-1
TUMOR TYPES:
•SCCHN – HPV 
+/HPV – or HPV 
unknown
•I-O naïve
Min 12 weeks
Survival
N = approx. 40
Combo D
• Daratumumab 16 mg/kg q1W 
– Week 1 to 8; q2W –Week 9  
to 24 and q4W starting on 
Week 25 until toxicity, 
withdrawal of consent, or a 
maximum of 24 months
• Nivolumab 240 mg q2W –
starting on Week 3  and 480 
mg q4W starting  from Week 
25 until toxicity, withdrawal of 
consent, or a maximum of 24 
months
Revised Protocol No.: 07
Date: 07-May-2019
79
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Duration of Study: The last visit will be defined as the latest survival visit included in the final 
analysis of OS (ie, the latest subject death, loss to follow up, or withdrawal of consent) for a tumor 
type within each cohort. 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 collection has concluded.
3.1.1
Viral Status Determination Prior to Entry
The study will enroll prospective subjects diagnosed with gastric cancer in the Metastatic 
Monotherapy Cohort. Gastric subjects will provide pre-screening informed consent for 
determination of EBV+ viral status during the screening period and be registered in IRT. Viral 
testing will be performed locally or by a central laboratory and test results will be collected. After 
positive test result confirmation, consent for demographic and further eligibility will be collected. 
Subjects with EBV negative gastric cancer will be considered screen failures and will not be 
eligible for the study.
The study will enroll prospective subjects diagnosed with SCCHN. SCCHN subjects will provide 
consent, via pre-screening informed consent, for determination of HPV viral status, if prior results 
are not available during the screening period and be registered in IRT (Combo A and C). Viral 
testing will be performed locally or by a central laboratory and test results will be collected. After 
viral test result is confirmed positive, consent for demographic and further eligibility will be 
collected. If subjects decline pre-screening informed consent or are unwilling to undergo viral 
testing, they are eligible to enroll in Combo D. However, viral status should be determined 
retrospectively.
The requirement for viral status for each tumor type by cohort is described below and in Table
3.1.1-1.
Neoadjuvant cohort: Confirmation of viral status is required prior to study drug assignment for 
SCCHN subjects enrolled. Viral testing determined more than 35 days prior to first dose may be 
used. For SCCHN tumor types in the neoadjuvant cohort, 21 evaluable subjects with virus positive 
disease and 21 evaluable subjects with virus negative disease will be enrolled. No prior screening 
for Gyn (cervical, vaginal, vulvar) or MCC cohorts is necessary due to the high prevalence of viral 
positivity and the technical aspects of the MCPyV assay. Viral positivity will be tested
retrospectively for MCC and Gyn tumor types.  
Metastatic monotherapy cohort: Gastric and SCCHN subjects will be tested for viral status prior 
to study drug assignment. Gastric subjects must be EBV positive, and SCCHN subjects must be 
HPV positive to enroll in this cohort. MCC, NPC, and Gyn (cervical, vaginal, vulvar) subjects will 
not require viral screening prior to study entry. With the exception of gastric cancer (n=12), each 
specific tumor type in the metastatic monotherapy cohort will contain 23 subjects. Subjects will 
be treated with nivolumab 240 mg IV every 2 weeks until disease progression, unacceptable 
toxicity, or 24 months of treatment. Viral positivity will be tested retrospectively for MCC, NPC, 
and Gyn tumor types.
Metastatic combination therapy cohort - Combo A, Combo B, and Combo C: SCCHN 
subjects will be tested for HPV viral status prior to study drug assignment. Viral positivity will be 
Revised Protocol No.: 07
Date: 07-May-2019
80
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
tested retrospectively for subjects with MCC, NPC, cervical cancer and anogenital HPV associated 
tumors (vaginal, vulvar, anal canal, and penile); confirmation of viral positivity will not require 
viral screening prior to study entry. 
Approximately 40 subjects with each of the following tumor types will be enrolled into Combo A
and Combo B into a 1:1 ratio: cervical cancer and anogenital HPV associated tumors (vaginal, 
vulvar, anal canal, and penile). Additionally, 40 subjects with each of the following tumor types 
will be enrolled into Combo A: MCC, HPV+ SCCHN, and NPC. With Revised Protocol 06, no 
new subjects will be randomized in the anogenital HPV associated tumors cohorts.
Approximately 40 subjects with SCCHN [prior anti-PD-1 or anti-PD-L1 antibody therapy] will be 
enrolled into Combo C. As of Revised Protocol 05, enrollment will close. 
Combo D: Approximately 40 subjects with HPV positive, negative or unknown SCCHN [I-O 
naive] will be enrolled into Combo D. On 26-May-2018 enrollment was closed. Subsequently, the 
administration of daratumumab in combination with nivolumab was terminated.  
Table 3.1.1-1:
Testing for Viral Status Prior to Treatment
Cohort
Tumor Type
Viral status required prior to 
study drug (Testing)
Neoadjuvant
SCCHN
YES (p16 IHC)
Gyn
NO
MCC
NO
Metastatic Monotherapy 
EBV+ Gastric
Yes 
In situ hybridization EBV RNA 
(EBER)
Metastatic Combination Therapy
HPV+/- SCCHN
YES (p16 IHC) (except for Combo 
D)
Cervical and other HPV associated 
anogenital tumors (vulvar, vaginal, 
anal canal, penile)
NO
MCC
NO
NPC
NO
Gyn = cervical, vaginal, vulvar 
HPV positive, negative or unknown, I-O naive SCCHN patients may participate in Combo D
All subjects (if clinically feasible) in each cohort will receive pre-treatment and on-treatment tumor 
biopsies. Primary analysis for the Neoadjuvant, Metastatic monotherapy, and Metastatic 
combination therapy cohorts will be conducted separately after a minimum of at least six months
after the first treatment of the last patient for a tumor type enrolled in each cohort. All analyses 
will be performed independently by cohort and by tumor type. 
Revised Protocol No.: 07
Date: 07-May-2019
81
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
3.1.2
Neoadjuvant Cohort
The primary objective of the neoadjuvant cohort is to evaluate the safety and tolerability of 
neoadjuvant nivolumab administration in subjects with select tumor types. 
For subjects in the neoadjuvant cohort, radiographic tumor assessments will occur at the following 
time points (see Table 5.4.1-2). 
•
Screening to ensure the subject has resectable disease.
•
Within 7 days and prior to the planned surgery or chemotherapy/radiation
•
Post-surgery (SCCHN, MCC, Gyn) or post-chemotherapy/radiation (Gyn cohort when 
appropriate) at indicated Follow-Up visit times.
All subjects must have tumor amenable to pre-treatment biopsy (core needle); post-treatment 
biopsy will consist of the operative specimen or core needle biopsy for the cervical/vaginal/vulvar 
subjects.
Treatment within the neoadjuvant cohort will consist of:
•
A pre-treatment, core-needle, biopsy for all subjects. (Four core-needle biopsies, as described 
in the laboratory manual, are suggested.)
•
Two doses of nivolumab will be administered at 240 mg IV on Day 1 and Day 15
•
Surgical resections (SCCHN, MCC, Gyn), or biopsy followed by chemotherapy/radiation 
(where appropriate for Gyn patients only) will occur on Day 29 (± 7 days). No other 
pre-surgical therapy is allowed. 
•
After neoadjuvant nivolumab treatment followed by surgical resection or biopsy, subjects 
will receive standard of care (observation, chemo and/or RT, according to physician’s 
choice). 
•
Subjects who develop unresectable recurrent or metastatic disease within 1 year of surgery or
chemotherapy/radiation completion may receive nivolumab at 240 mg IV every 2 weeks until 
24 months of treatment, toxicity, or disease progression, if medically eligible, ie, meet 
eligibility criteria for metastatic cohort. Written approval from the sponsor’s medical monitor 
is required for subject to be considered eligible. Nivolumab can be administered no earlier 
than 4 weeks after the last standard of care treatment. 
•
Enrollment for each tumor type in the neoadjuvant cohort will pause after the first 
10 subjects are treated to assess safety and determine the number of subjects with 
chemotherapy/radiation or surgical delays beyond 4 weeks from the planned surgery date or
planned start date for chemoradiation. If ≥3 of the first 10 subjects for a single tumor type 
have delays beyond 4 weeks from the planned surgery date or planned start date for 
chemoradiation due to a nivolumab immune-related adverse event(s) specified in the label in 
the region of treatment, that specific tumor cohort will close. The remaining tumor types in 
the neoadjuvant cohort will not close enrollment should a tumor type(s) close due to a delay 
in surgery due to nivolumab. If the first 8 patients treated for a single tumor type experience 
no delay, a pause in enrollment will not be required.  
Revised Protocol No.: 07
Date: 07-May-2019
82
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Details regarding the procedures associated with the neoadjuvant cohort can be found in Table 5.1-
4. Details regarding procedures required for subjects who develop unresectable recurrent or 
metastatic disease within 1 year of surgery or chemotherapy/radiation and receive nivolumab can 
be found in Table 5.1-2. 
3.1.3
Subjects in the Metastatic Monotherapy Cohort
For subjects without resectable disease, nivolumab will be administered at 240 mg every 2 weeks 
until toxicity, disease progression, withdrawal of consent, or 24 months of treatment, whichever 
comes first. For subjects in the metastatic cohort, radiographic tumor assessments by CT 
(preferred)/MRI will begin 8 weeks (± 1 week) after the start of therapy and will continue every 8
weeks (± 1 week) for the first year of treatment. CT (preferred)/MRI will continue every 12 weeks 
(± 2 weeks) for the second year and beyond. Tumor assessments will follow the above schedule 
until disease progression is documented. If the subject discontinues treatment prior to disease 
progression, tumor assessment will continue per protocol as described in Table 5.4.1-1. Disease 
progression is defined by investigator-assessed RECIST 1.1 criteria. The primary endpoint of this 
cohort is objective response rate (ORR) based on investigator assessments, using RECIST 1.1
criteria. Exploratory endpoints include complete and partial remission rates and durations based 
on radiological assessments. Individual tumors types will be analyzed separate from each other.  
In all subjects for each tumor type, biopsy and submission of fresh tumor tissue, or submission of 
archived tumor tissue, is mandatory for all subjects. Subjects with accessible lesions where biopsy 
is deemed safe by the Investigator should undergo biopsy per protocol.
3.1.4
Subjects in the Metastatic Combination Cohorts
Upon approval of Revised Protocol 05, all Metastatic Combination Cohorts A, B, and D will enroll 
patients concurrently, and enrollment in Cohorts C will be closed. 
Subjects with SCCHN, MCC or NPC enrolled in Combo A will be treated with nivolumab 3mg/kg 
every 2 weeks plus ipilimumab 1mg/kg every 6 weeks (Combo A) for a maximum of 24 months 
or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes 
first. 
Subjects with cervical cancer and anogenital HPV associated tumors (vulvar/vaginal/anal 
canal/penile) will be randomized (1:1) to treatment with either Combo A - nivolumab 3mg/kg 
every 2 weeks plus ipilimumab 1mg/kg every 6 weeks or Combo B - nivolumab 1mg/kg plus 
ipilimumab 3mg/kg every 3 weeks for 4 doses followed by nivolumab 240 mg every 2 weeks for 
a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of 
consent, whichever comes first. With Revised Protocol 06, no new subjects will be randomized in 
the anogenital HPV associated tumors cohorts.
Subjects with HPV+ SCCHN with prior PD-1/PD-L1 treatment who are enrolled in Metastatic 
Combination Cohort (Combo C) will be treated with BMS-986016 (relatlimab) 80 mg plus 
nivolumab 240 mg q2w for a maximum of 24 months until disease progression, unacceptable 
toxicity, or withdrawal of consent, whichever comes first.
Revised Protocol No.: 07
Date: 07-May-2019
83
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Subjects with HPV negative, positive, or unknown SCCHN who are I-O naive will be enrolled
into the metastatic SCCHN Combo D (nivolumab plus daratumumab).
For subjects in the metastatic cohorts, radiographic tumor assessments by CT (preferred)/MRI will 
begin 8 weeks (± 1 week) after the start of therapy and will continue every 8 weeks (± 1 week) for 
the first year of treatment. CT (preferred)/MRI will continue every 12 weeks (± 2 weeks) for the 
second year and beyond. Tumor assessments will follow the above schedule until disease 
progression is documented. If the subject discontinues treatment prior to disease progression, 
tumor assessment will continue per protocol as described in Table 5.4.1-1. Study treatment will be 
administered until unacceptable toxicity, 24 months of treatment, or disease progression which is 
defined by investigator assessed RECIST 1.1 criteria. The primary endpoint of this cohort is 
objective response rate (ORR) based on investigator assessments, using RECIST 1.1 criteria. 
Exploratory endpoints include complete and partial remission rates and durations based on 
radiological assessments. Individual tumors types will be analyzed separate from each other.  
In all subjects for each tumor type, biopsy and submission of fresh tumor tissue, or submission of 
archived tumor tissue, is mandatory for all subjects. Subjects with accessible lesions where biopsy 
is deemed safe by the Investigator should undergo biopsy per protocol.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug for the maximum treatment duration specified in 
Section 3.1. 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 subject 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.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, and other requirements of the study.
Revised Protocol No.: 07
Date: 07-May-2019
84
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
2. Target Population
a) Histopathologic confirmation of the following tumor types
i)
Merkel Cell Carcinoma 
(1) MCPyV status will be determined after enrollment
ii) EBV-Positive Gastric or Gastro-Esophageal junction carcinoma (including 
adenocarcinoma arising from the lower esophagus)
(1) For subjects in the metastatic monotherapy cohort with gastric tumor types, EBV 
positivity is defined by EBER in situ hybridization. Testing for EBV positivity will 
be performed prior to study drug assignment using the EBER1 DNP probe from 
Ventana in a properly certified lab. Samples interpreted as (+) if nuclear staining of 
any intensity above the background in tumor cells, provided the negative internal 
controls (adjacent normal tissue) are negative.
iii) Nasopharyngeal Carcinoma 
(1) For subjects in the metastatic cohorts (monotherapy and combination) with 
nasopharyngeal carcinoma tumor types, EBV positivity is as defined by EBER in 
situ hybridization
as specified above. Virus testing will be performed 
retrospectively only if results from prior accepted testing are not available.
iv) Squamous cell carcinoma of the cervix, vagina, vulva, penile or anal carcinoma
(1) For subjects in the neoadjuvant and metastatic (monotherapy and combination)
cohorts with gynecological tumors, HPV positivity is defined by FDA approved 
tests (Cobas HPV Test; Digene Hybrid Capture 2 High-Risk HPV DNA Test; 
Cervista™ HPV HR and Genfind™ DNA Extraction Kit; Cervista™ HPV 16/18; 
APTIMA® HPV Assay) or other well validated commercially available tests (such 
as Ventana Inform HPV ISH test) comprising in situ hybridization, real-time PCR, 
or immunohistochemistry (IHC). High-risk HPV positivity includes the following 
subtypes:  16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68. Virus testing will 
be performed retrospectively only if results from prior accepted testing are not 
available.  
v) Squamous cell carcinoma of the Head and Neck
(1) For subjects in the neoadjuvant and metastatic (monotherapy and combination)
cohorts HPV positivity is defined by p16INK4a (p16) IHC employing clone E6H4 
from MTM (Roche). The p16 IHC should be interpreted as positive if > 70% strong 
and diffuse nuclear and cytoplasmic staining is specific to tumor cells. Testing for 
p16 will be performed prior to study drug assignment using an appropriately 
validated test. 
(2) HPV positive status can be obtained from either the primary tumor or metastatic 
lymph node.
(3) For subjects in the virus negative neoadjuvant cohort, HPV status should be 
documented as defined above. The p16 IHC should be interpreted as negative if 
< 70% strong and diffuse nuclear and cytoplasmic staining is specific to tumor 
cells.
Revised Protocol No.: 07
Date: 07-May-2019
85
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
b) For subjects in the neoadjuvant cohort 
i)
Squamous cell carcinoma of the Head and Neck for whom surgical resection is planned. 
(1) Subjects must have newly diagnosed, histologically or cytologically confirmed 
squamous cell carcinoma or undifferentiated carcinoma of the oral cavity, pharynx 
and larynx. Subjects must have been determined to have resectable disease.
(2) Subjects must have tumor amenable to pre-treatment biopsy. Post-treatment biopsy 
will consist of the operative specimen. Excisional, incisional or core needle samples 
are acceptable. Fine needle aspirates are prohibited. See Section 5.6.9 for further 
details. The biopsy may have been obtained from the primary tumor or metastatic 
lymph node. 
(3) Subjects must have:
a.
T1 or greater primary lesions, AND
b. N1 or greater nodal disease,
ii) Squamous cell cervical, vulvar, or vaginal cancer
(1) Stage II to IVA cervical cancer who have planned surgical staging or 
chemotherapy/radiation treatment
(2) Stage II to IVA vulvar or vaginal cancer who have planned curative intent surgery
or chemotherapy/radiation treatment
(3) Subjects must have tumor amenable to pre-treatment biopsy. Post-treatment biopsy 
will consist of the operative specimen. Excisional, incisional or core needle samples 
are acceptable. Fine needle aspirates are prohibited. See Section 5.6.9 for further 
details.
iii) Merkel Cell Carcinoma: 
(1) Subjects must have tumor amenable to pre-treatment biopsy. Post-treatment biopsy 
will consist of the operative specimen. Excisional, incisional or core needle samples 
are acceptable. Fine needle aspirates are prohibited. See Section 5.6.9 for further 
details.
(2) Resectable disease of the following tumor types. Subjects must have one of the 
following Stages of disease
a.
Stage II A-IIIB: 
i.
Primary tumor ≥2 cm, or 
ii.
Primary tumor of any size with palpable regional lymph node metastases or 
resectable in-transit metastases.  
b. Stage IV disease with resectable limited metastasis
c.
Local/Regional recurrent disease as defined as total burden ≥1 cm diameter 
with resectable disease defined by local or institutional surgical practices 
c) For subjects in the metastatic cohorts (monotherapy and combination)
i)
Progressive metastatic or recurrent disease treated with no more than 2 prior systemic 
therapies or regimens in the metastatic setting.
ii) Measurable disease by CT or MRI per RECIST 1.1 criteria (Appendix 3) (radiographic 
tumor assessment must be performed within 35 days prior to first dose).
Revised Protocol No.: 07
Date: 07-May-2019
86
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
iii) Subjects who actively refuse chemotherapy or other standard therapies for the treatment 
of unresectable or metastatic disease (advanced Stage III or Stage IV), despite being 
informed by the investigator about the treatment options may enroll. The subject’s 
refusal must be thoroughly documented. The investigator will discuss each individual 
subject refusing chemotherapy with the sponsor’s medical monitor or study director to 
confirm eligibility. Written approval from the sponsor’s medical monitor is required 
for eligibility. 
iv) The following tumor types
(1) Histologically confirmed Gastric or Gastro-Esophageal Junction Carcinoma
(monotherapy cohort only) (including adenocarcinoma arising from the lower 
esophagus) who are EBV positive, as defined above. 
(2) Histologically confirmed HPV positive (monotherapy and Cohorts A and C) or
HPV negative or unknown (Combo D only), as defined above, Squamous Cell 
Carcinoma of the Head and Neck (oral cavity, pharynx, larynx) not amenable to 
local therapy with curative intent (surgery or radiation therapy with or without 
chemotherapy). 
a.
Histologically confirmed HPV positive or HPV negative or unknown -subjects 
naive to I-O 
i.
Subjects cannot have had prior exposure to IO therapies such as, but not 
limited 
to,
other 
anti-CD38 
therapies,
anti-CTLA-4, 
anti-PD-1, 
combination of PD-1/CTLA-4 antibody, anti-PD-L1, anti-PD-L2, anti-KIR, 
anti-CD137, or anti-OX40 antibodies.
b. Histologically confirmed HPV positive subjects progressing while on or after 
therapy with anti-PD-1 or anti-PD-L1 antibody as most recent therapy, defined 
as Squamous Cell Carcinoma of the Head and Neck (oral cavity, pharynx, 
larynx) not amenable to local therapy with curative intent (surgery or radiation 
therapy with or without chemotherapy). (Combo C only)
i.
Cannot have had therapy discontinued due to serious and/or life-threatening 
anti-PD-1; anti-PD-L1 or anti-CTLA-4 antibody-related toxicity (e.g., dose-
limiting toxicity in prior study) per Investigator’s assessment in 
consultation with the BMS Medical Monitor.
ii.
Last dose of antibody therapy must have been received ≥ 30 days of first 
dose of study medication
iii.
Cannot have had prior exposure to other IOs, such as, but not limited to,
anti-CTLA-4 anti-PD-L2, anti-KIR, anti-CD137, or anti OX40 antibodies.
iv.
anti-PD-1/PD-L1/CTLA-4 does not need to be considered a 1 of the 
previous lines of therapy. 
(3) Histologically confirmed cervical, vulvar, or vaginal cancer, as defined above. If 
the viral results are known prior to enrollment, and they are viral negative, the 
patient would be ineligible.
(4) Histologically confirmed Merkel Cell Carcinoma
a.
Subjects with no prior systemic treatment will be allowed to enroll
Revised Protocol No.: 07
Date: 07-May-2019
87
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
(5) Histologically confirmed Nasopharyngeal Carcinoma, as defined above. If the viral 
results are known prior to enrollment, and they are viral negative, the patient would 
be ineligible.
a.
HPV associated NPC is excluded in this cohort
b.
Keratinizing squamous cell carcinoma (WHO Type I) is excluded in this cohort 
due to the low prevalence of EBV infection in this population.
(6) Histologically confirmed anal canal or penile carcinoma. If the viral results are 
known prior to enrollment, and they are viral negative, the patient would be 
ineligible. (Metastatic Combination Cohorts only).
v) Recurrent/metastatic SCC of the cervix subjects not amenable to curative treatment 
with surgery and/or radiation therapy who are unsuitable for platinum-based therapy 
(ie, creatinine clearance of less than 60 mL/min or have experienced toxicity from prior 
platinum-based therapy) may enroll in the cervical cancer Combination B expansion 
cohort.
d) For both neoadjuvant and metastatic (monotherapy and combination)cohorts
i)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
ii) Men and women of age 18 or older.
iii) Subject willing to comply to provide tumor tissue for PD-L1 expression analysis and 
other biomarker correlative studies. See Section 5.6.9 for further details. Biopsy should 
be excisional, incisional or core needle. Fine needle aspirates are prohibited.
e) All baseline laboratory requirements will be assessed and should be obtained within 
-14 days of first dose (unless otherwise specified in Table 5.1-1). Screening laboratory 
values must meet the following criteria:
i)
WBCs ≥2000/μL
ii) Neutrophils ≥1500/μL
iii) Platelets ≥100 x 10³/μL
iv) Hemoglobin ≥9.0 g/dL
v) Creatinine Serum creatinine ≤
1.5 x ULN or creatinine clearance (CrCl) 
≥40 mL/minute (using Cockcroft/Gault formula)
vi) AST ≤3 x ULN 
vii)ALT ≤3 x ULN 
viii)
Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome who can have 
total bilirubin < 3.0 mg/dL)
ix) Cardiac Troponin T (cTnT) or I (cTnI) ≤ 2 × institutional ULN. Subjects with cTnT or 
cTnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours 
are ≤ 1 ULN (Combo C only)
(1) If cTnT or cTnI levels are >1 ULN at 24 hours, the subject may undergo a cardiac 
evaluation and be considered for treatment, following a discussion with the BMS 
Medical Monitor or designee.
Revised Protocol No.: 07
Date: 07-May-2019
88
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
f)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has 
not been treated). If re-enrolled, the subject must be re-consented.
g) LVEF assessment with documented LVEF ≥ 50% by either TTE or MUGA (TTE preferred 
test) within 6 months from first study drug administration (Combo C only)
3. Age and Reproductive Status
a) Men and women, 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 with study drug(s) plus approximately 5 half-lives 
of study drug(s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post 
treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug(s) plus 
approximately 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a 
total of 7 months post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use one highly effective method of contraception as 
listed in Appendix 4.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for at least 4 weeks after treatment is complete and within 28 days 
prior to first dose of study drug administration. There must also be no requirement for 
immunosuppressive doses
of
systemic corticosteroids (>10 mg/day prednisone 
equivalents) for at least 2 weeks prior to study drug administration.
Revised Protocol No.: 07
Date: 07-May-2019
89
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
2. Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
b) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured or successfully resected, such as basal or squamous cell skin 
cancer, superficial bladder cancer, or gastric cancer, or carcinoma in situ of the prostate, 
cervix, or breast.
c) Subjects with active, known or suspected autoimmune disease. Subjects with skin disorders 
(such as vitiligo, psoriasis, or alopecia), type I diabetes mellitus, hypothyroidism only 
requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
d) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids, and adrenal replacement doses are 
permitted in the absence of active autoimmune disease.
e) Subjects with primary tumor or nodal metastasis fixed to the carotid artery, skull base or 
cervical spine.
f)
Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or 
checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting 
T cell co-stimulation or checkpoint pathways is also prohibited. Exception: Combo C
SCCHN prior anti-PD-1/anti-PD-L1/anti-CTLA-4 exposure tumor types.
g) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after platinum 
based therapy, are permitted to enroll.
h) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 28 days of first administration of study treatment (subjects 
with prior cytotoxic or investigational products < 4 weeks prior to treatment might be 
eligible after discussion between investigator and sponsor, if toxicities from the prior 
treatment have been resolved to Grade 1 (NCI CTCAE version 4).
i)
active neurological disease or confirmed history of encephalitis, meningitis, or 
uncontrolled seizures in the year prior to informed consent for Combo C only
j)
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following (Combo C only):
i)
Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 
6 months prior to consent
ii) Uncontrolled angina within the 3 months prior to consent
Revised Protocol No.: 07
Date: 07-May-2019
90
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
iv) QTc prolongation > 480 msec
v) History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, 
congestive heart failure with New York Heart Association [NYHA] functional 
classification III-IV, pericarditis, significant pericardial effusion, significant coronary 
stent occlusion, deep venous thrombosis, etc.)
vi) Cardiovascular disease-related requirement for daily supplemental oxygen 
vii)History of two or more MIs OR two or more coronary revascularization procedures
viii) Subjects with history of myocarditis, regardless of etiology
k) For Combo D only
i)
Known history of stage 3 or 4 chronic obstructive pulmonary disease (COPD). 
ii) Known moderate or severe persistent asthma within the past 2 years, or uncontrolled 
asthma of any classification. Note that subjects who currently have controlled 
intermittent asthma or controlled mild persistent asthma are allowed to participate in 
the study.
iii) Screening 12-lead ECG showing a baseline QT interval as corrected (QTc) >480 msec
l)
Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 2 
weeks prior to randomization/treatment. Refer to Section 3.4.1 for prohibited therapies.
m) For the expansion cohort for subjects with SCC of the cervix and for subjects eligible to 
receive study drug (Combo B) as first-line treatment for their recurrent/metastatic disease, 
must not have been treated previously with chemotherapy except when used concurrently 
with radiation therapy.
3. Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus (e.g. surface antigen [HBV sAg, Australia 
antigen] positive) or hepatitis C virus (Hepatic 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). NOTE: Testing for HIV must be performed 
at sites where mandated locally.
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
Revised Protocol No.: 07
Date: 07-May-2019
91
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
5. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
drug
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
See Appendix 4 for more details.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:
•
Immunosuppressive agents (except to treat a drug-related adverse event)
•
Immunosuppressive doses of systemic corticosteroids (> 10 mg daily prednisone 
equivalent), except as stated in Section 3.4.2 or to treat a drug-related adverse event. 
•
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, radiation therapy except for palliative radiation therapy described in 
Section 3.4.2 or standard or investigational agents for treatment of cancer).
•
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.  
•
LAG-3 targeting agents.
Supportive care for disease-related symptoms may be offered to all subjects on the trial.
Revised Protocol No.: 07
Date: 07-May-2019
92
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
3.4.1.1
Restricted Treatments
Restricted therapies are not prohibited but are not recommended; consult BMS medical 
monitor/designee if the following are clearly medically indicated:
•
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.
3.4.2
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses including 
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.
Oral Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase. 
Initiate antiviral prophylaxis within 1 week after starting daratumumab, and continue for 3 months 
following treatment discontinuation (Combo D only).
Subjects must receive pre-infusion and post-infusion medications with each dose of daratumumab, 
per the daratumumab Investigators Brochure; additional details are provided in Section 4.7.7.  
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted if the 
following criteria are met:
•
The subject is considered to have progressed at the time of palliative therapy and meets 
criteria to continue with treatment beyond progression (Section 4.7.8).
•
The case is discussed with the BMS medical monitor. 
•
Palliative therapy must be clearly documented as such in the study record.
The potential for overlapping toxicities with radiotherapy and nivolumab alone or in combination 
with either ipilimumab, BMS-986016 (relatlimab), or daratumumab currently is not known. 
Therefore, palliative radiotherapy is not recommended while receiving study drug. If palliative 
radiotherapy is required, then study drug should be withheld for at least 1 week before, during and 
1 week after radiation. Subjects should be closely monitored for any potential toxicity during and 
after receiving radiotherapy, and AEs considered related to radiotherapy should resolve to Grade 
≤1 prior to resuming study drug. 
Only non-target lesions included in the planned radiation field or CNS lesions may receive 
palliative radiotherapy. Details of palliative radiotherapy should be documented in the source 
records and electronic case report form (eCRF). Details in the source records should include: dates 
of treatment, anatomical site, dose administered and fractionation schedule, and adverse events. 
Subjects receiving limited field palliative radiation therapy will be considered to have unequivocal 
Revised Protocol No.: 07
Date: 07-May-2019
93
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
progression of disease in the non-target lesion. Symptoms requiring palliative radiotherapy should 
be evaluated for objective evidence of disease progression. Administration of additional study drug
to subjects who received limited field palliative radiation should follow guidelines specified in 
Section 4.7.8 Treatment Beyond Disease Progression.
3.4.3
Surgical Resection Following Initial Response
Investigators may choose to resect solitary lesions in subjects with residual disease and render the 
subject free of macroscopic disease. Subjects treated in this study may have lesions surgically 
resected only following consultation with the Medical Monitor and following the Week 25 tumor 
imaging assessments. If additional tumor shrinkage is noted compared to the tumor imaging 
assessments at Week 17, it is highly encouraged that surgical resection be delayed until subsequent 
scans fail to demonstrate further shrinkage. Subjects with a confirmed PR who go on to have 
surgical resection of remaining disease will be considered a PR. Subjects with SD who go on to 
have surgical resection of remaining disease will be considered a SD. Subjects may continue 
treatment after surgery. Tumor tissue of any resected solitary lesion should be submitted to BMS 
(see Section 5.6.9). Detailed instructions of the obtaining, processing, labeling, handling, storage 
and shipment of these specimens will be provided in a separate Procedure Manual at the time of 
study initiation.
3.4.4
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 treatment 
assignment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, allergy 
history, diabetic history and renal status), the appropriate imaging modality and contrast regimen 
for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with 
severe 
renal 
insufficiency 
(ie, 
estimated 
glomerular 
filtration 
rate 
(eGFR) 
< 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
Blood typing (Combo D only).  
Blood Type, Rh, and IAT should be done before the first dose of daratumumab. Subject RBC 
phenotyping (standard or extended) is an alternative option to the IAT test, if locally required. 
Either method must be completed prior to first daratumumab infusion. Daratumumab interferes 
with the Indirect Antiglobulin Test (IAT), which is a routine pre-transfusion test performed  to 
identify a patient’s antibodies to minor antigens so that suitable donor blood can be given for 
Revised Protocol No.: 07
Date: 07-May-2019
94
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
transfusion. Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very 
low levels on erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a 
positive IAT (Indirect Coombs Test). This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for transfusion.
This effect occurs during daratumumab treatment and for up to 6 months after treatment ends. 
Subjects will receive a patient identification wallet card for the study that includes the blood profile 
(ABO, Rh, and IAT or phenotyping) determined before the first infusion of daratumumab along 
with information on the IAT interference for healthcare providers/blood banks. Subjects are to 
carry this card throughout the treatment period and for at least 6 months after treatment ends. Blood 
banks can eliminate the daratumumab IAT interference with IAT by treating reagent RBCs with 
dithiothreitol (DTT).185
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically (standard or extended 
phenotyping) or genotypically matched units
b)
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is needed 
emergently as per local blood bank practice. Despite daratumumab binding to CD38 on 
erythrocytes, no indication of clinical significant hemolysis has been observed in daratumumab 
studies.
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
For discontinuation criteria related to nivolumab-and/or ipilimumab, BMS-986016
(relatlimab) or daratumumab-related adverse events, please refer to Section 4.7.6. 
Follow-up begins when the decision to discontinue a subject from study therapy is made 
(no further treatment with study therapy).
•
Subjects will have two follow-up visits for safety. Follow-up visit 1, 35 days from the last 
dose or from the date decision is made to discontinue subject from the study (only 
Revised Protocol No.: 07
Date: 07-May-2019
95
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
applicable for early treatment discontinuation) (± 7 days) and follow-up visit 2 80 days 
(± 7 days) after follow-up visit 1. After follow-up visit 2, subjects will be followed every 
3 months for ongoing drug-related adverse events until resolved, return to baseline or 
deemed irreversible, or until lost to follow-up, withdrawal of study consent, or start of a 
subsequent anti-cancer therapy.
•
Subjects who discontinue study therapy for reasons other than disease progression will 
continue to have radiographic assessments as per defined schedule until disease 
progression, lost to follow-up, or withdrawal of study consent.
•
PK and immunogenicity samples will be collected at the first 2 follow-up visits.
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. Please contact the Sponsor or designee within 24 hours of awareness of 
the pregnancy. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
This study will end when analysis of the primary endpoint is complete. Additional survival analysis 
may be conducted for up to 5 years beyond analysis of the primary endpoint.
3.6
Post Study Drug Study Follow-up
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drug must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected on all treated/randomized subjects outside of the 
protocol defined window (refer to Section 5.1). At the time of this request, each subject will be 
contacted to determine their survival status unless the subject has withdrawn consent for all 
contacts or is lost to follow-up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
Revised Protocol No.: 07
Date: 07-May-2019
96
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
•
Study required premedication, and 
•
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)
•
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
Revised Protocol No.: 07
Date: 07-May-2019
97
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 4.-1:
Product Description: Treatment Period
Product Description / Class and Dosage 
Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging/ 
Appearance
Storage Conditions
(per label)
BMS-936558-01 (Nivolumab) Solution 
for Injectiona
100 mg 
(10 mg/mL)
IP
Open Label
Various packaging 
configurations
Refer to the label on container 
and/or pharmacy manual
Ipilimumab Solution for
Injection
200 mg 
(5 mg/mL)
IP
Open Label
Various packaging 
configurations
Refer to the label on container 
and/or pharmacy manual
BMS-986016-01b
Injection
80 or 100 mg
(10 mg/mL)
IP
Open Label
Various packaging 
configurations
Refer to the label on container 
and/or pharmacy manual
Daratumumab
Injectionc
100 mg (20 
mg/mL)
and/or 400 mg 
(20 mg/mL)
IP
Open Label
Various packaging 
configurations
Refer to the label on container 
and/or pharmacy manual
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b Designated as BMS-986016 or relatlimab in the protocol
c These product may be obtained by the investigational sites as local commercial products in certain countries if allowed by local regulations. In these cases, 
products may be in a different pack size/potency/pharmaceutical form than listed in the table. These products should be prepared/stored/administered in 
accordance with the package inserts or summaries of product characteristics (SmPCs).
Revised Protocol No.: 07
Date: 07-May-2019
98
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, the investigational product is: nivolumab for the neoadjuvant and metastatic 
monotherapy cohorts.
For the metastatic combination therapy cohort, the investigational products are nivolumab and 
ipilimumab for combination therapy Combo A and B, nivolumab and BMS-986016 (relatlimab)
for combination therapy Combo C, and nivolumab and daratumumab for combination therapy 
Combo D.
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. 
Standard of care treatment will be procured by the investigator.
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% sodium chloride injection, 5% dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information for nivolumab, ipilimumab, 
BMS-986016 (relatlimab), and daratumumab.
Revised Protocol No.: 07
Date: 07-May-2019
99
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Nivolumab is to be administered as an IV infusion. Nivolumab infusion must be promptly followed 
by a flush of diluent to clear the line. For Combo A and B, ipilimumab is to be administered as an 
approximately 30-minute IV infusion. At the end of the infusion, flush the line with a sufficient 
quantity of normal saline or 5% dextrose solution. When both study drugs (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 nivolumab infusion must be 
promptly followed by a flush of diluent to clear the line of nivolumab before starting the 
ipilimumab infusion. The second infusion will always be ipilimumab, and will start after the 
infusion line has been flushed, filters changed and patient has been observed to ensure no infusion 
reaction has occurred. The time in between infusions is expected to be approximately 30 minutes 
after completion of the nivolumab infusion.
For Combo C, where both nivolumab and BMS-986016 (relatlimab) are administered, nivolumab 
will be administered first, as an approximately 30-minute IV infusion. At the end of the infusion, 
flush the line with a sufficient quantity of normal saline or 5% dextrose solution. When both study 
drugs (nivolumab and BMS-986016) 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 
nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the BMS-986016 infusion. The second infusion will be BMS-986016 and will start 
after the infusion line has been flushed, filters changed and patient has been observed to ensure no 
infusion reaction has occurred. BMS-986016 infusion will start within 60 minutes after completion 
of the nivolumab infusion. Further details regarding preparation and administration will be 
provided separately in site/pharmacy training materials.
For Combo D, daratumumab injection for IV infusion is considered IMP for this study. 
Daratumumab is an immunoglobulin G1 kappa human monoclonal antibody against CD38 
antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant 
DNA technology. The molecular weight of daratumumab is approximately 148 kDa. 
Daratumumab is supplied as a colorless to pale yellow preservative-free solution for intravenous 
infusion in single-dose vials. Starting on week 3, when both nivolumab and daratumumab are 
administered, nivolumab will be administered first followed by daratumumab by at least 30 
minutes after completion of nivolumab infusion. 
Pre-infusion medications should be administered before starting daratumumab infusions. On days
when nivolumab and daratumumab are both administered, daratumumab pre-medications may be 
administered before the start of the nivolumab infusion. Post-infusion medications should be 
administered upon completion of the daratumumab infusion.
Therefore, the sequence of administration on days when nivolumab and daratumumab are 
administered should be as follows:
•
Daratumumab pre-infusion medications
•
Nivolumab infusion
•
Daratumumab infusion
•
Daratumumab post-infusion medications
Revised Protocol No.: 07
Date: 07-May-2019
100
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Daratumumab Infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL (second 
and subsequent doses) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation 
of infusion bags should be done on the day of the planned infusion. Daratumumab must be 
administered as an IV infusion given through a well-functioning IV catheter by using an infusion 
pump. The study drug must be filtered by using an inline filter (0.2 μM) during the infusion. The 
infusion rates for the first, second, and subsequent daratumumab infusions should closely follow 
the specifications of the currently approved (USPI)/pharmacy reference manual.184 Pharmacy 
manuals with detailed descriptions for preparation and administration of daratumumab will be 
supplied to each pharmacy and site.
Because of this high risk of infusion related reactions daratumumab infusions will be administered 
per the Investigator’s Brochure by a healthcare professional, with immediate access to emergency 
equipment and appropriate medical support to manage infusion reactions if they occur, and all 
subjects will receive pre-infusion and post-infusion medication per the descriptions in 
Section 4.7.7 of the protocol. 
Before administration the drug product should be stored and prepared as per the instructions in 
pharmacy manual. Daratumumab (dose) will be administered as an IV infusion. Each subject’s 
dose will be calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest 
kilogram. The dose of daratumumab to be administered to a subject will be calculated by 
multiplying the subject’s weight (kg) by 16 mg/kg. The dose of daratumumab will remain constant 
throughout the study, unless the subject’s weight changes more than 10% from Cycle 1 Day 1. All 
infusions will be planned as outpatient visits. Subjects will receive pre-infusion medications and 
post-infusion medications as detailed in the protocol (Section 4.7.7). 
The infusion start and stop time will be recorded in the CRF. If the infusion is stopped mid-session 
for any reason, the stop/start time must be recorded together with an explanation.
The dilution volumes, initial infusion rates, and increment for the first, second, and subsequent 
doses are provided in Table 4.3-1. The infusion rates for the first, second, and subsequent 
daratumumab infusions should closely follow the specifications of the currently approved 
(USPI)/pharmacy reference manual. The maximum infusion rate for all infusions is 200 mL/hour. 
Additional details for administration times and rates, as well as pre-infusion medications, will be 
provided in the pharmacy manual.
Revised Protocol No.: 07
Date: 07-May-2019
101
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 4.3-1:
Daratumumab Infusion Rates
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum 
Infusion Rate
First infusion
1000 mL
50 mL/hour
50 mL/hour
every hour
200 mL/hour
Second infusiona
500 mL
50 mL/hour
50 mL/hour
every hour
200 mL/hour
Subsequent infusionsb
500 mL
100 mL/hour
50 mL/hour
every hour
200 mL/hour
a Modified rates should only be used if the first infusion of daratumumab was well tolerated as defined by an absence 
of > Grade 1 infusion-related reactions during the first 3 hours.
b Modified rates should only be used if the first 2 infusions of daratumumab were well tolerated as defined by an 
absence of > Grade 1 infusion-related reactions during a final infusion rate of ≥100 mL/hr.
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or 
subjects with stage 2 COPD who have a known FEV1 <80% at screening or developed FEV1 
<80% during the study without any medical history) the following post infusion medications 
should be considered:
•
Antihistamine (diphenhydramine or equivalent) 
•
Leukotriene inhibitor (montelukast or equivalent)
•
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
•
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 
adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators such as 
tiotropium or salmeterol ± inhaled corticosteroids for subjects with COPD)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their spirometry test (FEV1) should be performed before 
discharge. If these subjects are not hospitalized, then a follow up telephone call should be made to 
monitor their condition within 48 hours after all infusions. If no infusion-related reaction has 
occurred, the follow-up telephone call 48 hours after the infusion is not required. If the subject has 
not experienced a significant medical event but is hospitalized overnight only for observation, then 
the hospitalization should not be reported as a serious adverse event. Investigators may prescribe 
bronchodilators, H1-antihistamines, and corticosteroids that are deemed necessary to provide 
adequate supportive care in the event a bronchospasm occurs after subjects are released from the 
hospital/clinic. If an at-risk subject experiences no major infusion-related reactions, then these 
post-infusion medications may be waived after 4 doses at the investigator’s discretion. 
Any post-infusion medication will be administered after the infusion has completed.
4.4
Method of Assigning Subject Identification
The subject number will be assigned through an interactive response technology (IRT) system
once the subject has signed the informed consent form and is registered. Every subject that signs 
Revised Protocol No.: 07
Date: 07-May-2019
102
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
the informed consent form must be assigned a subject number in IRT. Specific instructions for 
using IRT will be provided to the investigational site in a separate document.
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Confirm that informed consent was obtained
•
Date of birth
•
Gender at birth
•
Subject Identification Method
•
Which cohort the subject will be enrolled (Neoadjuvant or Metastatic)
•
Tumor type for subject
Once enrolled subjects have met all eligibility criteria the IRT must be contacted again for 
treatment assignment, drug vial (nivolumab, nivolumab plus ipilimumab, nivolumab plus 
BMS-986016, nivolumab plus daratumumab), and to confirm that the Cohort/Tumor Type that the 
subject would qualify for is not closed for the study. 
Upon approval of Revised Protocol 05, enrollment will be concurrent for metastatic/recurrent 
combinations A, B, and D, and enrollment in Cohorts C will be closed.
The following information is required for drug vial assignment:
•
Subject number
•
Date of birth
•
Confirmation of viral status (for Neoadjuvant Cohort: SCCHN subjects, and Metastatic 
Cohorts: Gastric and SCCHN subjects, see Table 3.1.1-1)
Confirmation of viral status will be required prior to study drug assignment for EBV gastric cancer 
and HPV SCCHN tumor types in the metastatic cohorts. Confirmation of viral status will also be 
required prior to study drug assignment for SCCHN subjects enrolled in the neoadjuvant cohort. 
Subjects with gastric cancer or SCCHN tumor types will provide consent, via pre-screening 
informed consent, for determination of viral status.
Results will be entered into the IRT by sites at the screening visit, or results will be transferred 
from the central laboratory to the IRT via an automated feed. After positive test result 
confirmation, consent for demographic and further eligibility will be collected. If the viral status 
result cannot be confirmed for EBV gastric cancer and HPV SCCHN tumor types in the metastatic 
cohorts, and HPV SCCHN tumor types in the neoadjuvant cohort, those subjects will not be able 
to enter the treatment phase of the study and will be considered enrollment failures.
If the Cohort/Tumor Type that the subject would qualify for has already met the maximum number 
of subjects, the subject will not be able to enter the treatment phase of the study and will be 
considered an enrollment failure.
The exact procedures for using the IRT will be detailed in the IRT manual.
Revised Protocol No.: 07
Date: 07-May-2019
103
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
4.5
Selection and Timing of Dose for Each Subject
Table 4.5-1:
Study Drug Dosing
Cohort
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Neoadjuvant
Nivolumab
240 mg flat
dose
Day 1,
Day 15
30 minute 
Intravenous (IV) 
infusion
Two doses
Metastatic
Monotherapy
Nivolumab
240 mg flat
dose
every 2 weeks
30 minute 
Intravenous (IV) 
infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
Neoadjuvant
Subjects Treated 
with Study Drug
Post-Standard of 
Care
Nivolumab
240 mg flat
dose
every 2 weeks
30 minute 
Intravenous (IV) 
infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
Metastatic 
Combination 
Cohort 
Combo A
Nivolumab
3 mg/kg
every 2weeks 
30 minute 
Intravenous (IV) 
infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
Ipilimumab
1 mg/kg 
every 6week
30 minute 
Intravenous (IV) 
infusion
Metastatic 
Combination 
Cohort Combo 
B
(Cervical cancer 
and anogenital 
HPV associated 
tumors only)
Nivolumab
1 mg/kg
every 3 weeks 
for 4 doses
30 minute 
Intravenous (IV) 
infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
240 mg flat 
dose
then every 2 
weeks
Ipilimumab
3 mg/kg 
every 3weeks 
for 4 doses
30 minute 
Intravenous (IV) 
infusion
Metastatic 
Combination 
Cohort
Combo C
Nivolumab
240 mg flat 
dose
every 4weeks
(every 
2 weeks)
30 minute 
Intravenous (IV) 
infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
BMS-986016
(relatlimab)
(80 mg)
(every 2 weeks)
60 minute 
Intravenous (IV) 
infusion
Revised Protocol No.: 07
Date: 07-May-2019
104
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 4.5-1:
Study Drug Dosing
Cohort
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
consent, whichever 
comes first 
discontinuation 
from study
Metastatic 
Combination 
Cohort
Combo D
Nivolumab
240 mg flat 
dose
Every 2 weeks 
starting at Week 
3
30 minute 
Intravenous (IV) 
infusion
Maximum of 
24 months or until 
disease 
progression, 
unacceptable 
toxicity, or 
withdrawal of 
consent, whichever 
comes first
480 mg flat 
dose
then every 4 
weeks starting at 
Week 25
Nivolumab will be administered 
before daratumumab when both 
study drugs are administered on 
the same day.
Daratumumab
16 mg/kg
Every week 
(Wks 1-8) then 
every 2 weeks 
(Wks 9-24), then 
every 4 weeks 
starting at Week 
25
Intravenous (IV) 
infusion
See Section 4.3
Neoadjuvant Cohort subjects will receive two doses of nivolumab administered at 240 mg IV on 
Day 1 and on Day 15 (+1 week). A delay of the 2nd dose of nivolumab is acceptable for up to 1 
week (up to Day 22); however, the 2nd dose of nivolumab should not be administered after Day 
22 in order to avoid postponing surgery/biopsy beyond Day 29 and subsequent standard of care.
Metastatic Monotherapy Cohort subjects will receive treatment with nivolumab on Day 1 of a 
treatment cycle every 2 weeks (14 days). 
Metastatic Combination Cohort subjects will be assigned to receive one of the following dosing 
schema (starting Day 1) based on tumor type and randomization:
•
Combo A: nivolumab 3 mg/kg q2 weeks + ipilimumab 1 mg/kg q6 weeks: ± 1 week
(no less than 5 weeks between doses)
•
Combo B: nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q3 weeks x4, followed by nivolumab 
240 mg q2 weeks: +/-3 days (no less than 18 days between doses)
•
Combo C: nivolumab 240 mg + BMS-986016 160 mg, q4 weeks: ± 2 days.
•
Combo D: daratumumab q1 week x8, q2 weeks (Weeks 9-24); q4 weeks starting at Week 
25 + nivolumab 240 mg q2 weeks (starting at Week 3); 480 mg q4 weeks starting at Week 
25. Nivolumab will be administered before daratumumab on study days when both drugs 
are administered on the same day. Dosing windows for daratumumab are as follows: 
Revised Protocol No.: 07
Date: 07-May-2019
105
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Weeks 1-8: -1 and +3 days; Weeks 9-24: ± 1 week; Week 25+: up to 14 days delayed. For 
nivolumab, no less than 12 days between dosing is allowed.
Subjects who complete the neoadjuvant portion of the study and complete standard of care 
treatment post-surgery/biopsy who develop unresectable recurrent or metastatic disease within 1 
year of surgical resection, or completion of standard of care (whichever is later), may receive 
treatment with nivolumab monotherapy, if eligible. Eligibility assessments are detailed in Table 
5.1-5.
Please refer to the Pharmacy Manual for more detail. There are no pre-medications recommended 
on the first cycle, except for Combo D. All subjects in Combo D will receive pre-infusion and 
post-infusion medication per the descriptions in Section 4.7.7 of the protocol. If an acute infusion 
reaction is noted, subjects should be managed according to Section 4.7.7.
Dosing modifications:
There will be no dose modifications allowed for the management of toxicities of individual 
subjects.
Dosing window: 
When nivolumab is administered alone and in combination with BMS-986016 (relatlimab), 
subjects may be dosed no less than 12 days between doses during Q2 week dosing. For ipilimumab 
(Combo A), subjects may be dosed within a ± 1-week window and no less than 5 weeks from the 
previous dose. For subjects in Combo B, when nivolumab is administered in combination with 
ipilimumab, subjects may be dosed within a ± 3-day window and no less than 18 days from the 
previous dose. A dose given more than 3 days after the intended dose date will be considered a 
delay, except for subjects receiving ipilimumab in Combo A. A maximum delay of 6 weeks 
between doses is allowed, except for subjects in the Neoadjuvant cohort.
Daratumumab will be administered at a dose of 16 mg/kg as an IV infusion every week for the 
8 doses (-1 and +3 days window is allowed), every two weeks from weeks 9 to 24 (can be delayed 
up to 1 week) and every four weeks from weeks 25 onwards (can be delayed up to 14 days) until 
toxicity or disease progression.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.7.1
Premedications
Antiemetic medications should not be routinely administered prior to dosing of nivolumab, 
ipilimumab, and BMS-986016 (relatlimab). See Section 4.7.7 for subsequent premedication 
recommendations following a study drug-related infusion reaction.
Revised Protocol No.: 07
Date: 07-May-2019
106
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
See Section 4.3 for post-infusion medications for subjects at higher risk of respiratory 
complications (Combo D only). All subjects in Combo D will receive pre-infusion and post-
infusion medication per the descriptions in Section 4.7.7 of the protocol.
4.7.2
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab, ipilimumab, 
BMS-986016 (relatlimab), and daratumumab are considered immuno-oncology agents in this 
protocol. Early recognition and management of adverse events associated with immuno-oncology 
agents may mitigate severe toxicity. Management algorithms have been developed to assist 
investigators in assessing and managing the following groups of adverse events:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathies
•
Skin
•
Neurological
The safety management algorithms are provided in Appendix 2 of this protocol.
4.7.3
Dose Delay Criteria
Study drug administration (nivolumab, ipilimumab, and BMS-986016) should be delayed for the 
following:
•
Grade 2 non-skin, drug-related adverse event, except for fatigue.
•
Grade 3 skin, drug-related adverse event
•
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin
•
Grade 3 drug-related fatigue, nausea, vomiting, and anemia (Combination Cohort C only)
•
Grade  3 drug-related laboratory abnormality, with the following exceptions:
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require a dose delay
−
Grade ≥ 3 AST, ALT, or total bilirubin will require dose discontinuation (Section 4.7.6)
•
All troponin elevations require a dose delay to allow for prompt cardiac evaluation (Combo C 
only)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study drug.
•
Subjects receiving ipilimumab or BMS-986016 in combination with nivolumab that have drug-
related toxicities that meet the criteria for dose delay, should have both drugs (nivolumab and 
either ipilimumab, or BMS-986016) delayed until retreatment criteria are met.
•
Subjects who require delay of study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria are 
met.
Revised Protocol No.: 07
Date: 07-May-2019
107
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
For subjects receiving Combo D treatment, daratumumab dose should be delayed if any of the 
following criteria below are met, to allow for recovery from toxicity related to daratumumab. For 
subjects whose dose delay is not related to nivolumab, treatment with nivolumab may continue:
•
Grade 4 hematologic toxicity, except for grade 4 lymphopenia
•
Grade 3 or higher thrombocytopenia with bleeding
•
Febrile neutropenia
•
Neutropenia with infection, of any grade
•
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
−
Grade 3 nausea that responds to antiemetic treatment within 7 days
−
Grade 3 vomiting that responds to antiemetic treatment within 7 days
−
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
−
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
−
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Table 4.7.3-1:
Daratumumab Dose Delay Guidance
Week
Frequency
Dose Held
Dosing Re-start
1-8
Weekly (q1wk)
>3 days
next planned weekly dosing date
9-24
Biweekly (q2wks)
>7 days
next planned biweekly dosing date
25+
Every 4 weeks (q4wks)
>14 days
next planned every 4 weeks dosing date
•
Subjects experiencing a Grade 3 infusion reaction related to daratumumab must permanently 
discontinue daratumumab.
•
Any adverse event deemed to be related to daratumumab that requires a dose hold of more than 
3 consecutive planned doses will result in permanent discontinuation of daratumumab. If a 
dose delay occurs, then pharmacokinetic and pharmacodynamic assessments should be 
performed on the actual day of study drug administration, not on the original scheduled 
administration day
•
Subjects who miss ≥3 consecutive planned doses of daratumumab for reasons other than 
toxicity should be withdrawn from study drug, unless, upon consultation with the sponsor and 
the review of safety and efficacy, continuation is agreed upon. Subjects who are withdrawn 
from daratumumab may continue to receive nivolumab.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study drug.
Doses of daratumumab may be delayed up to 4 weeks during Weeks 1-24 or up to 6 weeks from 
Week 25 and beyond. Any adverse event deemed to be related to daratumumab that requires a 
dose hold longer than those specified above will result in permanent discontinuation of 
daratumumab. If a dose delay occurs, then pharmacokinetic and pharmacodynamic assessments 
Revised Protocol No.: 07
Date: 07-May-2019
108
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
should be performed on the actual administration day of daratumumab, not on the original 
scheduled administration day. 
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully 
recovered.
If daratumumab administration does not commence within the prespecified window (Table 4.7.3-
1) of the scheduled administration date, then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
Rescheduling (Combo A or B):
•
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.
•
A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 4.7.6.
4.7.4
Dose Reductions
There will be no dose reductions for nivolumab, ipilimumab, BMS-986016 or daratumumab.
4.7.5
Criteria to Resume Dosing
Subjects may resume treatment with study drug when the drug-related AE(s) resolve(s) to Grade 1 
or baseline, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue.
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
•
For 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. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
•
Subjects 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.
Revised Protocol No.: 07
Date: 07-May-2019
109
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor. Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.
•
Troponin elevations will require the participant to undergo a cardiac evaluation. Following this 
evaluation, determination of further treatment will be based on the discussion with the BMS 
medical monitor/designee.
•
Dose delay of nivolumab, BMS-986016 and ipilimumab (Combo B), which results in treatment 
interruption of > 6 weeks requires treatment discontinuation, with exceptions as noted in 
Section 4.7.6.
•
Dose delay of ipilimumab in Combo A, which results in treatment interruption of > 12 weeks 
requires treatment discontinuation, with exceptions as noted in Section 4.7.6. 
•
Ipilimumab may not be resumed sooner than 6 weeks (+/- 3 days) after the prior ipilimumab 
dose for Combo A.
•
In general, subjects 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 
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 
subject's medical chart. The BMS Medical Monitor should be consulted prior to resuming 
nivolumab in such subjects.
•
Subjects may resume treatment with daratumumab in Combo D, when the toxicity has resolved 
to Grade 2 or baseline, with the exception that Grade 2 laryngeal edema or Grade 2 
bronchospasm must be fully recovered. If the daratumumab administration does not commence 
within the pre-specified window of the scheduled administration date, then the dose will be 
considered a missed dose. Administration may resume at the next planned dosing date.
4.7.6
Discontinuation Criteria
Treatment with study drug should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the 
following exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-
related uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, myocarditis, infusion 
reactions, and endocrinopathies:
Revised Protocol No.: 07
Date: 07-May-2019
110
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
−
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.  
Note: * In most cases of Grade 3 AST or ALT elevation, study drug(s) will be 
permanently discontinued. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug(s), a discussion between 
the investigator and the BMS Medical Monitor/designee must occur.
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events, which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events such as hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (steroids, thyroid hormones) or glucose-controlling agents, respectively, may 
not require discontinuation after discussion with and approval from the BMS Medical 
Monitor.
•
Daratumumab treatment should be permanently discontinued for the following reasons:
−
Grade 4 infusion reactions related to daratumumab.
−
For Grade 3 infusion reactions related to daratumumab: Once reaction symptoms resolve, 
consider restarting the infusion at no more than half the rate at which the reaction occurred. 
If the patient does not experience additional symptoms, resume infusion rate escalation at 
increments and intervals as outlined in Table 4.3-1. Repeat the procedure above in the event 
of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third 
occurrence of a Grade 3 or greater infusion reaction 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued study drug
dosing.
Revised Protocol No.: 07
Date: 07-May-2019
111
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
Any event that leads to delay in dosing lasting > 6 weeks for Combo B and C, and > 12 
weeks for Combo A 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 (Combo A and C) or >12 weeks (Combo A) from the 
previous dose that occur for non-drug-related reasons may be allowed if approved by the 
BMS medical monitor. 
For Combo A, B, and C, prior to re-initiating treatment in a subject with a dosing delay lasting 
> 6 weeks (Combo B and C) and > 12 weeks (Combo A), the BMS medical monitor 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 study drug should be made separately considering each 
study drug. If discontinuation criteria are attributed with only one drug used in this trial, once the 
subject meets criteria to resume therapy, the subject may continue dosing with the remaining study 
drug not attributed to criteria for discontinuation. In the nivolumab and BMS-986016 (relatlimab)
combination (Combo C), if discontinuation criteria are met, both drugs (nivolumab and BMS-
986016) will be discontinued regardless of the assessment of attribution to a particular study drug.
If a subject meets criteria for discontinuation and investigator is unable to determine whether the 
event is related to both or one study drug, the subject should discontinue all study drugs and be 
taken off the treatment phase of the study. 
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.
4.7.7
Treatment of Study Drug-related Infusion Reactions
Since 
nivolumab,
ipilimumab, 
and 
BMS-986016
(relatlimab)
contain 
only 
human 
immunoglobulin protein sequences, it is unlikely to be immunogenic and induce infusion or 
hypersensitivity reactions. However, if such a reaction were to occur, it might manifest with fever, 
chills, rigors, headache, rash, pruritus, 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) guidelines.
For subjects in the combination cohorts A, B and C when ipilimumab or BMS-986016 (relatlimab)
are scheduled to be administered on the same day as nivolumab, if a subject has an infusion 
reaction with nivolumab, the ipilimumab or BMS-986016 (relatlimab) infusion can be given 
(without prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling 
purposes after a nivolumab infusion reaction, the ipilimumab or BMS-986016 (relatlimab) 
infusion may be given the next day. Prophylactic pre-infusion medications should be given prior 
to all subsequent nivolumab infusions.
Revised Protocol No.: 07
Date: 07-May-2019
112
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 
30 minutes before additional study drug 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 infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further study drug will be administered at that visit. Administer diphenhydramine 
50 mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). 
The following prophylactic premedications are recommended for future infusions: 
•
Diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of 
IV hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae [eg, 
renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or ventilatory support 
indicated).
•
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
Revised Protocol No.: 07
Date: 07-May-2019
113
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
Guidelines for prevention and management of daratumumab infusion-related reactions
Prevention of Daratumumab Infusion related reactions:
•
Pre-infusion medication to be administered to all subjects approximately 1 hour prior to every 
daratumumab infusion (can be administered before the nivolumab infusion):
o
IV corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate acting 
or long-acting corticosteroid). Following the second infusion, the dose of corticosteroid 
may be reduced (methylprednisolone 60 mg IV), PLUS
o
Oral antipyretics (acetaminophen 650 to 1000 mg), PLUS
o
Oral or IV antihistamine (diphenhydramine 25 to 50 mg or Leukotriene Inhibitor (optional) 
on Cycle 1 Day 1: montelukast 10 mg PO, or equivalent).
•
Post-infusion medication to be administered to all subjects to reduce the risk of delayed 
infusion reactions:
o
Oral corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid in 
accordance with local standards) on the first and second day after all infusions
o
At the investigator discretion, for subjects with a history of obstructive pulmonary disorder, 
short and long-acting bronchodilators and inhaled corticosteroids can be administered. 
Following the first 4 infusions, if subjects experience no major infusion reactions, these 
additional inhaled post-infusion medications may be discontinued. 
Subjects should be carefully monitored for infusion reactions during daratumumab administration. 
Trained study staff at the clinic should be prepared to intervene in case of any infusion reactions, 
and resources necessary for resuscitation must be available. All subjects should have blood 
pressure monitored before and after all infusions. For the first two infusions, blood pressure should 
also be monitored during the infusion. There will be no dose escalations or reductions of 
daratumumab allowed. Doses of daratumumab may be interrupted, delayed, or discontinued 
depending on how well the subject tolerates the treatment.
Revised Protocol No.: 07
Date: 07-May-2019
114
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
If an acute infusion reaction is noted, subjects should be managed according to the Investigator’s 
Brochure and as summarized below.
Management of Daratumumab Infusion related reactions:
Per Revised Protocol 06, enrollment and treatment in this cohort have been terminated. Subjects 
should be carefully observed during daratumumab infusions. Trained study staff at the clinic 
should be prepared to intervene in case of any infusion reactions, and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at bedside. Attention to staffing should be considered when multiple subjects will be dosed at the 
same time.
Interrupt the daratumumab infusion for infusion-related reactions of any severity. Management of 
infusion reactions may require further reduction in the rate of infusion, or treatment 
discontinuation of daratumumab.
Subjects who experience adverse events during the infusion must be treated according to the 
investigator’s judgment and best clinical practice. Subjects should be treated with acetaminophen, 
antihistamine, and/or corticosteroids as needed. Intravenous saline may be indicated. For 
bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen, corticosteroids, 
or bronchodilators. For hypotension, subjects may require vasopressors.
If an infusion is interrupted, then a longer-than-anticipated infusion time may occur. Overnight 
stays at the hospital because of slow infusion times should not be reported as serious adverse 
events. However, if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such.
Infusion-related reactions of grade 1 or grade 2: Once reaction symptoms resolve, resume the 
infusion at no more than half the rate at which the reaction occurred. If the patient does not 
experience any further reaction symptoms, infusion rate escalation may resume at increments and 
intervals as appropriate as outlined in Table 4.3-1.
Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more 
than half the rate at which the reaction occurred. If the subject does not experience additional 
symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 4.3-1. 
Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently 
discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion-related 
reaction.
Grade 4 (life threatening): Permanently discontinue daratumumab treatment.
4.7.8
Treatment Beyond Disease Progression
Accumulating clinical evidence indicates some subjects 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 subjects in the Phase 1 study of nivolumab and also with ipilimumab 
Revised Protocol No.: 07
Date: 07-May-2019
115
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
monotherapy.186 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, subjects will be allowed to continue study therapy after 
initial investigator-assessed RECIST 1.1 defined progression as long as they meet the following 
criteria:
1) Investigator-assessed clinical benefit, and do not have rapid disease progression
2) Tolerance of study drug as defined by the investigator
3) Stable performance status
4) Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
5) Subject provides a new written informed consent prior to receiving any additional study drug 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
Patients enrolled to the nivolumab monotherapy, the nivolumab plus ipilimumab, nivolumab plus 
BMS-986016 (relatlimab), or the nivolumab plus daratumumab combination arms may be allowed 
to continue treatment beyond initial progression for up to a maximum of 24 months from the date 
of first dose. In this instance, subjects may continue therapy with assigned treatment.
All decisions to continue treatment beyond initial progression must be discussed with the BMS 
Medical Monitor and documented in the study records. Subjects will be re-consented with an 
ICF describing any reasonably foreseeable risks or discomforts.
Subjects should discontinue study therapy upon further evidence of further progression, defined 
as an additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions).
New lesions are considered measurable 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-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden measurement if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have an increase in 
short axis to at least 15 mm).
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
Revised Protocol No.: 07
Date: 07-May-2019
116
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.
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. 
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.
Revised Protocol No.: 07
Date: 07-May-2019
117
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Screening Procedural Outline for All Subjects (CA209358)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Register in Interactive Response Technology (IRT) system to obtain subject 
number.
Pre-screening informed consent will be obtained to perform viral testing for 
Gastric and SCCHN subjects. Register subject in IRT. Once viral status is 
confirmed positive, informed consent will be obtained for full eligibility 
assessments. See Viral Testing row below in this table for additional details. 
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed 
prior to first dose
Medical History
X
Serious Adverse Event Assessment
X
Serious Adverse Events from time of consent. See Section 6.
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose
Physical Measurements
X
Include Height and Weight
Within 14 days prior to first dose
Vital Signs 
X
Temperature, BP and HR 
Within 72 hours of first dose
Performance Status (ECOG)
X
Within 14 days prior to first dose
See Appendix 1 for ECOG scale
Echocardiogram
X (see 
notes)
For Combo C only:  LVEF assessment with documented LVEF ≥ 50% by either 
TTE or MUGA (TTE preferred test) within 6 months from first study drug 
administration
Revised Protocol No.: 07
Date: 07-May-2019
118
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline for All Subjects (CA209358)
Procedure
Screening
Visita
Notes
ECG
X
Within 14 days prior to first dose
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days 
prior to first dose.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Laboratory Tests
X
CBC with differential and platelet count, Chemistry panel including LDH, AST, 
ALT, ALP, T.Bili, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, P, 
glucose, bicarbonate or total CO2 (if locally available), albumin, amylase, lipase, 
TSH (reflex to free T3, free T4 for abnormal TSH result), hepatitis B surface 
antigen (HBV sAg, Australia antigen), and hepatitis C antibody (HCV Ab or 
RNA)
Within 14 days prior to first dose.
Combo C only -  Cardiac Troponin Levels: T (cTnT) or I (cTnI)
Viral Testing
X
See Section 5.6.1.
Pre-screening informed consent will be obtained prior to viral testing
•
Confirmation of viral status will be required prior to study drug assignment for 
EBV gastric cancer and HPV SCCHN tumor types in the metastatic cohorts 
(monotherapy and combination).
•
If SCCHN subjects decline pre-screening informed consent or are unwilling to 
undergo viral testing, they are eligible to enroll in Combo D. However, viral 
status should be determined retrospectively.
•
Confirmation of viral status will be required prior to study drug assignment for 
SCCHN subjects enrolled in the neoadjuvant cohort.
•
See the Efficacy/Biomarker Assessment section of this table for additional 
information regarding other tumor types. 
Pregnancy Test
X
Serum or urine pregnancy testing to be done at screening visit and repeated within 
24 hours of first dose.
Blood type (ABO, Rh, and indirect antiglobulin testing -
Cohort D only)
X
Within 14 days prior to first dose
Revised Protocol No.: 07
Date: 07-May-2019
119
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline for All Subjects (CA209358)
Procedure
Screening
Visita
Notes
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
Spiral CT/MRI of Chest, Abdomen, Pelvis, and any other 
known sites of disease 
X
Should be performed within 35 days prior to first dose.
Additional sites of known or suspected disease (including CNS) should be imaged 
at the screening visit and at subsequent on-study assessments. 
Collection of tumor tissue 
X
For both the Neoadjuvant and Metastatic Cohorts: Submission of tumor tissue is 
mandatory. A fresh biopsy is preferred. An archived sample of an FFPE tumor 
tissue block or 15 unstained slides collected as a standard of care procedure within 
90 days prior to obtaining informed consent is acceptable for metastatic cohorts. 
Fresh Biopsies are mandatory for neoadjuvant cohort patients.
Fresh biopsy samples should be excisional, incisional, or core needle. Fine needle 
aspirates are not acceptable. Tumor biopsies should be placed in formalin for IHC 
of tumor and TIL, RNALater for gene expression, and media for flow cytometry 
analysis (neo-adjuvant cohort only) as described in the laboratory manual.
If HPV viral status of the gynecological (cervical, vaginal, vulvar) or anogenital 
HPV associated tumor types (anal canal, penile) is not available, a fresh collection 
of tumor cells will be required. Please see laboratory manual for details.
See Section 5.6.9 for Biomarker Sampling Schedules.
Record Historic mutation/markers of interest 
X
EBV gastric (metastatic monotherapy cohort only):  EBV status, HER2, CDH1, 
PIK3CA
HPV Head/Neck:  HPV status, PIK3CA
Cervical, Vaginal, Vulvar, Anal Canal, Penile:  HPV status
MCC:  Polyomavirus status, BRAF (V599), CK20, TFF-1
HPV NPC:  HPV Status, KRAS, NRAS, PIK3CA
Revised Protocol No.: 07
Date: 07-May-2019
120
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline for All Subjects (CA209358)
Procedure
Screening
Visita
Notes
IRT/Clinical Drug Supplies
Phone calls to IRT
X
Phone calls must be made to IRT as follows:
•
For subject number assignment at the time of pre-screening informed consent 
is obtained (Gastric and SCCHN patients)
•
For subject number assignment at the time informed consent is obtained.
•
Prior to dosing for study drug vial assignment (call should be made within 
5 days prior to dosing).
•
Confirmation of viral status will be required prior to study drug assignment for 
EBV gastric cancer (metastatic monotherapy cohort only) and HPV SCCHN 
tumor types in the neoadjuvant and metastatic cohorts (monotherapy or 
Combos A and C).
•
If SCCHN subjects decline pre-screening informed consent or are unwilling to 
undergo viral testing, they are eligible to enroll in Combo D. However, viral 
status should be determined retrospectively.
a Within 35 days prior to first dose
Revised Protocol No.: 07
Date: 07-May-2019
121
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments Metastatic Monotherapy Cohort (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle (every 
2 Weeks) on 
Day 1 (± 3 days)
Notes
Safety Assessments
Targeted Physical Examination
X
X
Targeted examination must include at a minimum the following body 
systems:
•
Cardiovascular
•
Gastrointestinal
•
Pulmonary
•
Neurological exam for subjects with brain metastases
Within 72 hours prior to dosing
Vital Signs
X
X
Temperature, BP, and HR prior to dosing and at any time a subject has 
any new or worsening respiratory symptoms. 
Obtain vital signs within 72 hours prior to dosing.
Physical Measurements
X
X
Includes Weight and ECOG performance status
See Appendix 1 for ECOG scale
Obtain physical measurements within 72 hrs prior to dosing.
Adverse Events Assessment
------ Continuously -------
Assessed using NCI CTCAE version 4.
Review of Concomitant Medications
X
X
Laboratory Tests
X
X
On-study local laboratory assessments should be done within 72 hours
prior to dosing for every cycle and include: CBC with differential and 
platelet count, BUN or serum urea level, serum creatinine, sodium, 
potassium, calcium, magnesium, phosphorus, chloride, bicarbonate or 
total CO2 (if locally available), amylase, lipase, glucose, AST, ALT, 
total bilirubin, alkaline phosphatase, LDH, albumin.
Labs required prior to first dose do not have to be repeated if screening 
labs were performed within 14 days prior to first dose.
Thyroid Function Testing
See Note
TSH (reflex to free T3 and free T4 if abnormal result) to be performed 
every 6 weeks (± 1 week).
Revised Protocol No.: 07
Date: 07-May-2019
122
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments Metastatic Monotherapy Cohort (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle (every 
2 Weeks) on 
Day 1 (± 3 days)
Notes
Pregnancy Test
X
See Note
Serum or urine within 24 hours prior to first dose and then at least once 
every 4 weeks (+/- 1 week) regardless of dosing schedule.
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
Spiral CT/MRI of Chest, Abdomen, Pelvis, and
any other known sites of disease
See Table 5.4.1-1 for imaging frequency.
See Appendix 3 (RECIST 1.1 Guidelines) for details regarding imaging methodology 
requirements and assessments
Collection of Tumor Tissue
Collection of tumor tissue (FFPE tumor tissue block or 15 unstained slides) for determination of PD-L1 
expression and other exploratory biomarker analysis.
Biopsy samples should be excisional, incisional, or core needle. Tumor biopsies should be placed in 
formalin for IHC of tumor and TIL and RNALater for gene expression.
See Table 5.6.9-2 for Biomarker Sampling Schedule
Serum
Plasma
PBMC
Whole Blood
See Table 5.6.9-2 for Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See Table 5.5-1 of PK and Immunogenicity Sampling
Immunogenicity samples
See Table 5.5-1 of PK and Immunogenicity Sampling
Outcomes Research Assessments
EORTC QLQ-C30
X
See note
Assessments to be collected every 4 cycles for the first 17 cycles:
Day 1 (prior to dosing) of Cycles 5, 9, 13, 17
every 6 cycles thereafter:
Day 1 (prior to dosing) of Cycles 23, 29, 35+.
EQ-5D
X
See note
Revised Protocol No.: 07
Date: 07-May-2019
123
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments Metastatic Monotherapy Cohort (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle (every 
2 Weeks) on 
Day 1 (± 3 days)
Notes
Clinical Drug Supplies
Administer Study Drug
X
X
First dose to be administered within 5 days of study drug assignment.
Confirmation of viral status will be required prior to study drug 
assignment for EBV gastric cancer and HPV SCCHN tumor types in the 
metastatic cohort.
Revised Protocol No.: 07
Date: 07-May-2019
124
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Safety Assessments
Targeted Physical 
Examination
X
X
X
X
Targeted examination must include at 
a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with 
brain metastases
Within 72 hours prior to dosing
Neurologic examination
X
Obtain neurological exam (performed 
by a neurologist) in subjects who 
experience a study drug related ≥ 
Grade 2 neurological AE.
Vital Signs
X
X
X
X
Temperature, BP, and HR prior to 
dosing and at any time a subject has 
any new or worsening respiratory 
symptoms.
Obtain vital signs within 72 hours 
prior to dosing.
Physical Measurements
X
X
X
X
Includes Weight and ECOG 
performance status
Revised Protocol No.: 07
Date: 07-May-2019
125
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Note: a change of +/- 10% of body 
weight from the prior dosing visit 
requires recalculation of dosea
See Appendix 1 for ECOG scale
Obtain physical measurements within 
72 hrs prior to dosing.
12-lead electrocardiogram
(ECG)
X (See Notes)
12-lead ECG to be performed within 
72 hrs prior to dosing using site’s own 
ECG machine.
Adverse Events Assessment
------ Continuously -------
Assessed using NCI CTCAE version 
4.
Review of Concomitant 
Medications
X
X
X
X
Revised Protocol No.: 07
Date: 07-May-2019
126
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Laboratory Tests (Cohorts 
A, C, and D)
X
X
X
On-study local laboratory assessments 
should be done within 72 hours prior 
to dosing for every cycle and include: 
CBC with differential and platelet 
count, BUN or serum urea level, 
serum creatinine, sodium, potassium, 
calcium, magnesium, phosphorus, 
chloride, bicarbonate or total CO2 (if 
locally available), amylase, lipase, 
glucose, AST, ALT, total bilirubin, 
alkaline phosphatase, LDH, albumin.
Labs required prior to first dose do not 
have to be repeated if screening labs 
were performed within 14 days prior
to first dose.
In addition, the following tests at 
Week 7 and 13, then every 6 weeks 
(3 cycles of nivolumab): TSH (Reflex 
to free T3 and free T4 if TSH 
abnormal. Total T3/T4 are acceptable 
if free T3/T4 are not available).
Combo C only:  Cardiac Troponin 
Levels: T (cTnT) or I (cTnI). Labs are 
performed locally, and may be 
collected within 72 hours prior to each 
dosing. Results must be reviewed by 
the Investigator or appropriate 
designee prior to dose administration.
Revised Protocol No.: 07
Date: 07-May-2019
127
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Laboratory Tests (Cohort B)
X
On-study local laboratory assessments 
should be done within 72 hours prior 
to dosing for every cycle and include: 
CBC with differential and platelet 
count, BUN or serum urea level, 
serum creatinine, sodium, potassium, 
calcium, magnesium, phosphorus, 
chloride, bicarbonate or total CO2 (if 
locally available), amylase, lipase, 
glucose, AST, ALT, total bilirubin, 
alkaline phosphatase, LDH, albumin.
Labs required prior to first dose do not 
have to be repeated if screening labs 
were performed within 14 days prior 
to first dose.
In addition, the following tests at 
Week 7 and 13, then every 6 weeks 
(3 cycles of nivolumab 240 mg): TSH 
(Reflex to free T3 and free T4 if TSH 
abnormal. Total T3/T4 are acceptable 
if free T3/T4 are not available)
Pregnancy Test (Cohort A, 
C, and D)
X
X
X
Serum or urine within 24 hours prior 
to first dose and then at least once 
every 4 weeks (+/- 1 week) regardless 
of dosing schedule.
Pregnancy Test (Cohort B)
X
Serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or 
Revised Protocol No.: 07
Date: 07-May-2019
128
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
equivalent units of HCG) to be done 
within 24 hours prior to first dose, and 
then at Week 4, 7, 10 and every 4 
weeks (+/- 1 week), regardless of 
dosing schedule.
Efficacy/Biomarker Assessments
Radiographic Tumor 
Assessment
Spiral CT/MRI of Chest, 
Abdomen, Pelvis, and any 
other known sites of disease
See Table 5.4.1-1 for imaging frequency.
See Appendix 3 (RECIST 1.1 Guidelines) for details regarding imaging methodology requirements and assessments.
Collection of Tumor Tissue
Collection of tumor tissue (FFPE tumor tissue block or 15 unstained slides) for determination of PD-L1 expression and other 
exploratory biomarker analysis.
Biopsy samples should be excisional, incisional, or core needle. Tumor biopsies should be placed in formalin for IHC of tumor
and TIL and RNALater for gene expression.
See Table 5.6.9-2 and Table 5.6.9-3 for Biomarker Sampling Schedule
Serum
Plasma
PBMC
Whole Blood
See Table 5.6.9-2 and Table 5.6.9-3 for Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See Table 5.5-1 through Table 5.5-8 for PK and Immunogenicity Sampling
Immunogenicity samples
Revised Protocol No.: 07
Date: 07-May-2019
129
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Outcomes Research Assessments s
EORTC QLQ-C30 (Cohorts 
A, C, and D)
X
X
X
Assessments to be collected at Day 1 
Week 1 every 4 cycles for the first 
17 cycles:
Day 1 (prior to dosing) of Cycles 1, 5, 
9, 13, 17;
Then every 6 cycles thereafter:
Day 1 (prior to dosing) of Cycles 23, 
29, 35+.
EORTC QLQ-C30 (Cohort 
B)
X
Assessments to be collected prior to 
dosing at Cycle 1 Day 1 and Cycle 4 
Day 1, and then every 4 cycles for 
16 cycles:
Day 1 (prior to dosing) Cycles 1, 4, 8, 
12, 16; 
Then every 6 cycles thereafter:
Day 1 (prior to dosing) Cycles 22, 28, 
34+
EQ-5D (Cohort A, C, and 
D)
X
X
X
Assessments to be collected at Day 1 
Week 1 every 4 cycles for the first 
17 cycles;
Day 1 (prior to dosing) of Cycles 1,5, 
9, 13, 17;
every 6 cycles thereafter; 
Day 1 (prior to dosing) of Cycles 23, 
29, 35+. 
Revised Protocol No.: 07
Date: 07-May-2019
130
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
EQ-5D (Cohort B)
X
Assessments to be collected prior to 
dosing at Cycle 1 Day 1 and Cycle 4 
Day 1, and then every 4 cycles for 
16 cycles:
Day 1 (prior to dosing) Cycles 1, 4, 8, 
12, 16; 
Then every 6 cycles thereafter:
Day 1 (prior to dosing) Cycles 22, 28, 
34+
Revised Protocol No.: 07
Date: 07-May-2019
131
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Clinical Drug Supplies
Administer Study Drug
(Cohort A)
Xa
First dose to be administered within 5 
days of study drug assignment.
Confirmation of viral status will be 
required prior to study drug 
assignment for HPV SCCHN tumor 
types in the metastatic cohort.
Dosing Window: +/-1 week 
Subjects may be dosed no less than 12 
days for nivolumab and 5 weeks for 
ipilimumab.
Administer Study Drug
(Cohort B)
Xa
First dose to be administered within 5 
days of study drug assignment.
Confirmation of viral status will be 
required prior to study drug 
assignment for HPV SCCHN tumor 
types in the metastatic cohort.
Dosing window: ± 3 days
Subjects may be dosed no less than 19 
days between q3week doses of 
nivolumab and ipilimumab, and no 
less than 12 days for nivolumab 
monotherapy after completion of 
ipilimumab induction.
Revised Protocol No.: 07
Date: 07-May-2019
132
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Administer Study Drug
(Cohort C)
X
First dose to be administered within 5 
days of study drug assignment.
Confirmation of viral status will be 
required prior to study drug 
assignment for HPV SCCHN tumor 
types in the metastatic cohort.
Dosing window +/-2 days.
Subjects may be dosed no less than 12 
days for nivolumab and BMS-986016.
Administer Study Drug
(Cohort D)
X
First dose to be administered within 5 
days of study drug assignment.
Viral testing may be done 
retrospectively for HPV SCCHN 
tumor type in the metastatic cohort
(Combo D).
Please see Table 4.7.3-1 for 
Daratumumab Dose Delay Guidance.
Dosing windows for 
Daratumumab
Wks 1-8: -1/ +3 days
Wks 9-24: +/-1 week
Wk 25+: up to 21 days delayed
Subjects may be dosed no less than 12 
days between nivolumab doses 
through Week 24 (240 mg)
Revised Protocol No.: 07
Date: 07-May-2019
133
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments Metastatic Combination Therapy Cohorts (CA209358)
Procedure
Combo A
During 
Treatment
Nivo 3mg q2w 
+ Ipi 1 mg/kg 
q6w
Combo B During 
Treatment
Nivo 1 mg/kg + Ipi 
3 mg/kg q3w x 4, 
followed by Nivo
240 mg q2w
Combo C
During Treatment 
Nivo 240 mg + 
BMS-986016 80 
mg q2w 
Combo D During 
Treatment 
Daratumumab q1 
week/q2weeks/q4 
weeks + Nivo 240 
mg q2 weeks/
480 mg every 4 
wks. 
Notes
See note sections below for dosing 
windows 
Subjects may be dosed no less than 21 
days between nivolumab doses 
beyond Week 25 (480 mg)
a Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to re-calculate subsequent doses if the participant weight is 
within 10% of the weight used to calculate the previous dose. All doses should be rounded up or to the nearest milligram per institutional standard.
Revised Protocol No.: 07
Date: 07-May-2019
134
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Assessments Neoadjuvant Cohort (CA209358)
Procedure
Day 1
Day 15
Pre-Surgery Visit
(up to7 days prior to 
surgery)
Notes
Safety Assessments
Targeted Physical Examination
X
X
X
Targeted examination must include at a minimum the 
following body systems:
•
Cardiovascular
•
Gastrointestinal
•
Pulmonary
•
Neurological exam for subjects with brain 
metastases
•
Site of resection of primary tumor
Once within 72 hours prior to nivolumab or surgery
Vital Signs 
X
X
X
Temperature, BP, and HR at rest and after exertion 
(also monitor amount of supplemental oxygen if 
applicable) prior to dosing and at any time a subject 
has any new or worsening respiratory symptoms.
Obtain vital signs within 72 hours prior to dosing.
Physical Measurements
X
X
X
Includes Weight and ECOG performance status
See Appendix 1 for ECOG scale
Adverse Events Assessment
---------- Continuously ----------
Assessed using NCI CTCAE version 4
Review of Concomitant Medications
X
X
X
Revised Protocol No.: 07
Date: 07-May-2019
135
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Assessments Neoadjuvant Cohort (CA209358)
Procedure
Day 1
Day 15
Pre-Surgery Visit
(up to7 days prior to 
surgery)
Notes
Laboratory Tests
X
X
X
Laboratory assessments should be done within 
72 hours prior to dosing for Day 1 and 15 and the 
Pre-Surgery Visit and include: CBC with differential 
and platelet count, BUN or serum urea level, serum 
creatinine, sodium, potassium, calcium, magnesium, 
phosphorus, chloride, bicarbonate or total CO2 (if 
locally available), amylase, lipase, glucose, AST, ALT, 
total bilirubin, alkaline phosphatase, LDH, albumin.
Labs required prior to first dose do not have to be 
repeated if screening labs were performed within 
14 days prior to first dose.
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result) 
Pregnancy Test
X
X
Serum or urine within 24 hours prior to first dose and 
then at least once every 4 weeks regardless of dosing 
schedule.
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
Spiral CT/MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
See Note
Post-Surgery: CT or MRI scan per local practices
See Table 5.4.1-2 for imaging frequency
See Appendix 3 (RECIST 1.1 Guidelines) for details 
regarding imaging methodology requirements and 
assessments
Revised Protocol No.: 07
Date: 07-May-2019
136
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Assessments Neoadjuvant Cohort (CA209358)
Procedure
Day 1
Day 15
Pre-Surgery Visit
(up to7 days prior to 
surgery)
Notes
Tumor Assessment (Surgery or Biopsy)
X
Sample sent for biomarkers. 
Surgery (SCCHN, MCC, Gyn) or biopsy (Gyn pts, 
where appropriate) on Day 29 ±7 days 
Collection of tumor tissue (FFPE tumor tissue block or 
15 unstained slides) for determination of PD-L1 
expression and other exploratory biomarker analysis.
Biopsy samples should be excisional, incisional, or 
core needle. Tumor biopsies should be placed in 
formalin for IHC of tumor and TIL, RNALater for 
gene expression, and media for flow cytometry 
analysis.
See Table 5.6.9-1 for Biomarker Sampling Schedule
Additional Exploratory Biomarker Assessments
Serum
Plasma
PBMC
Whole Blood
See Table 5.6.9-1 for Biomarker Sampling Schedule
Subsequent therapy
See Note
Postoperative treatment of participants
Adjuvant chemotherapy and/or radiation therapy: 
Postoperative treatment will be administered at the 
discretion of the treating physician based on 
established standard indications. Postoperative 
treatment will start at a time based on the standard of 
care approach at the institution taking into account 
postoperative recovery time for the subject. 
Postoperative treatment should not commence until 
nivolumab-related toxicity has resolved to < grade 2.
Revised Protocol No.: 07
Date: 07-May-2019
137
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-4:
On Treatment Assessments Neoadjuvant Cohort (CA209358)
Procedure
Day 1
Day 15
Pre-Surgery Visit
(up to7 days prior to 
surgery)
Notes
PK and Immunogenicity Assessments
PK samples
See Table 5.5-2 of PK and Immunogenicity Sampling
Immunogenicity samples
See Table 5.5-2 of PK and Immunogenicity Sampling
Outcomes Research Assessments
EORTC QLQ-C30
X
X
EQ-5D
X
X
Clinical Drug Supplies
Administer Study Drug
X
X
First dose to be administered within 5 days of study 
drug assignment.
Subjects may be dosed no less than 12 days between 
doses and no more than 7 days from the scheduled 2nd 
dose.
Confirmation of viral status will be required prior to 
study drug assignment for SCCHN subjects enrolled in 
the neoadjuvant cohort.
Revised Protocol No.: 07
Date: 07-May-2019
138
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-5:
Eligibility Assessments and On-Treatment Assessments - Subjects Receiving Study Drug Post-
Standard of Care (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle 
(every 2 
Weeks) on 
Day 1
(± 3 days)
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Eligibility must be assessed within 72 hours per inclusion/exclusion criteria 
for metastatic subjects as defined in Section 3.3, with the following 
exceptions/specificities:
•
Subjects who completed the neoadjuvant portion of the study must 
have developed unresectable recurrent or metastatic disease within 1 
year of surgery or chemotherapy/radiation completion to be eligible. 
•
Exclusion criterion ‘2.f’ regarding prior therapies is not applicable.
Subjects who meet discontinuation criteria at Cycle 1 Day 1 are not eligible 
to receive nivolumab. See Section 3.5 for discontinuation criteria. 
Safety Assessments
Targeted Physical Examination
X
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Within 72 hours prior to dosing
Vital Signs 
X
X
Temperature, BP, and HR prior to dosing and at any time a subject has any 
new or worsening respiratory symptoms. 
Obtain vital signs within 72 hours prior to dosing.
Physical Measurements
X
X
Includes Weighta and ECOG performance status
See Appendix 1 for ECOG scale
Revised Protocol No.: 07
Date: 07-May-2019
139
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-5:
Eligibility Assessments and On-Treatment Assessments - Subjects Receiving Study Drug Post-
Standard of Care (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle 
(every 2 
Weeks) on 
Day 1
(± 3 days)
Notes
Obtain physical measurements within 72 hrs. prior to dosing.
Adverse Events Assessment
------- Continuously -------
Assessed using NCI CTCAE version 4.
Review of Concomitant Medications
X
X
Laboratory Tests
X
X
On-study local laboratory assessments should be done within 72 hours prior 
to dosing for every cycle and include: CBC with differential and platelet 
count, BUN or serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, phosphorus, chloride, bicarbonate or total CO2 (if 
locally available), amylase, lipase, glucose, AST, ALT, total bilirubin, 
alkaline phosphatase, LDH, albumin.
Thyroid Function Testing
See Note
TSH (reflex to free T3 and free T4 if abnormal result) to be performed every 
6 weeks (± 1 week).
Pregnancy Test
X
See Note
Serum or urine within 24 hours prior to first dose and then at least once 
every 4 weeks (+/- 1 week) regardless of dosing schedule.
Revised Protocol No.: 07
Date: 07-May-2019
140
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-5:
Eligibility Assessments and On-Treatment Assessments - Subjects Receiving Study Drug Post-
Standard of Care (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle 
(every 2 
Weeks) on 
Day 1
(± 3 days)
Notes
Efficacy Assessments
Radiographic Tumor Assessment
Spiral CT/MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
See Note
See Table 5.4.1-1 for imaging frequency
See Appendix 3 (RECIST 1.1 Guidelines) for details regarding imaging 
methodology requirements and assessments
Should be performed within 35 days prior to first dose or restarting 
nivolumab.
Additional sites of known or suspected disease (including CNS) should be 
imaged at the screening visit and at subsequent on-study assessments.
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
PMBC
See Note
See Note
See Table 5.6.9-4 for Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See Note
See Table 5.5-3 of PK and Immunogenicity Sampling
Immunogenicity samples
See Note
See Table 5.5-3 of PK and Immunogenicity Sampling
Outcomes Research Assessments
EORTC QLQ-C30
X
See Note
Assessments to be collected every 4 cycles for the first 17 cycles;
Day 1 (prior to dosing) of Cycles 5, 9, 13, 17
every 6 cycles thereafter;
Day 1 (prior to dosing) of Cycles 23, 29, 35+.
EQ-5D
X
See Note
Revised Protocol No.: 07
Date: 07-May-2019
141
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-5:
Eligibility Assessments and On-Treatment Assessments - Subjects Receiving Study Drug Post-
Standard of Care (CA209358)
Procedure
Cycle 1
Day 1 
(C1D1)
Each Cycle 
(every 2 
Weeks) on 
Day 1
(± 3 days)
Notes
Clinical Drug Supplies
Administer Study Drug
X
X
Within 5 days from vial allocation, the subject must receive the first dose of 
study drug. Subjects may be dosed no less than 12 days between doses and 
no more than 3 days from the scheduled dose
a Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to re-calculate subsequent doses if the participant weight is 
within 10% of the weight used to calculate the previous dose. All doses should be rounded up or to the nearest milligram per institutional standard.
Revised Protocol No.: 07
Date: 07-May-2019
142
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-6:
Follow-Up Assessments - All Subjects (CA209358)
Procedure
X, Follow-Upa
Visits X01 and 
X02
Follow-Up Assessments 
for Neoadjuvant Cohort 
Subjects
4, 8, and 12 Months Post-
Surgeryb
S, Survival 
Follow-Upc Visits
Notes
Safety Assessments
Targeted Physical Examination
X
Lymph node areas (eg, submandibular, 
cervical, supraclavicular, axillary, or inguinal 
lymph node), and abdominal organs 
(eg, spleen, liver).
To assess for potential late emergent study drug 
related issues
Adverse Events Assessment
X
X
NSAEs and SAEs must be collected up to 100 
days after study drug discontinuation. SAEs 
that relate to any later protocol specified 
procedure must be collected.
Review of Medical History and 
Subsequent Cancer Therapy 
Information 
X
X
X
Laboratory Tests
X
CBC with differential and platelet count, BUN
or serum urea level, serum creatinine, sodium, 
potassium, calcium, magnesium, phosphorus, 
chloride, bicarbonate or total CO2 (if locally 
available), amylase, lipase, glucose, AST, 
ALT, total bilirubin, alkaline phosphatase, 
LDH, albumin..
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal 
result)
Pregnancy Test
X
Serum or urine
Revised Protocol No.: 07
Date: 07-May-2019
143
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-6:
Follow-Up Assessments - All Subjects (CA209358)
Procedure
X, Follow-Upa
Visits X01 and 
X02
Follow-Up Assessments 
for Neoadjuvant Cohort 
Subjects
4, 8, and 12 Months Post-
Surgeryb
S, Survival 
Follow-Upc Visits
Notes
Efficacy Assessments
Radiographic Tumor 
Assessment
Spiral CT/MRI 
See Note
X
See note
Only for subjects without progression and no 
longer on study therapy
See Table 5.4.1-1 for Spiral CT/MRI. For 
subjects in the neoadjuvant cohort, 
radiographic tumor assessment should be at 4 
mo, 8 mo and 12 mo post-surgery.b
Subjects with a history of brain metastasis may 
have surveillance MRI approximately every 12 
weeks or sooner if clinically indicated
Outcomes Research Assessments
EORTC QLQ-C30
X
EQ-5D
X
X
EQ-5D during the survival follow-up will be 
assessed during a clinic visit or via a phone 
contact
Pharmacokinetic/Immunogenicity Assessments
PK Samples
X
See Table 5.5-1, Table 5.5-2, Table 5.5-3, 
Table 5.5-4, Table 5.5-5, and Table 5.5-8 for PK 
and Immunogenicity Sampling
Immunogenicity samples
X
Revised Protocol No.: 07
Date: 07-May-2019
144
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.1-6:
Follow-Up Assessments - All Subjects (CA209358)
Procedure
X, Follow-Upa
Visits X01 and 
X02
Follow-Up Assessments 
for Neoadjuvant Cohort 
Subjects
4, 8, and 12 Months Post-
Surgeryb
S, Survival 
Follow-Upc Visits
Notes
Additional Exploratory Biomarker Testing
Serum
See Note.
Collection of Biomarker samples at time of 
progression is optional.
See Table 5.6.9-1, Table 5.6.9-2, and Table 
5.6.9-3, and Table 5.6.9-4 for Biomarker 
Sampling Schedule.
Whole Blood 
Tumor Biopsy 
PMBC
Plasma
Subject Status
Survival Status
X
X
X
Every 3 months after X02; may be 
accomplished by visit or phone contact, to 
update survival information and assess 
subsequent anti-cancer therapy.
a X visits occur as follows: X01 = 35 days ± 7 days from last dose or from the date decision is made to discontinue subject from the study (only applicable for 
early treatment discontinuation), X02 = 80 days ± 7 days from X01. Neoadjuvant cohort subjects will have these visits labeled as E01 (35 days +/ 7 days from 
last dose) and E02 (80 days +/ 7 days) visits in the CRF. For neoadjuvant cohort subjects receiving nivolumab as part of the post-standard of care, X01 and X02 
visits will be completed after the last dose
b Follow-Up Assessments for Neoadjuvant Cohort Subjects, 4, 8, and 12 Months Post-Surgery, may occur ±7 days from scheduled time point.
4 Month Post-Surgery may occur ±3 weeks from scheduled time point. Neoadjuvant Cohort. E02 and E03 follow-up can occur at the same time.
c S, Survival Follow-Up visits continue every 3 months after X visits.
Revised Protocol No.: 07
Date: 07-May-2019
145
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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 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 treatment) and 
is the value by which study inclusion will be assessed, as it represents the subject’s most current, 
clinical state.
5.2
Study Materials
•
NCI CTCAE version 4
•
BMS-936558 (nivolumab) Investigator Brochure
•
Ipilimumab Investigator Brochure
•
BMS-986016 (relatlimab) Investigator Brochure
•
Daratumumab Investigator Brochure
•
Pharmacy Binder
•
Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens
•
Site manual for operation of interactive response technology system, including enrollment 
worksheets
•
Manual for entry of local laboratory data
•
Pregnancy Surveillance Forms
•
Serious Adverse Events (or eSAE) case report forms
•
EORTC QLQ-C30 and EQ-5D questionnaires
•
CT/MRI/PET Subject Scanning Guide 
•
CT-MRI Subject Data Transmittal Form
•
PET-CT Subject Data Transmittal Form
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include signs and symptoms, weight, height, ECOG Performance 
Status, BP, HR, temperature, and respiratory rate should be performed within 14 days prior to first 
dose except where noted in Table 5.1-1. Concomitant medications will also be collected from 
within 14 days prior to first dose and through the study treatment period (See Table 5.1-1, Table 
5.1-2, Table 5.1-3, Table 5.1-4, and Table 5.1-5). 
Baseline safety laboratory assessments should be done within 14 days prior to the first dose and 
include: CBC with differential and platelet count, Chemistry panel including LDH, AST, ALT, 
ALP, T.Bili, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, P, glucose, bicarbonate or 
total CO2 (if locally available), albumin, amylase, lipase, TSH (reflex to free T3, free T4 for 
abnormal TSH result), hepatitis B surface antigen (HBV sAg, Australia antigen), and hepatitis C 
antibody (HCV Ab, RNA) (see Table 5.1-1). Pregnancy testing for WOCBP (done locally) to be 
done within 24 hours prior to first dose, and then every 4 weeks (± 1 week) regardless of dosing 
schedule, and at each safety follow up visit. Safety assessments for subjects assigned to Combo C 
Revised Protocol No.: 07
Date: 07-May-2019
146
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
will also include cardiac troponin levels: T (cTnT) or I (cTnI). If the pre-dose troponin level is 
above the ULN dosing should be held, subject should undergo prompt cardiac evaluation, and the 
medical monitor should be notified.
Determination of safety lab results is required prior to dosing. If there are delays with obtaining 
results for certain tests, please contact the medical monitor to determine clinical significance.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be performed continuously during the treatment phase. During the safety follow-up phase 
(Table 5.1-6) toxicity assessments should be done in person. Once subjects reach the survival 
follow-up phase, either in-person visits or documented telephone calls to assess the subject’s status 
are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.
On-study weight and ECOG performance status should be assessed at each on-study visit prior to 
nivolumab dosing. On treatment vital signs may be performed within 72 hours prior to dose. In 
addition, vital signs can also be taken as per institutional standard of care prior to; during and after 
the infusion. The start and stop time of the nivolumab infusion should be documented. Physical 
examinations are to be performed at treatment visits 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 
inducted liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline or are deemed irreversible.
Some of the previously referred to assessments may not be captured as data in the eCRF. They are 
intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.4
Efficacy Assessments
5.4.1
Imaging Assessments for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
Study evaluations will take place in accordance with the flow charts in Section 5.1, Table 5.4.1-1, 
Table 5.4.1-2, and Appendix 3. For the Neoadjuvant cohort, any images obtained prior to Month 4 
as standard of care should also be assessed.
In addition to chest, abdomen, and pelvis, all known sites of disease should be assessed at baseline. 
Subsequent assessments should include chest, abdomen, and pelvis, and all known sites of disease 
and should use the same imaging method as was used at baseline. Baseline MRI for brain should 
be done for known or suspected disease. 
Revised Protocol No.: 07
Date: 07-May-2019
147
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Tumor imaging assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria, see 
Appendix 3.
All study images will be submitted to an imaging core laboratory for review. Sites should be 
trained prior to sending in the first image. Image acquisition guidelines and submission process 
will be outlined in the CA209358 Imaging Manual to be provided by the core imaging laboratory.
Table 5.4.1-1:
Schedule of Spiral CT/MRI Tumor Assessments for Metastatic 
Cohorts (Monotherapy and Combination Therapy), and Subjects 
Treated with Study Drug Post-Standard of Care Adjuvant 
Treatment
Time On Study
Assessment Frequency
Assessment Week
(Day 1 of Week Shown)
Assessment 
Window
Metastatic Cohort Subjects 
During First Year of Treatment
At screening (within 35 days of 
first dose), then every 8 weeks
Screening, 8, 16, 24, 32, 
40, 48
± 1 week
Metastatic Cohort Subjects 
During Second Year of Treatment 
and Beyond
Every 12 weeks
60, 72, 84, 96, etc.
± 2 weeks
Neoadjuvant Subjects Treated 
with Study Drug Post-Standard of 
Care
Scan documenting progression 
is required, then every 8 weeks
Screening, 8, 16, 24, 32, 
40, 48
± 1 weeks 
For Subjects Treated with Study 
Drug Post-Standard of Care
During Second Year of Treatment 
and Beyond
Every 12 weeks
60, 72, 84, 96, etc.
± 2 weeks
Table 5.4.1-2:
Schedule of Spiral CT/MRI Tumor Assessments for Neoadjuvant 
Cohort
Time On Study
Assessment Frequency
Assessment Window
Screening
At screening (within 35 days of first dose)
Within 35 days of first dose
Pre-Surgery
Day 29 (within 7 days prior to the planned surgery 
date)
within 7 days prior to the planned 
surgery date
Post-Surgery
Months 4, 8, and 12a
Months 4 (within +3 weeks), 8, 
and 12b
a Any images obtained prior to Month 4 as standard of care should also be assessed.
b 4-Month Post-Surgery Assessments for Neoadjuvant Cohort Subjects may occur ± 3 weeks from scheduled time
point. Follow-up assessments 8 and 12 Months Post-Surgery may occur ± 7 days from the scheduled time point. 
Neoadjuvant Cohort E02 and E03 Follow Up may occur at same time.
Revised Protocol No.: 07
Date: 07-May-2019
148
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
For the Metastatic Cohorts (monotherapy and combination therapy), baseline tumor assessments 
should be performed within 35 days prior to the first dose. Subjects will then be evaluated for 
tumor response beginning 8 weeks from the date of first dose (± 1 wk.), then every 8 weeks 
(± 1 wk.) thereafter up to 48 weeks, then it will be every 12 weeks (± 2 weeks) until disease 
progression is documented, or when treatment is discontinued (whichever occurs later). 
For the Neoadjuvant Cohort, a Day 29 tumor scan is required for within 7 days prior to the planned 
surgery date. 
For Neoadjuvant Cohort subjects who progress to unresectable recurrent or metastatic disease 
within 1 year of surgical resection or chemotherapy/radiation and receive nivolumab, a baseline 
tumor scan documenting progression is required prior to restarting nivolumab. Subjects will then 
be evaluated for tumor response beginning 8 weeks from the date of first dose of treatment 
(± 1 wk.), then every 8 weeks (± 1 wk.) thereafter up to 48 weeks, then it will be every 12 weeks 
(± 2 week) until disease progression is documented, or when treatment is discontinued, (whichever 
occurs later).
5.4.2
Primary Efficacy Assessment
The investigator objective response rate (ORR) of nivolumab monotherapy is the primary endpoint 
among all treated subjects in the recurrent/metastatic monotherapy cohort. The investigator 
objective response rate (ORR) of nivolumab combination therapy (ipilimumab, BMS-986016, 
daratumumab) is the primary endpoint among all treated subjects in the recurrent/metastatic 
combination cohort for combination therapies, Combo A, B, C and D.
ORR is defined as the number of subjects with a best overall response (BOR) of confirmed 
complete response (CR) or partial response (PR) divided by the number of all treated subjects. 
BOR is defined as the best response designation recorded between the date of first dose and the 
date of the initial objectively documented tumor progression per investigator assessment using 
RECIST 1.1 criteria or the date of subsequent therapy, whichever occurs first.
5.4.3
Secondary Efficacy Assessments
Not applicable
5.5
Pharmacokinetic Assessments
Samples for pharmacokinetic and immunogenicity assessments will be collected for all subjects 
receiving nivolumab as a monotherapy or in combination with ipilimumab, BMS-986016
(relatlimab), or daratumumab. Table 5.5-1, Table 5.5-2, and Table 5.5-3 list the sampling schedule 
to be followed for pharmacokinetics and immunogenicity of nivolumab. Table 5.5-4 and Table 
5.5-5 list the sampling schedule to be followed for pharmacokinetics and immunogenicity of 
nivolumab and ipilimumab. Table 5.5-6 lists the sampling schedule to be followed for 
pharmacokinetics and immunogenicity of nivolumab and BMS-986016 (relatlimab). Table 5.5-7
and Table 5.5-8 list the sampling schedule to be followed for pharmacokinetics and 
immunogenicity of nivolumab and daratumumab, respectively, for nivolumab and daratumumab 
combination cohort. All time points in nivolumab/ipilimumab and nivolumab/BMS-986016 
Revised Protocol No.: 07
Date: 07-May-2019
149
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
(relatlimab) combination cohorts are relative to the start of nivolumab infusion. In the 
nivolumab/daratumumab combination cohort, daratumumab will be administered after nivolumab 
and predose sample for daratumumab should be drawn with a window of -2 hours before the start 
of daratumumab dosing. Daratumumab post-dose samples should be drawn within 2 hours after 
the end of the infusion. All on-treatment PK time points are intended to align with days on which 
nivolumab is administered. If it is known that a dose is going to be delayed, then the predose 
sample should be collected just prior to the delayed dose. However, if a predose sample is 
collected, but the dose is subsequently delayed, an additional predose sample should not be 
collected. 
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
for sample collection requirements. Collected samples must be stored under the specified and 
controlled conditions for the temperatures indicated in the Laboratory Manual. Additional 
information about the collection, handling, and shipment of biological samples can be found in the 
Laboratory Manual.
Table 5.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule
(Metastatic Monotherapy Cohort)
Study Day
Event 
(Relative to Start 
of Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 1 (Week 1 Day 1)
predosea
00:00
X
X
Cycle 5 Day 1(Week 9 Day 1)
predosea
00:00
X
X
Cycle 7 Day 1 (Week 13 Day 
1)
predosea
00:00
X
X
Day 1 of every 8th cycle (every 
16 weeks) until discontinuation 
of study treatmentb
predosea
00:00
X
X
First 2 Follow-up visits- X01 & 
X02
X
X
a Predose samples should be taken just prior to the administration (preferably within 30 minutes). If the infusion is 
delayed and a pre-dose sample was already collected, there is no need to collect an additional pre-dose sample.
b For subjects during second year of treatment and beyond, PK collections will occur every 24 weeks instead of every 
16 weeks.
Revised Protocol No.: 07
Date: 07-May-2019
150
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule 
(Neoadjuvant Cohort)
Study Day
Event 
(Relative to Start 
of Infusion/Event)
Time 
(Relative to Start of 
Nivolumab Infusion)
Hour:Min
Nivolumab PK 
Blood Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 1
(Week 1 Day 1)
predosea
00:00
X
X
Pre-Surgery Visit
(Up to 7 days prior to 
surgery)
Prior to surgery
00:00
X
X
First 2 Follow-up visits-
X01 & X02
X
X
a Predose samples should be taken just prior to the administration (preferably within 30 minutes). If the infusion is 
delayed and a pre-dose sample was already collected, there is no need to collect an additional pre-dose sample.
Table 5.5-3:
Pharmacokinetic and Immunogenicity Sampling Schedule (Subjects 
Receiving Nivolumab Post-Standard of Care)
Study Day
Event 
(Relative to 
Start of 
Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 1 (Week 1 Day 1)a
predoseb
00:00
X
X
Cycle 5 Day 1(Week 9 Day 1)
predoseb
00:00
X
X
Cycle 7 Day 1(Week 13 Day 1)
predoseb
00:00
X
X
Day 1 of every 8th cycle (every 
16 weeks) until discontinuation 
of study treatmentc
predoseb
00:00
X
X
First 2 Follow-up visits- X01 & 
X02
X
X
a The day subjects start study drug after standard of care will be considered Cycle 1 Day 1 (Week 1 Day 1).
b Predose samples should be taken just prior to the administration (preferably within 30 minutes). If the infusion is 
delayed and a pre-dose sample was already collected, there is no need to collect an additional pre-dose sample. 
c For subjects during second year of treatment and beyond, PK collections will occur every 24 weeks instead of every 
16 weeks.
Revised Protocol No.: 07
Date: 07-May-2019
151
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.5-4:
Pharmacokinetic and Immunogenicity Sampling Schedule 
(Nivolumab and Ipilimumab Combination - Combo A)
Study Daya
Event 
(Relative to 
Start of 
Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
PK Blood 
Sample
Immunogenicity 
Sample for 
Nivolumab and 
Ipilimumab
Week 1 Day 1
predoseb
00:00
X
X
Week 7 Day 1
predoseb
00:00
X
X
Week 19 Day 1
predoseb
00:00
X
X
Day 1 of every 18 weeks after 
Week 19 until discontinuation of 
study treatment
predoseb
00:00
X
X
First 2 Follow-up visits- X01 & 
X02
X
X
a If a subject permanently discontinues both study drug treatments during the sampling period, they will move to 
sampling at the follow up visits. 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. If nivolumab is discontinued and ipilimumab continues, nivolumab PK and ADA should be collected 
only for the next 2 time points (corresponding to ipilimumab sample collection) according to the PK table.
b Pre-dose samples should be taken just prior to the start of infusion (preferably within 30 minutes). If the infusion 
is delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample.
Table 5.5-5:
Pharmacokinetic and Immunogenicity Sampling Schedule 
(Nivolumab and Ipilimumab Combination - Combo B)
Study Daya
Event 
(Relative to Start 
of Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
PK Blood 
Sample
Immunogenicity 
Sample for 
Nivolumab and 
Ipilimumab
Week 1 Day 1
predoseb
00:00
X
X
Week 4 Day 1
predoseb
00:00
X
X
Week 7 Day 1
predoseb
00:00
X
X
On Day 1 every 18 weeks 
beyond Week 7 until 
discontinuation of study 
treatment
predoseb
00:00
Xc
Xc
First 2 Follow-up visits- X01 
& X02
Xc
Xc
Revised Protocol No.: 07
Date: 07-May-2019
152
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
a If a subject permanently discontinues both study drug treatments during the sampling period, they will move to 
sampling at the follow up visits. 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. If nivolumab is discontinued and ipilimumab continues, nivolumab PK and ADA should be collected 
only for the next 2 time points (corresponding to ipilimumab sample collection) according to the PK table.
b Pre-dose samples should be taken just prior to the start of infusion (preferably within 30 minutes). If the infusion 
is delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample. 
c PK and immunogenicity samples will be collected only for nivolumab. For ipilimumab, only week 25 PK and 
immunogenicity samples will be collected.
Table 5.5-6:
Pharmacokinetic and Immunogenicity Sampling Schedule 
(Nivolumab and Relatlimab Combination - Combo C)
Study Daya
Event
(Relative to Start 
of 
Infusion/Event)
Time
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
PK Blood 
Sample for 
Nivolumab 
and 
Relatlimab
Immunogenicity 
Sample for 
Nivolumab and 
Relatlimab
Cycle 1 Day 1 (Week 1 Day 1)
Predoseb
00:00
X
X
Cycle 3/5c Day 1 (Week 9 Day 
1)
predoseb
00:00
X
X
Cycle 4/7 Day 1 (Week 13 
Day 1)d
predoseb
00:00
X
X
Day 1 of every 8th cycle 
(every 16 weeks) until 
discontinuation of study 
treatment or up to 2 years of 
treatment
predoseb
00:00
X
X
a If relatlimab is discontinued and nivolumab continues, relatlimab PK and ADA should be collected only for the 
next 2 time points (corresponding to nivolumab sample collection) according to the PK table. If nivolumab is 
discontinued and relatlimab continues, nivolumab PK and ADA should be collected only for the next 2 time points 
(corresponding to relatlimab sample collection) according to the PK table.
b Pre-dose samples should be taken just prior to the start of infusion (preferably within 30 minutes). If the infusion 
is delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample.
c Cycle 3 pertains to the nivolumab every 4 week (q4w) regimen; Cycle 5 pertains to the nivolumab every 2 week 
(q2w) regimen.
d Cycle 4 pertains to the nivolumab every 4 week (q4w) regimen; Cycle 7 pertains to the nivolumab every 2 week 
(q2w) regimen.
Revised Protocol No.: 07
Date: 07-May-2019
153
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.5-7:
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Nivolumab (Nivolumab and Daratumumab Combination -
Combo D)
Study Day
(1 Cycle  = 1 week from Weeks 
1-8
1 Cycle -= 2 weeks from Weeks 
9-24
1 Cycle = 4 weeks from Week 
25)
Event 
(Relative to 
Start of 
Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
PK Blood 
Sample for 
Nivolumab 
Immunogenicity 
Sample for 
Nivolumab 
Cycle 3 Day 1 (Week 3 Day 1)a
Predoseb
00:00
X
X
Cycle 9 Day 1(Week 9 Day 1)
Predoseb
00:00
X
X
Cycle 11 Day 1(Week 13 Day 1)
Predoseb
00:00
X
X
Cycle 17 day 1 (Week 25 Day 
1)c
Predoseb
00:00
X
X
Day 1 of every 4th cycle (every 
16 weeks) until discontinuation 
of study treatment or up to 2 
years of treatment
Predoseb
00:00
X
X
a Nivolumab will start at Week 3.
b Pre-dose samples should be taken prior to the start of both nivolumab and daratumumab infusion. If the infusion is 
delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample
c Starting from Week 25, nivolumab will be given 480 mg Q4W
Table 5.5-8:
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Daratumumab (Nivolumab and Daratumumab Combination -
Combo D)
Study Day
Event
(Relative to Start 
of Daratumumab 
Infusion/Event)a
Time
(Relative to Start 
of Daratumumab 
Infusion)
Hour:Min
PK Blood Sample 
for 
Daratumumab
Immunogenicity 
Assessment for 
Daratumumab 
(taken from Dara 
PK sample)b
Week 1 Day 1
Predosea
00:00
X
X
Week 1 Day 1
Postdose
EOI
X
Week 5 Day 1
Predose
00:00
X
X
Week 5 Day 1
Postdose
EOI
X
Week 9 Day 1
Predosea
00:00
X
X
Week 13 Day 1
Predosea
00:00
X
X
Revised Protocol No.: 07
Date: 07-May-2019
154
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.5-8:
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Daratumumab (Nivolumab and Daratumumab Combination -
Combo D)
Study Day
Event
(Relative to Start 
of Daratumumab 
Infusion/Event)a
Time
(Relative to Start 
of Daratumumab 
Infusion)
Hour:Min
PK Blood Sample 
for 
Daratumumab
Immunogenicity 
Assessment for 
Daratumumab 
(taken from Dara 
PK sample)b
Week 25 Day 1
Predosea
00:00
X
X
Week 41 Day 1
Predosea
00:00
X
Week 57 Day 1
Predosea
00:00
X
X
Week 73 Day 1
Predosea
00:00
X
Week 89 Day 1
Predosea
00:00
X
Week 105 Day 1
Predosea
00:00
X
X
Follow-up visit 1
4 weeks (± 1 week) 
after last dose of 
dara 
X
X
Follow up visit 2
8 weeks (± 1 week) 
after last dose  of 
dara
X
X
a Daratumumab predose PK samples should be drawn before administration of either nivolumab or daratumumab 
(window of -2 hours before that start of dara dosing). Daratumumab post dose samples should be drawn within 2 
hours after the end of the infusion.  
b Daratumumab immunogenicity will be assessed from an aliquot of the daratumumab PK blood sample – no 
additional blood draw is required.
5.5.1
Pharmacokinetic Sample Analysis
Serum samples will be analyzed for nivolumab, ipilimumab, BMS-986016 (relatlimab), or 
daratumumab concentrations by a validated method. In addition, selected samples may be analyzed 
by an exploratory analytical method that measures nivolumab, ipilimumab, BMS-986016
(relatlimab), or daratumumab for technology exploration purposes; exploratory results will not be 
reported.
5.6
Biomarker Assessments
Peripheral blood and tumor tissue will be collected prior to therapy and at selected time points on 
treatment as outlined in the Biomarker Sampling Schedule in Table 5.6.9-1, Table 5.6.9-2, Table 
5.6.9-3, and Table 5.6.9-4 unless restricted by local requirements. Detailed instructions of the 
obtaining, processing, labeling, handling, storage and shipment of specimens will be provided in 
a separate Procedure Manual at the time of study initiation.
Revised Protocol No.: 07
Date: 07-May-2019
155
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
5.6.1
Determination of Tumor’s Viral Positivity
Confirmation of viral status will be required prior to study drug assignment for EBV gastric cancer 
and HPV SCCHN tumor types in the metastatic cohorts. Confirmation of viral status will also be 
required prior to study drug assignment for SCCHN subjects enrolled in the neoadjuvant cohort
and Metastatic Combination Cohorts A and C. For SCCHN subjects in Cohort D and in all other 
tumor types, viral status will not be required prior to subject enrollment, but will be determined 
retrospectively if the viral status is not already known. Viral testing determined more than 35 days 
prior to first dose may be used. Viral status will be determined using an appropriately validated 
test as described below for each of the tumor types.
EBV Gastric:  In situ hybridization EBV RNA (EBER) of FFPE sections. Testing for EBV 
positivity will be performed prior to study drug assignment using the EBER1 DNP probe from 
Ventana in a properly certified lab. Samples interpreted as (+) if nuclear staining of any intensity 
above the background in tumor cells, provided the negative internal controls (adjacent normal 
tissue) are negative.
HPV Head and Neck:  HPV p-16 status should be assessed using the following criteria: p16 IHC 
should be done with anti-p16INK4a clone E6H4 from MTM labs (Roche). Interpretation as 
positive if > 70% strong and diffuse nuclear and cytoplasmic staining is specific to tumor cells; p-
16 status will be reported as either p-16 positive or p-16 negative. If results acquired according to 
these criteria are not available, then a sample (tissue on microscopic slides, tissue block or a fresh 
tissue biopsy in formalin) should be sent to sponsor-contracted laboratory for analysis. HPV 16 in 
situ hybridization may also be performed retrospectively.  
Polyomavirus MCC:  Assessment of polyomavirus by IHC will be performed retrospectively at a 
sponsor-contracted laboratory if the polyomavirus status is unknown. If the polyomavirus status is 
known, please report this information on the provided case report form.
Cervical, vaginal, vulvar, anal canal and penile: HPV positivity is defined by FDA approved tests 
(Cobas HPV Test; Digene Hybrid Capture 2 High-Risk HPV DNA Test; Cervista™ HPV HR and 
Genfind™ DNA Extraction Kit; Cervista™ HPV 16/18; APTIMA® HPV Assay) or other well 
validated commercially available tests (such as Ventana Inform HPV ISH test) comprising in situ 
hybridization, real-time PCR, or immunohistochemistry (IHC). High-risk HPV positivity includes 
the following subtypes:  16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Virus testing will 
be performed retrospectively only if results from prior accepted testing are not available. If the 
HPV status is known please report this information on the provided case report form. 
EBV Nasopharyngeal: In situ hybridization EBV RNA (EBER) of FFPE sections. Testing for EBV 
positivity will be performed using the EBER1 DNP probe from Ventana in a properly certified 
lab. Samples interpreted as (+) if nuclear staining of any intensity above the background in tumor 
cells, provided the negative internal controls (adjacent normal tissue) are negative.
Soluble Biomarkers: Soluble factors, such as cytokines, chemokines, soluble receptors, and 
antibodies to tumor antigens may be characterized and quantified by immunoassays in serum. 
Analyses may include, but not necessarily be limited to, soluble CD25, soluble PD-1, soluble 
Revised Protocol No.: 07
Date: 07-May-2019
156
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
LAG-3, and CXCL-9. Collected serum samples may also be used for the assessment of tumor 
antigen-specific responses elicited following treatment with monotherapy to explore which 
antitumor antibodies are most associated with clinical response. Antibody levels to cancer test 
antigens will be assessed by multiplex assays and enzyme-linked immunosorbent assay (ELISA).
5.6.2
Viral-related Assessments
Quantification of EBV DNA by PCR, when appropriate, to correlate viral load to response. MHC 
tetramers assay may be used for analysis of virus-specific T cells. The seropositivity to viral 
oncoprotein antibodies and anti-viral antibodies may be examined in serum samples. PBMCs
and/or lymphocytes isolated from tumors may be used in ELISPOT assays for T cell responses to 
viral antigens and/or epitope spreading.   
5.6.3
HLA Genotyping
HLA typing of peripheral blood samples may be assessed by standard genotyping methods.
5.6.4
Immunophenotyping
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory and 
inhibitory markers in peripheral blood mononuclear cell (PBMC) preparations may be quantified 
by cytometry. Analyses may include, but not necessarily be limited to, the proportion of T, B, and 
NK cells, proportion of memory and effector T cell subsets, and expression levels of PD-1, PD-L1, 
PD-L2, ICOS, and Ki67. Whole blood samples will also be collected to quantify myeloid-derived 
suppressor cells (MDSC) before and after treatment.  
5.6.5
Ex Vivo Functional Assays
To explore whether nivolumab may restore T cell activation and function, peripheral blood 
mononuclear cells (PBMCs) will be isolated and cryopreserved. Assays of the functional status of 
effector T cells may be performed, including but not limited to, assays for interferon-gamma 
(IFN-ϒ) and CD107. 
5.6.6
Peripheral Blood Gene Expression
The expression level of genes and miRNA related to response to nivolumab as monotherapy or in 
combination with either ipilimumab, BMS-986016 (relatlimab), or daratumumab will be 
quantified by molecular methods such as nanostring, RNAseq, microarray, and/or quantitative 
reverse transcription polymerase chain reaction (RT-PCR) analysis of whole blood samples. 
Analysis may include, but not necessarily be limited to, genes associated with immune-related 
pathways, such as T cell activation and antigen processing and presentation.
5.6.7
T Cell Repertoire Analysis
Low diversity of the peripheral T cell compartment has been shown to correlate with poor overall 
survival in metastatic breast cancer.187 A standing theory in immuno-oncology suggests 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 maybe 
Revised Protocol No.: 07
Date: 07-May-2019
157
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
performed on DNA isolated from peripheral blood and tumor tissue to quantitate the composition 
of the T cell repertoire prior to and during monotherapy.
5.6.8
Single Nucleotide Polymorphism (SNP) Analysis
In order to identify potential polymorphisms associated with safety and efficacy of nivolumab, 
selected genes may be evaluated for single nucleotide polymorphisms (SNP). Analysis may 
include but will not be limited to sequence polymorphisms linked to genes associated with the 
PD-1/PD-L1 pathway and activated T cell phenotype, including PD-1, PD-L1, PD-L2, and 
CTLA-4. A blood sample will be obtained at Day 1, unless restricted by local regulations.
5.6.9
Tumor Samples
Tumor tissue specimen requirements for the Neoadjuvant Cohort are as follows:
•
At Baseline (Prior to first dose of study drug): Biopsy and submission of fresh tumor tissue is 
mandatory for all subjects. Biopsy is indicated for subjects with accessible lesions where 
biopsy is deemed safe by the Investigator.
•
Day 29 (On-treatment) fresh samples obtained via scheduled surgical resection or scheduled 
biopsy are mandatory. 
•
Day 29 (On-treatment) samples must be reviewed by pathologist and a copy of the pathology 
report must be sent to BMS
•
All other time points where tumor tissue collections are indicated, aside from baseline and Day 
29, are described in Table 5.6.9-1. 
Tumor tissue specimen requirements for the Metastatic Cohort (Monotherapy and 
Combination Therapy) are as follows:
•
At Baseline (Prior to first dose of study drug): Biopsy and submission of fresh tumor tissue, or
submission of archived tumor tissue, is mandatory for all subjects. Biopsy is indicated for 
subjects with accessible lesions where biopsy is deemed safe by the Investigator. 
•
An on-treatment biopsy and submission of fresh tumor tissue is mandatory for subjects in each 
tumor type in the metastatic cohort to ensure an adequate number of paired samples to perform 
meaningful analyses to support biomarker objectives. Subjects with accessible lesions where 
biopsy is deemed safe by the Investigator should undergo biopsy per protocol.
•
All other time points where tumor tissue collections are indicated, aside from baseline and the 
one mandatory on-treatment biopsy, are described in Table 5.6.9-2 and Table 5.6.9-3.
Tumor tissue specimen requirements for Subjects Treated with Study Drug Post-Standard 
of Care are as follows:
•
At Cycle 1 Day 1 biopsy and submission of fresh tumor tissue is strongly encouraged for 
subjects with accessible lesions where biopsy is deemed safe by the Investigator.
•
All other time points where tumor tissue collections are indicated, aside from Cycle 1 Day 1, 
are described in Table 5.6.9-4.
Revised Protocol No.: 07
Date: 07-May-2019
158
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Submission of fresh tumor tissue collected via biopsy is required for TILs isolation for ex-vivo 
functional assays (RPMI media preparation), and also for gene expression profiling (RNALater 
samples). Please refer to Central Lab Manual for detailed sample requirements.
Submission of tissue samples (FFPE tumor tissue block or slides) is required for characterization 
of tumor infiltrating lymphocytes (TILs) and tumor, utilizing immunohistochemistry (IHC) 
methods. A minimum of 1 FFPE tumor tissue block (preferred) OR minimum of 15 FFPE 
unstained sections are required for this purpose. Tissue for this purpose may be obtained during 
the screening phase, prior to resection, or collected as a standard of care procedure within 90 days 
prior to obtaining informed consent, and is mandatory. Please refer to Central Lab Manual for 
detailed sample requirements.
Tissue for protocol purposes should be obtained via excision, incision or core needle. Fine needle 
aspirates are prohibited.
Tumor samples obtained from bone metastases are not considered acceptable for PD-L1 testing 
because the PD-L1 assay does not include a decalcification step. For any cases where the only 
tumor tissue available is from a bone metastasis lesion, please discuss further with the study 
Medical Monitor.
All subjects may volunteer to undergo tumor biopsies at any time during therapy, if clinically 
indicated. When tumor biopsy is performed during these times, submission of tumor biopsy is 
strongly encouraged.
All tumor tissue sample submission upon progression is optional, and can be taken within 7 days 
at the discretion of the investigator.
Tumor-Based Biomarker Measures
Tumor biopsy specimens will be obtained from consenting subjects prior to administration of study 
drug to characterize immune cell populations and expression of selected tumor markers. Tumor 
biopsy collection and submission is mandatory for subjects with accessible lesions prior to therapy. 
Tumor tissue (obtained during the screening phase or collected as a standard of care procedure 
within 90 days prior to obtaining informed consent) will be provided for biomarker analysis if 
accessible and deemed safe by the investigator. For subjects where tumor tissue cannot be provided
due to issues related to safety, the reason must be clearly documented in the medical record AND 
the BMS Medical Monitor must be contacted. Archival tissue should be submitted for these 
subjects. Submission of archival tissue is also encouraged for all subjects, irrespective of whether 
fresh biopsy tissue is available. 
For cases when a complete response occurs, and an on-treatment biopsy is required but not 
feasible, these cases must be clearly documented in the medical record AND the BMS Medical 
Monitor must be contacted.
A tumor biopsy sample of subjects that have confirmed progression is optional, but strongly 
encouraged for the purposes of understanding mechanisms of resistance to therapy. 
Biopsy samples may be used for the following assessments:
Revised Protocol No.: 07
Date: 07-May-2019
159
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Characterization of tumor infiltrating lymphocytes (TILs) and tumor. Immunohistochemistry 
(IHC) will 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 may include, but not necessarily be 
limited to, the following markers: PD-L1, PD-L2, PD-1, LAG3, IDO, GITR, T cell and 
macrophage markers. For the neo-adjuvant arm only TILs may also be assessed in fresh baseline 
biopsies and surgical resections by cytometry. Analysis of cytokines including but not limited to 
IFN-g, IL-4, IL-13, IL-10, IL-17, and IL-32g may be done with multiplex qRT-PCR and/or 
amplified in situ hybridization (ISH) using fixed tumor tissue. 
Tumor genotyping, mutational analysis, and tumor antigen profiling
RNA and DNA from tumor samples may be analyzed using whole-exome and transcriptome 
sequencing or another technology to determine the number of mutations found within a given 
sample relative to a normal host tissue, such as adjacent non-transformed cells or PBMC. 
Mutations that are detected will be analyzed for their ability to bind the MHC I and MHC II 
proteins using prediction algorithms. Evaluating the ability of tumor mutations to bind MHC 
molecules will provide evidence that these mutations are serving as antigens that are recognized 
the immune system and are potential rejection antigens. 
In addition to viral positivity, chromosomal translocations, aberrant expressions, and epigenetic 
modifications within tumor cells may be characterized and explored by IHC and RNA/DNA 
analysis of tumor biopsies. Associations of altered tumor cell genetic structure with nivolumab 
efficacy will be performed. This includes, but is not limited to, assessments of 9p24 copy number 
alterations.
Characterization of T cell repertoire. As described above, DNA sequencing may be performed 
on pre- and post-treatment tumor tissue to assess the composition of the T cell repertoire. DNA 
may be isolated from either the FFPE tumor block or from RNAlater, or equivalent preparations.  
Gene expression profiling. Tumor biopsies that are collected in RNAlater or equivalent fixative 
maybe examined for mRNA and miRNA gene expression by nanostring, RNAseq, microarray, 
and/or quantitative real-time polymerase chain reaction (qPCR) to detect expression of selected 
immune related genes and regulatory pathways.
Ex vivo Functional Assays. To explore whether nivolumab may restore T cell activation and 
function, Tumor infiltrating Lymphocytes (TILs) will be isolated. Assays for phenotypic 
characteristic as well as functional status of effector T cells may be performed, including but not 
limited to, flow cytometry and peptide restimulation.
Revised Protocol No.: 07
Date: 07-May-2019
160
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.6.9-1:
CA209358 Biomarker Sampling Schedule (Neo-Adjuvant Cohort)
Collection 
Timea
Serum
Plasma
PBMC (US and European Sites Only)
Tumor Biopsy
Whole Blood
Study Day
Soluble Biomarker
Immuno-
phenotyping
Ex-vivo 
Functional
Gene 
Expression
MDSC
SNP
Screening
Xb
Cycle 1 Day 1
X
X
X
X
X
X
X
Cycle 2 Day 1
X
X
X
Prior to 
Resection (Day 
29)
X
X
X
Xc
X
CR Evaluationc
X
X
X (optional)c
X
During 
Treatment
(when clinically 
indicated)
Xc
Upon 
Progressiond
X 
(optional)
X (optional)
X (optional)
X (optional)
X (optional)
X (optional)
a Serum, PBMC, Plasma, and Whole Blood samples may be obtained ± 3 days of the indicated time except for Cycle 1 Day 1 samples which must be collected 
prior to treatment.
b Submission of fresh tumor tissue collected via biopsy is required for TILs isolation for ex-vivo functional assays (RPMI media preparation), and also for gene 
expression profiling (RNALater samples). 
Submission of tissue samples (FFPE tumor tissue block or slides) is required for characterization of tumor infiltrating lymphocytes (TILs) and tumor, utilizing 
immunohistochemistry (IHC) methods. Tissue for this purpose may be obtained during the screening phase, prior to resection, or collected as a standard of care 
procedure within 90 days prior to obtaining informed consent, and is mandatory.
c Fresh tumor tissue is required to be collected on Day 29. Day 29 tumor biopsy may be collected ± 7 days. Day 29 biopsy must be reviewed by pathologist and 
the pathology report must be sent to BMS.
d All sample submission upon progression is optional and can be taken at any time after progression at the discretion of the investigator.
Revised Protocol No.: 07
Date: 07-May-2019
161
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.6.9-2:
CA209358 Biomarker Sampling Schedule (Metastatic Monotherapy Cohorts and Metastatic Cohort 
Combo A and B)
Collection Timea
Serum
Plasma
PBMC (US and European Sites 
Only)
Tumor Biopsy
Whole Blood
Study Day
Soluble Biomarker
Immuno-
phenotyping
Ex-vivo 
Functional
Gene 
Expressio
n
MDSC
SNP
Screening
Xb
Week 1 Day 1
X
X
X
X
X
X
X
Week 3 Day 1
Mono & 
Combo Ac
Mono & 
Combo Ac
Mono & 
Combo Ac
Week 4 Day 1
Combo B 
Onlyd
Combo B 
Onlyd
Combo B
Only
Combo B 
Onlyd
Week 5 Day 1
Mono & 
Combo Ac
Mono & 
Combo Ac
Combo A only
Xb
Week 7 Day 1
X
X
X
X
X
Week 19 Day 1
Combo A 
Only
Combo A 
Only
Combo A Only
Combo A 
Only
CR Evaluation
X
X
X (optional)e
X
During Treatment (when 
clinically indicated)e
Xe
Upon Progressionf
X 
(optional)
X (optional)
X (optional)
X (optional)
X 
(optional)
X (optional)
a Serum, PBMC, Plasma, and whole blood samples may be obtained ± 3 days of the indicated time except for Cycle 1 Day 1 samples which must be collected 
prior to treatment.
b Submission of fresh tumor tissue is required for gene expression profiling (RNALater samples).
c For Monotherapy, and Combo A; excludes Combo B
d For cervical cancer and anogenital HPV associated tumors (vulvar/vaginal/anal canal/penile) only
e All subjects may volunteer to undergo tumor biopsies at any time during therapy if clinically indicated. When tumor biopsy is performed, submission of tumor 
biopsy is strongly encouraged. 
Revised Protocol No.: 07
Date: 07-May-2019
162
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
f All sample submission upon progression is optional and can be taken at any time after progression at the discretion of the investigator.
Submission of tissue samples (FFPE tumor tissue block or slides) is required for characterization of tumor infiltrating lymphocytes (TILs) and tumor, utilizing 
immunohistochemistry (IHC) methods. Tissue for this purpose may be obtained during the screening phase, prior to resection, or collected as a standard of care 
procedure within 90 days prior to obtaining informed consent. On-treatment tumor biopsies are mandatory. On-treatment tumor biopsy may be collected +/- 7 
days.
Revised Protocol No.: 07
Date: 07-May-2019
163
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.6.9-3:
CA209358 Biomarker Sampling Schedule (Metastatic Combination Cohort Combo C and Combo D)
Collection Timea
Serum
Plasma
PBMC (US and European Sites 
Only)
Tumor Biopsy
Whole Blood
Study Day
Soluble 
Biomarker
Immuno-
phenotyping
Ex-vivo 
Functional
Gene 
Expression
MDSC
SNP
Screening
Xb
Week 1 Day 1
X
X
X
X
X
X
X
Week 5 Day 1
X
X
Xb
Week 9 Day 1
X
X
X
X
X
CR Evaluation
X
X
X (optional)c
X
During Treatment (when 
clinically indicated)
Xc
Upon Progressiond
X 
(option
al)
X (optional)
X (optional)
X (optional)
X (optional)
X (optional)
Upon Drug-Related AE
•
≥Grade 2 drug 
related 
neurological AE
X
X
X
a Serum, PBMC, plasma, and whole blood samples may be obtained ± 3 days of the indicated time except for Cycle 1 Day 1 samples which must be collected 
prior to treatment.
b Submission of fresh tumor tissue is required for gene expression profiling (RNALater samples).
c All subjects may volunteer to undergo tumor biopsies at any time during therapy if clinically indicated. When tumor biopsy is performed, submission of tumor 
biopsy is strongly encouraged.
d All sample submission upon progression is optional and can be taken at any time after progression at the discretion of the investigator.
Submission of tissue samples (FFPE tumor tissue block or slides) is required for characterization of tumor infiltrating lymphocytes (TILs) and tumor, utilizing 
immunohistochemistry (IHC) methods. Tissue for this purpose may be obtained during the screening phase, prior to resection, or collected as a standard of care 
procedure within 90 days prior to obtaining informed consent. On-treatment tumor biopsies are mandatory. On-treatment tumor biopsy may be collected +/- 7 
days
Revised Protocol No.: 07
Date: 07-May-2019
164
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 5.6.9-4:
CA209358 Biomarker Sampling Schedule (Subjects Treated with Study Drug Post-Standard of Care)
Collection Timea
Serum
PBMC (US and European Sites Only)
Tumor Biopsy
Whole Blood
Study Day
Soluble 
Biomarker
Immuno-
phenotyping
Ex-vivo 
Functional
Gene 
Expression
MDSC
Cycle 1 Day 1
X
X
X
Xb
X
X
Cycle 2 Day 1
X
X
X
Cycle 3 Day 1
X
X
Cycle 4 Day 1
X
X
X
X
X
CR Evaluation
X
X
X (optional)c
X
During Treatment (when 
clinically indicated)c
Xc
Upon Progressiond
X (optional)
X (optional)
X (optional)
X (optional)
X (optional)
X (optional)
a Serum, PBMC and whole blood samples may be obtained ± 3 days of the indicated time except for Cycle 1 Day 1 samples which must be collected prior to 
treatment.
b Submission of tumor tissue is strongly encouraged, if feasible.
c All subjects may volunteer to undergo tumor biopsies at any time during therapy if clinically indicated. When tumor biopsy is performed, submission of tumor 
biopsy is strongly encouraged.
d All sample submission upon progression is optional and can be taken at any point after progression at the discretion of the investigator.
Revised Protocol No.: 07
Date: 07-May-2019
165
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
5.7
Outcomes Research Assessments
The evaluation of hearth-related quality of life is an increasingly important aspect of clinical 
efficacy in oncology trials. Such data provides an understanding of the impact of treatment from 
the participant’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.
The 3-level version of the EQ-5D (EQ-5D-3L) will be used to assess treatment effects on perceived 
health status and to generate utility data for health economic evaluations. The EQ-5D-3L is a 
generic multi-attribute health-state classification system by which health is described in 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is evaluated using 3 levels: no problems, some problems, and extreme problems. 
Responses to these 5 dimensions are converted into 1 of 243 unique health state descriptions, which 
range between no problems in all 5 dimensions (11111) to extreme problems in all 5 dimensions 
(33333). Using appropriate country-specific value weighting algorithms, a respondent’s self-
described health state can be converted into a utility representing the societal desirability of his or 
her own health. In addition, the EQ-5D includes a visual analogue scale (VAS) allowing a 
respondent to rate his/her health on a scale ranging from 0 to 100 with 0 being the worst health 
state imaginable and 100 being the best health state imaginable. 
The European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire–Core 30 (QLQ-C30) will be used to assess the effects of disease symptoms on 
functioning and well-being. The EORTC QLQ-C30 is the most commonly used quality of life 
instrument in oncology trials. The instrument’s 30 items are divided among five functional scales 
(physical, role, cognitive, emotional, and social), eight symptom scales (fatigue, pain, 
nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, and diarrhea), a scale measuring 
financial difficulties, and a global health or quality of life scale. With the exception of two items 
included in the global health or quality of life scale, for which responses range from 1 (Very poor) 
to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the 
QLQ-C30 and are transformed to a 0-100 metric such that higher values indicate better functioning 
or QoL or a higher level of symptoms.
5.8
Immunogenicity Assessments
Serum samples collected at time points identified from Table 5.5-1 to Table 5.5-8 will be analyzed 
by validated immunoassay methods. Additional characterization (ie, neutralizing antibodies) for 
any detected anti-drug antibodies (ADA) response to study drug may also be performed. All 
samples collected for detection of anti-drug antibodies will also be assessed for the respective 
serum drug concentrations to enable interpretation of the antibody data. All on-treatment PK time 
points are intended to align with days on which nivolumab is administered. If it is known that a 
dose is going to be delayed, then the predose sample should be collected just prior to the delayed 
dose. However, if a predose sample is collected, but the dose is subsequently delayed, an additional 
predose sample should not be collected. Selected serum samples may be analyzed by an 
exploratory method that measures anti-nivolumab,
anti-ipilimumab,
anti-BMS-986016
Revised Protocol No.: 07
Date: 07-May-2019
166
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
(relatlimab), or anti-daratumumab antibodies for technology exploration purposes; exploratory 
results will not be reported.
In addition, serum samples designated for PK or biomarker assessments may also be used for
immunogenicity analysis if required (eg, if there is insufficient volume for complete
immunogenicity assessment or to follow up on suspected immunogenicity related AE).
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE).The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term “reasonable causal relationship” means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
Revised Protocol No.: 07
Date: 07-May-2019
167
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs, (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
−
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within
100 days of the last dose of study drug. For participants assigned to treatment and never treated 
with study drug, SAEs should be collected for 30 days from the date of treatment assignment. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
Revised Protocol No.: 07
Date: 07-May-2019
168
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. 
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
Revised Protocol No.: 07
Date: 07-May-2019
169
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
All non-serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the subject’s case report form.
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 (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
approximately 5 half-lives after product administration plus 30 days, the investigator must 
immediately notify the BMS Medical Monitor/designee of this event and complete and forward a 
Pregnancy Surveillance Form to BMS Designee within 24 hours of awareness of the event and in 
accordance with SAE reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject
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 
Revised Protocol No.: 07
Date: 07-May-2019
170
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
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
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
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. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
•
Sample size determination is not based on statistical power calculation.
Revised Protocol No.: 07
Date: 07-May-2019
171
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
1) Neoadjuvant cohort:
The SCCHN tumor types will contain 21 HPV-positive and 21 HPV-negative evaluable subjects. 
MCC and cervical, vaginal, or vulvar cancers tumor types will contain 21 evaluable subjects each. 
A sample size of 21 can detect, with more than 66% and 89% probability, a safety event that occurs 
at an incident rate of 5% and 10%, respectively. Assuming 10%, 15%, and 20% for pathologic 
complete response rate, a sample size of 21 can detect more than 89%, 97% and 99% probability, 
at least one pathologic complete response respectively.
2) Recurrent/metastatic monotherapy cohort:
HPV+ SCCHN, GYN, MCC and NPC tumor types in the recurrent/metastatic cohort will contain 
approximately 23 subjects. Table 8.1-1 shows the probabilities of observing 0, 1 or 2 responders 
and ≥3 responders assuming 5%, 20% and 30% true response rate of ORR. Table 8.1-2 shows the 
two-sided 95% exact CI using Clopper-Pearson methods based on observed 3, 4 and 5 responders 
out of 23 subjects.
EBV+ Gastric tumor type will contain approximately 12 subjects, due to the low prevalence. Table 
8.1-5 shows the precision of the estimation of ORR based on the two sided 95% exact CI using 
Clopper-Pearson methods based on 1, 2, 3, 4 and 5 responders out of 12 subjects.
Table 8.1-1:
Probability of Observing Responses Given True ORR for Sample 
Size of 23 Subjects
True ORR
Probability of observing 0, 1 or 2 
responses
Probability of observing 
≥3 responses
5%
89.5%
10.5%
20%
13.3%
86.7%
30%
1.6%
98.4%
Table 8.1-2:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
Number of Observed Responses out of 23 Subjects
The number of observed 
responses
3
4
5
Observed Response Rate
3/23 (13.0%)
4/23 (17.4%)
5/23 (21.7%)
95% exact CI
(2.8%, 33.6%)
(5.0%, 38.8%)
(7.5%, 43.7%)
3) Recurrent/metastatic combination cohort:
The HPV+ SCCHN, MCC, and NPC tumor types in the recurrent/metastatic cohort will each 
contain approximately 40 subjects that will be enrolled to the Combo A treatment arm. Patients 
with cervical cancer and anogenital HPV associated tumors (vulvar/vaginal/anal canal/penile) 
tumor types will be randomized in a 1:1 ratio to one of two dosing schema (Combo A or Combo B). 
Revised Protocol No.: 07
Date: 07-May-2019
172
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Each dosing schema will contain approximately 40 subjects. With Revised Protocol 06, no new 
subjects will be randomized in the anogenital HPV associated tumors cohorts.
Additionally, the metastatic cervical Combination B cohort will be expanded to treat
approximately 50 subjects as first-line treatment for their recurrent/metastatic disease if unfit or 
unsuitable to receive platinum-based therapy and approximately 20 subjects as second-line
treatment for their recurrent/metastatic SCC of the cervix to confirm the efficacy signal. With 
Combo B and the Combo B expansion, there should be a total of approximately 75 subjects with 
first-line treatment and approximately 35 subjects with second-line treatment of cervical cancer
(approximately 110 cervical subjects total). 
The HPV+ SCCHN with prior PD-1/PD-L1 treatment tumor type will be enrolled in Metastatic 
Combination Cohort (Combo C). Combo C will contain approximately 40 subjects. However, at 
Revised Protocol 05, no new subjects will be enrolled in this cohort.
Approximately 40 HPV negative and HPV indeterminate I-O naive SCCHN subjects will be 
enrolled to the Combo D treatment arm. With Revised Protocol 06, no new subjects will be 
enrolled in this cohort.
Sample sizes of each treatment arm in each tumor type are summarized in Table 8.1-3.
An ORR in excess of 10% will be considered of clinical interest. Assuming the true ORR is 25%, 
40 subjects in each tumor type can provide approximately 79.8% power to reject the null 
hypothesis that the true ORR is 10%, considering a 2-sided alpha of 5%. In addition Table 8.1-4
shows the precision of the estimation of ORR based on the two sided 95% exact CI using Clopper-
Pearson methods based on 8, 9, 12, 16 and 20 responders out of 40 subjects. At observed more 
than or equal to 9 responders, ie, ORR ≥22.5%, the lower bound of the 95% CI excludes 10%.
Table 8.1-5 shows the precision of the estimation of ORR based on the two sided 95% exact CI 
using Clopper-Pearson methods based on 1, 2, 3, 4 and 5 responders out of 12 subjects. Assuming 
the true ORR is 25%, 12 subjects can provide approximately 84% probability to observe at least 2 
responders.
Table 8.1-6 shows the precision of the estimation of ORR based on the two sided 95% exact CI 
using Clopper-Pearson methods based on 20, 22, 26, 30, 33, and 35 responders out of 50 subjects. 
At observed more than or equal to 22 responders, ie, ORR ≥44%, the lower bound of the 95% CI 
excludes 30%; at observed more than or equal to 26 responders, ie, ORR ≥52%, the lower bound 
of the 95% CI excludes 37%.
Table 8.1-7 shows the precision of the estimation of ORR based on the two sided 95% exact CI 
using Clopper-Pearson methods based on 3, 5, 8, 10, 12 and 14 responders out of 35 subjects. At 
observed more than or equal to 8 responders, ie, ORR ≥22.9%, the lower bound of the 95% CI 
excludes 10%.
Due to the low prevalence of EBV+ Gastric tumor types and the current investigation of this tumor 
type in other BMS-sponsored studies, combination cohorts in this study will no longer include 
EBV+ Gastric tumor type.
Revised Protocol No.: 07
Date: 07-May-2019
173
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 8.1-3:
Sample Size in Recurrent/Metastatic Combination Cohort
Combo A
Nivo-3mg/kg q2w 
+ Ipi-1mg/kg q6w
Combo B
Nivo-1mg/kg + Ipi-
3mg/kg q3w x 4 
followed by Nivo
240mg q2w
Combo C
Nivo+Anti-Lag-3
Combo D
Nivo+Dara
Cervical
40
110a
Anogenital HPV
associated tumors
(vaginal/vulvar/anal 
canal/penile)
40
40
MCC
40
NPC
40
HPV+ SCCHN
(I/O naive)
40 
HPV+ SCCHN
(Prior PD-1/PD-L1)
40
I-O Naive SCCHN
40
a Includes 40 from Combination B and 70 from Combination B expansion.
Table 8.1-4:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 40 Subjects
Number of 
observed 
responses
8
9
12
16
20
Observed 
Response Rate
8/40 (20.0%)
9/40 (22.5%)
12/40 (30.0%)
16/40 (40.0%)
20/40 (50.0%)
95% exact CI 
(%)
(9.1, 35.6)
(10.8, 38.5)
(16.6, 46.5)
(24.9, 56.7)
(33.8, 66.2)
Table 8.1-5:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 12 Subjects
Number of 
observed 
responses
1
2
3
4
5
Observed 
Response Rate
1/12 (8.3%)
2/12 (16.7%)
3/12 (25.0%)
4/12 (33.3%)
5/12 (41.7%)
95% exact CI
(%)
(0.2, 38.5)
(2.1, 48.4)
(5.5, 57.2)
(9.9, 65.1)
(15.2, 72.3)
Revised Protocol No.: 07
Date: 07-May-2019
174
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Table 8.1-6:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 50 Subjects
Number of 
observed 
responses
20
22
26
30
33
35
Observed 
Response 
Rate
20/50
(40.0%)
22/50
(44%)
26/50
(52%)
30/50
(60%)
33/50
(66%)
35/50
(70%)
95% exact CI 
(%)
(26.4, 54.8)
(30.0, 58.8)
(37.4, 66.3)
(45.2, 73.6)
(51.2, 78.8)
(55.4, 82.1)
Table 8.1-7:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 35 Subjects
Number of 
observed 
responses
3
5
8
10
12
14
Observed 
Response 
Rate
3/35
(8.6%)
5/35
(14.3%)
8/35
(22.9%)
10/35
(28.6%)
12/35
(34.3%)
14/35
(40%)
95% exact CI 
(%)
(1.8,23.1)
(4.8, 30.3)
(10.4, 40.1)
(14.6, 46.3)
(19.1, 52.2)
(23.9,57.9)
8.2
Populations for Analyses
The analysis populations will be by cohort (neoadjuvant and metastatic), tumor type, and 
combination regimen. The following populations will be defined, and their specific applications 
will be documented in detail in the statistical analysis plan:
•
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IRT.
•
All Treated Subjects: All enrolled subjects who received at least one dose of study drug.
•
All Response Evaluable Subjects: All treated subjects in recurrent/metastatic cohorts 
(monotherapy and combination therapy) who have a BOR of CR, PR, SD, Non-CR/Non-
PD or PD, and target lesion(s) assessed at baseline, and one of the following: i) at least one 
on-study time point (before sub-sequent therapy) with all baseline target lesion(s) assessed; 
ii) clinical progression or death before any on-study tumor assessment.
•
All Evaluable Neoadjuvant Subjects: All treated subjects in neoadjuvant cohorts who have 
available paired tissue samples at Screening and Day 29.
•
Outcomes Research Subjects: All treated subjects who have an assessment at baseline and at 
least one post-baseline assessment.
•
Pharmacokinetic Subjects: All subjects who receive at least one dose of study drug and have 
available serum concentration data.
Revised Protocol No.: 07
Date: 07-May-2019
175
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
Immunogenicity Subjects: All treated subjects with baseline and at least 1 post-baseline 
immunogenicity assessment for nivolumab, ipilimumab and BMS-986016 (relatlimab); All 
treated subjects with at least 1 post-baseline immunogenicity assessment for daratumumab. 
•
Biomarker Subjects: All treated subjects who have available biomarker data.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
Neoadjuvant cohort: 
•
The safety and tolerability objective will be measured by the incidence of drug-related select 
AEs and drug-related SAEs.
•
Rate of surgery delay, which is defined as the proportion of subjects in the neoadjuvant cohort 
with surgery delayed > 4 weeks from the planned surgery date or planned start date for 
chemoradiation due to a drug-related AE will be reported for each tumor type.
Metastatic cohorts (monotherapy and combination therapies): 
•
The investigator-assessed objective response rate (ORR). ORR is defined as the number of 
subjects with a best overall response (BOR) of confirmed complete response (CR) or partial 
response (PR) divided by the number of treated subjects. BOR is defined as the best response 
designation recorded between the date of first dose and the date of the initial objectively 
documented tumor progression per investigator assessment using RECIST 1.1 criteria or the 
date of the last tumor assessment date prior to subsequent therapy. In this study, an ORR in 
excess of 10% will be considered of clinical interest, and an ORR of 25% or greater will be 
considered of strong clinical interest.  
8.3.2
Secondary Endpoint(s)
Metastatic cohorts (monotherapy and combination therapies):
•
Duration of response (DOR) is defined as the time from first confirmed response (CR or PR) 
to the date of the initial objectively documented tumor progression as determined per 
investigator assessment using RECIST 1.1 criteria or death due to any cause, whichever occurs 
first. Subjects who did not start subsequent anti-cancer therapy and die without a reported prior 
progression will be considered to have progressed on the date of their death. Subjects who did 
not progress or die will be censored on the date of their last tumor assessment. Subjects who 
did not have any on study tumor assessments and did not die will be censored on the date they 
were treated. Subjects who started any subsequent anti-cancer therapy prior to death and 
without a prior reported progression will be censored at the last tumor assessment prior to or 
on the date of initiation of the subsequent anti-cancer therapy. DOR will only be evaluated in 
subjects with objective response of CR or PR.
•
Overall survival (OS) is defined as the time from first dosing date to the date of death. A subject 
who has not died will be censored at last known date alive. 
•
Investigator-assessed progression free survival (PFS) is defined as the time from first dosing 
date to the date of the first documented tumor progression, as determined by investigators (per 
Revised Protocol No.: 07
Date: 07-May-2019
176
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
RECIST 1.1), or death due to any cause. Subjects who did not start subsequent anti-cancer 
therapy and die without a reported prior progression will be considered to have progressed on 
the date of their death. Subjects who did not progress or die will be censored on the date of 
their last tumor assessment. Subjects who did not have any on study tumor assessments and 
did not die will be censored on the date they were treated. Subjects who started any subsequent 
anti-cancer therapy prior to death and without a prior reported progression will be censored at 
the last tumor assessment prior to or on the date of initiation of the subsequent anti-cancer 
therapy.
8.3.3
Exploratory Endpoint(s)
Neoadjuvant cohort: 
•
The percent change from baseline of select immune cells and the percent change from baseline 
of select immune activation/inhibitory molecules of viral-specific T cells in tumor specific 
subsets of nivolumab treated subjects will be evaluated.
•
Recurrence-free survival (RFS), which is defined as the time from surgery to the date or 
recurrence(local, regional, metastasis, locally advanced unresectable recurrence, clinical or 
radiographic progression occurs after surgery) as determined by investigators, or death due to 
any cause, whichever occurs first. (Note: a subject who dies without reported recurrence will 
be considered to have recurred on the date of death.) For subjects who remain alive and whose 
disease has not recurred, RFS will be censored on the date of last evaluable disease assessment. 
Participants who did not have any post-surgery disease assessments and did not die will be 
censored on the surgery date. Further details on the censoring rules for consideration of 
subsequent therapies, will be described in the Statistical Analysis Plan (SAP).
•
The proportion of treated subjects who experiences pathologic complete response will be used 
to determine pathologic response rate of tumors after two doses of neoadjuvant nivolumab in 
HPV positive and negative SCCHN, resectable Merkel Cell Carcinoma, and cervical, vaginal, 
or vulvar cancer. Pathological complete response (pCR) is defined as the absence of residual 
viable invasive cancer on hematoxylin and eosin evaluation of the complete resected tumor
specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic 
therapy.
Metastatic cohorts (monotherapy and combination therapies):
•
The safety and tolerability objective will be measured by the incidence of adverse events, 
serious adverse events, deaths and laboratory abnormalities.
•
Pre- and post-treatment EBV DNA levels will be collected in the subjects with EBV positive 
gastric cancer and nasopharyngeal carcinoma. The change in EBV DNA levels will be used to 
determine the effect of BMS-936558 (nivolumab). (Monotherapy cohort only)
Revised Protocol No.: 07
Date: 07-May-2019
177
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Neoadjuvant and Metastatic cohorts (monotherapy and combination therapies):
•
The PK samples collected will be used to determine summary measures of nivolumab,
ipilimumab, BMS-986016 (relatlimab), and daratumumab exposures (see Section 8.4.4)
•
Exploratory endpoints for pharmacodynamics, outcomes research and immunogenicity are 
discussed in detail in Sections 5.6, 5.7 and 5.8.
Other exploratory endpoints will be discussed in detail in the statistical analysis plan.
8.4
Analyses
All analyses for neoadjuvant cohort will be performed as it completes safety follow-up. All 
analyses for each metastatic cohort (nivolumab monotherapy or combo A, B, C, or D) will be 
performed as it completes efficacy follow-up. All analyses will be performed independently by 
cohort, by tumor type, and regimen.
The randomization of the patients with metastatic cervical cancer and anogenital HPV associated 
(vulvar/vaginal/anal canal/penile) tumor types to combo A, B, or D is for administration purposes, 
not for comparison. Analyses will be done for each dosing schema separately. 
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline laboratory results will be summarized using descriptive statistics for all 
treated subjects.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
Neoadjuvant cohort: 
•
Analyses of drug-related select AEs and drug-related SAEs are discussed in Section 8.4.3
•
Rate of surgery delay will be summarized by binomial response rates and their corresponding 
two-sided 95% exact CIs using Clopper-Pearson method. 
Metastatic cohort (monotherapy and combination therapies):
•
The investigator assessed ORR in the metastatic cohort will be summarized by binomial 
response rates and their corresponding two-sided 95% exact CIs using Clopper-Pearson 
method. 
8.4.2.2
Secondary Endpoints Methods
Metastatic cohort (monotherapy and combination therapies):
•
Time to event distribution will be estimated using Kaplan Meier techniques. This will be done 
for PFS (based on investigator assessments) and OS. Median PFS or OS along with 95% CI 
will be constructed based on a log-log transformed CI for the survivor function. Rates at some 
fixed time points will be derived from the Kaplan Meier estimate and corresponding 
Revised Protocol No.: 07
Date: 07-May-2019
178
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
confidence interval will be derived based on Greenwood formula for variance derivation and 
on log-log transformation applied on the survivor function. 
•
The DOR will be summarized for all treated subjects who achieve confirmed PR or CR using 
the Kaplan-Meier (KM) product-limit method. Median values of DOR, along with two-sided 
95% CI using Brookmeyer and Crowley method, will also be calculated.
8.4.2.3
Exploratory Endpoints Methods
Methods for exploratory endpoints will be discussed in detail in the statistical analysis plan.
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4. All on-study AEs, drug-related, AEs, SAEs and 
drug-related SAEs will be tabulated using worst grade per NCI CTCAE version 4 criteria by 
system organ class and MedDRA preferred term. On-study lab parameters including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
grade per NCI CTCAE version 4 criteria.
The proportion of subjects in the neoadjuvant cohort with surgery delayed > 4 weeks due to a drug-
related AE will be reported for each tumor type and the Clopper-Pearson method will be used to 
estimate the two-sided 95% confidence interval.
8.4.4
Pharmacokinetic Analyses
The nivolumab, ipilimumab, BMS-986016 (relatlimab), and daratumumab concentration data 
obtained in this study may be combined with data from other studies in any of the clinical 
development programs (nivolumab, ipilimumab, BMS-986016, and daratumumab) to develop or 
refine a population PK model. The models may be used to evaluate the effects of intrinsic and 
extrinsic covariates on the PK of nivolumab or other compounds 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. If performed, 
results of population PK and exposure response-analyses will be reported separately.
8.4.5
Biomarker Analyses
The pharmacodynamic effects of nivolumab as monotherapy or in combination with ipilimumab,
BMS-986016 (relatlimab), or daratumumab on selected biomarkers will be assessed by summary 
statistics and corresponding changes (or percent changes) from baseline tabulated by time and 
cohort. In addition, the time course of biomarker outcomes will be investigated graphically, by 
summary plots or individual subject plots. If there is an indication of a meaningful 
pharmacodynamic trend, methods such as linear mixed models may be used to characterize the 
pattern of change over time. The potential association between PD-L1 expression level (IHC) and 
clinical efficacy measures will be assessed using Fisher’s exact test or other methodology as 
appropriate.
Revised Protocol No.: 07
Date: 07-May-2019
179
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Potential associations of various biomarker measures with pharmacokinetic exposure, safety and 
clinical efficacy measures will be investigated based on data availability. Methods such as, but not 
limited to, logistic regression and graphical summaries may be used to assess these associations.
The methodology for additional exploratory biomarker analyses will be described in the statistical 
analysis plan. 
8.4.6
Outcomes Research Analyses
8.4.6.1
EQ-5D
Outcomes Research Subject’s overall health on the EQ-5D VAS at each assessment time point 
will be summarized using descriptive statistics (N, mean, standard deviation, median, first and 
third quartiles, minimum, maximum). Proportion of subjects reporting problems for the 5 EQ-5D 
dimensions at each assessment time point will be summarized by level of problem. Percentages 
will be based on the number subjects with EQ-5D data at each assessment time point.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, self-
care, usual activities, pain/discomfort and anxiety/depression), health state (5 dimensions digits 
combined in a 5-digit number) and EQ-5D VAS will be provided.
8.4.6.2
EORTC QLQ-C30
The analysis of EORTC QLQ-C30 data will be performed in all Outcomes Research Subjects.
For each cohort, baseline scores and post-baseline score changes for all EORTC QLQ-C30 scales 
will be summarized using descriptive statistics (N, mean, standard deviation, median, first and 
third quartiles, minimum, maximum). Baseline and change from baseline in EORTC QLQ-C30 
global health status/QoL composite scale data and the remaining EORTC QLQ-C30 scale data will 
be summarized by time point using descriptive statistics for each cohort (N, mean, standard 
deviation, median, first and third quartiles, minimum, maximum). In addition, the percentage of 
subjects demonstrating a clinically meaningful deterioration (defined as a 10 point change from 
baseline) will be presented for each scale at each assessment time point. Percentages will be based 
on the number of subjects with EORTC QLQ-C30 data at each assessment time point.
8.4.7
Other Analyses
8.4.7.1
Immunogenicity Analyses
Immunogenicity may be reported for ADA positive status (such as persistent positive, neutralizing
positive, only last sample positive, baseline positive and other positive) and ADA negative status, 
relative to baseline. Effect of immunogenicity on safety, efficacy, biomarkers and PK may be 
explored. Additional details will be described in the SAP.
8.5
Interim Analyses
Under the circumstance that data of some tumor types mature faster than others or a strong signal 
is observed in some tumor types, interim analyses may be performed prior to the completion of 
the study in order to facilitate program decisions and to support presentations or publication. These 
interim analyses will not impact the study duration and the trial will continue as planned.
Revised Protocol No.: 07
Date: 07-May-2019
180
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 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. 
Revised Protocol No.: 07
Date: 07-May-2019
181
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
Records or logs must comply with applicable regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
Revised Protocol No.: 07
Date: 07-May-2019
182
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
Revised Protocol No.: 07
Date: 07-May-2019
183
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
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.
Revised Protocol No.: 07
Date: 07-May-2019
184
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (eg, 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
Revised Protocol No.: 07
Date: 07-May-2019
185
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
β-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
Revised Protocol No.: 07
Date: 07-May-2019
186
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Term
Definition
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
cHL
classical Hodgkin’s lymphoma
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Revised Protocol No.: 07
Date: 07-May-2019
187
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Term
Definition
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
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)
EORTC QLQ-C30
European Organization for the Research and Treatment of Cancer Quality 
of Life Questionnaire - Core 30
EQ-5D-3L
3-level EQ-5D questionnaire
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
%FE
percent fecal excretion
fu
fraction of unbound drug
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
Revised Protocol No.: 07
Date: 07-May-2019
188
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Term
Definition
G criteria
adjusted R2 value of terminal elimination phase
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
immunoglobulin
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IO
immuno-oncology
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
λz
terminal disposition rate constant
L
liter
LAG-3
lymphocyte activation gene 3
Revised Protocol No.: 07
Date: 07-May-2019
189
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Term
Definition
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining the
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the 
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
LVEF
left ventricular ejection fraction
MEL
melanoma
mg
milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
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
Revised Protocol No.: 07
Date: 07-May-2019
190
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Term
Definition
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
RCC
renal cell carcinoma
SAE
serious adverse event
SCC
squamous cell cancer
SCLC
small cell lung cancer
SD
standard deviation
SEB
staphylococcal enterotoxin B
SOC
standard of care
SOP
Standard Operating Procedures
sp.
species
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
Revised Protocol No.: 07
Date: 07-May-2019
191
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Term
Definition
T-HALFeff_AUC
Effective elimination half-life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half-life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
TIL
tumor infiltrating lymphocytes
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
Revised Protocol No.: 07
Date: 07-May-2019
192
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
12
REFERENCES
1
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of 
the PD 1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation 
of lymphocyte activation. J Exp Med 2000;192(7):1027-34.
2
Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. 
Trends Immunol. 2001; 22: 265-8.
3
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al., PD-L2 is a 
second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268.
4
Carter LL, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, et al. PD-1:PD-L inhibitory pathway 
affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur J Immunol. 2002;32(3):634-
43.
5
Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with immunoreceptor 
tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, 
but only receptor ligation prevents T cell activation. J Immunol. 2004; 173: 945-54.
6
Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of 
the ZAP70/CD3zeta signalosome and downstream signaling to PKC-theta. FEBS Letters. 
2004; 574: 37-41.
7
Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by 
disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 
1999; 11:141-51.
8
Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 
receptor-deficient mice. Science. 2001; 291: 319-22.
9
Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible 
for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003; 9: 1477-83.
10 Salama AD, Chitnis T, Imitola J, et al. Critical role of the programmed death-1 (PD-1) pathway 
in regulation of experimental autoimmune encephalomyelitis. J Exp Med. 2003; 198: 71-8.
11 Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 
engagement accelerates graft-versus-host disease lethality by an IFN-α-dependent mechanism. 
J Immunol. 2003; 171: 1272-7.
12 Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, et al. The programmed 
death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J 
Exp Med. 2003 Jul 7;198(1):63-9.
Revised Protocol No.: 07
Date: 07-May-2019
193
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
13 Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly 
immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2004; 17: 
133-44.
14 Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from 
host immune system and tumor immunotherapy by PD-1 blockade. Proc Natl Acad Sci USA. 
2002; 99: 12293-7.
15 Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer Res. 2003; 63: 6501-5.
16 Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: 
a potential mechanism of immune evasion. Nat Med. 2002; 8: 793-800.
17 Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies
potentiates cancer therapeutic immunity. Cancer Res. 2005 Feb 1;65(3):1089-96.
18 Blank C, Brown I Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor 
rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004; 64: 1140-45.
19 Keir M, Butte M, Freeman G, Sharpe A. PD-1 and its ligands in tolerance and immunity. Ann 
Rev Immunol. 2008;26:677-704.
20 Konishi J, Yamazaki K, Azuma M, et al. B7-H1 expression on non-small cell lung cancer cells 
and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin 
Cancer Res. 2004; 10: 5094-100.
21 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma 
subjects: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad 
Sci USA. 2004; 101: 17174-9.
22 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: 2947-53.
23 Tsushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its 
immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol. 2006; 42: 268-74.
24 Thompson RH, Weber WS, Cheville JC, et al. B7-H1 glycoprotein blockade: a novel strategy 
to enhance immunotherapy in subjects with renal cell carcinoma. Urology. 2005; 66: 10-4.
25 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and 
metastatic clear cell renal cell carcinoma. Cancer. 2005; 104: 2084-91.
26 Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med. 
2003; 81: 281-7.
Revised Protocol No.: 07
Date: 07-May-2019
194
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
27 Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with immunoreceptor 
tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, 
but only receptor ligation prevents T cell activation. J Immunol. 2004; 173: 945-54.
28 Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. 
Blood. 2008; 111: 3635-43.
29 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma 
subjects: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad 
Sci USA. 2004; 101: 17174-9.
30 Effect of MDX-1106 on CD4+ T cells during an allogeneic mixed lymphocyte reaction (MLR) 
(Medarex Study No. MDX-1106-026-R). Bristol-Myers Squibb Pharmaceutical Research 
Institute; 2006. Document Control No. 930046581.
31 Ferlay J, Soerjomataram I, Ervik M. et al. GLOBOCAN 2012 v1.0, cancer incidence and 
mortality worldwide. IARC Cancer Base 11, http://globocan.iarc.fr, Accessed on 13 August 
2014.
32 Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2011, 
National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on 
November 2013 SEER data submission, posted to the SEER web site, April 2014.
33 Karpeh MS, Leon L, Klimstra D, et al. Lymph node staging in gastric cancer: islocation 
important than number? An analysis of 1038 patients. Ann Surg 2000;232:362-371.
34 The Cancer Genome Atlas Network. Comprehensive molecular characterization of gastric 
adenocarcinoma. Nature 2014;513:202–209.
35 Murphy G, Pfeiffer R, Camargo MC, et al. Meta-analysis shows that prevalence of Epstein-
Barr virus-positive gastric cancer differs based on sex and anatomic location. 
Gastroenterology. 2009; 137:824-33. 
36 WHO Classification of Tumours of the Digestive System 4th edition (International Agency for 
Research on Cancer, 2010).
37 Carmargo MC, Kim WH, Chiaravalli AM, et al. Improved survival of gastric cancer with 
tumor Epstein-Barr virus positivity: an international pooled analysis. Gut. 2014;63:236-43.
38 Lee JH, Kim SH, Han SH, et al. Clinicopathological and molecular characteristics of Epstein-
Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 2009; 
24:354-65.
39 Atula S, Auvinen E, Grenman R, et al. Human papillomavirus and Epstein-Barr virus in 
epithelial carcinomas of the head and neck region. Anticancer Res 1997; 17:4427.
40 Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-
Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 1995; 
333:693.
Revised Protocol No.: 07
Date: 07-May-2019
195
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
41 Chien YC, Chen JY, Liu MY, et al. Serologic markers of Epstein-Barr virus infection and 
nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 2001; 345:1877.
42 Pathology and genetics of head and neck tumors. In: World Health Organization Classification 
of Tumours, Barnes L, Eveson JW, Reichart P, Sidransky D (Eds), IARC Press, Lyon 2005.
43 Leung SF, Zee B, Ma BB, et al. Plasma Epstein-Barr viral deoxyribonucleic acid quantitation 
complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J 
Clin Oncol 2006; 24:5414-18.
44 Lin JC, Wang WY, Chen KY, et al. Quantification of plasma Epstein-Barr virus DNA in 
patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350:2461-70.
45 Lin JC, Wang WY, Liang WM, et al. Long-term prognostic effects of plasma epstein-barr virus 
DNA by minor groove binder-probe real-time quantitative PCR on nasopharyngeal carcinoma 
patients receiving concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1342-
8.
46 Lee AW, Sze WM, Au JS, et al. Treatment results for nasopharyngeal carcinoma in the modern 
era: the Hong Kong experience. Int J Radiat Oncol Biol Phys. 2005;61:1107-16.
47 Jin Y, Cai XY, Shi YX, et al. Comparison of five cisplatin-based regimens frequently used as 
the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol. 
2012;138:1717-25. 
48 Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and 
metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral 
Oncol. 2003;39:361-6.
49 Poon D, Chowbay B, Cheung YB, et al. Phase II study of irinotecan (CPT-11) as salvage 
therapy for advanced nasopharyngeal carcinoma. Cancer. 2005;103:576-81.
50 Ngeow J, Lim WT, Leong SS, et al. Docetaxel is effective in heavily pretreated patients with 
disseminated nasopharyngeal carcinoma. Ann Oncol. 2011;22(3):718-22.
51 Chen C, Wang FH, Wang ZQ, et al. Salvage gemcitabine-vinorelbine chemotherapy in patients 
with metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral 
Oncol. 2012;48):1146-51. 
52 Yau TK, Shum T, Lee AW, et al. A phase II study of pemetrexed combined with cisplatin in 
patients with recurrent or metastatic nasopharyngeal carcinoma. Oral Oncol. 2012;48:441-4.
53 Argiris A, Karamouzis MV, Raben D, et al. Head and neck cancer. Lancet 2008;371:1695-
709.
54 Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for 
head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. 
MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. 
Lancet 2000;355:949-55.
Revised Protocol No.: 07
Date: 07-May-2019
196
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
55 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 ;64:9-29.
56 Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck 
cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 
2009;92:4-14.
57 Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation 
therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable 
squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.
58 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.
59 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally 
advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and 
relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21-8.
60 Gold KA, Lee HY, Kim ES. Targeted therapies in squamous cell carcinoma of the head and 
neck. Cancer 2009;115:922-35.
61 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.
62 Gillison ML, D'Souza G, Westra W, et al. Distinct risk factor profiles for human 
papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck 
cancers. J Natl Cancer Inst 2008;100:407-20.
63 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.
64 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.
65 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.
66 Leon X, Hitt R, Constenla M, et al. A retrospective analysis of the outcome of patients with 
recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a 
platinum-based chemotherapy. Clin Oncol (R Coll Radiol) 2005;17:418-24.
67 http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/125084s046LBL.pdf Accessed on 
23 Sept 2103
68 Price KAR and Cohen EE. Current Treatment Options for Metastatic Head and Neck Cancer. 
Curr Treat Options Oncol 2012;13:35-46.
Revised Protocol No.: 07
Date: 07-May-2019
197
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
69 Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study comparing 
docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer 
2004;40:2071-6. 
70 Knoedler M, Gauler TC, Gruenwald V, et al. Phase II Study of Cetuximab in Combination 
with Docetaxel in Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of the 
Head and Neck after Platinum-Containing Therapy: A Multicenter Study of the 
ArbeitsgemeinschaftInternisticshceOnkologie. Oncology 2013;84:284-89. 
71 Vermorken JB, Trigo J, Hitt R, et al. Open-Label, Uncontrolled, Multicenter Phase II Study to 
Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent in Patients With Recurrent 
and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Failed to Respond to 
Platinum-Based Therapy. JCO 2007;25:2171-77.
72 Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with 
Oropharyngeal Cancer. NEJM 2010;363:24-35.
73 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.
74 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.
75 Insinga RP, Liaw KL, Johnson LG, et al. A systematic review of the prevalence and attribution 
of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in 
the United States. Cancer Epidemiol Biomarkers Prev. 2008l;17:1611-22. 
76 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause 
of invasive cervical cancer worldwide. J Pathol. 1999;189:12-9.
77 Iwasawa A, Nieminen P, Lehtinen M, et al. Human papillomavirus in squamous cell carcinoma 
of the vulva by polymerase chain reaction. J. Obstet Gynecol. 1997;89:81-4.
78 http://www.cdc.gov/cancer/hpv/statistics/index.htm Accessed on 26 Dec 2014. 
79 Shylasree TS, Bryant A, Howells RE. Chemoradiation for advanced primary vulvar cancer. 
Cochrane Database Syst Rev. 2011;(4):CD003752. 
80 http://www.cancer.org/cancer/vulvarcancer/detailedguide/vulvar-cancer-survival-rates 
Accessed on 26 Dec 2014.
81 Maggino T, Landoni F, Sartori E, et al. Patterns of recurrence in patients with squamous cell 
carcinoma of the vulva. A multicenter CTF Study. Cancer. 2000;89:116-22.
82 http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-survival Accessed 
on 26 Dec 2014. 
83 Tewari KS1, Sill MW, Long HJ, et al. Improved survival with bevacizumab in advanced 
cervical cancer. N Engl J Med. 2014;370:734-43.
Revised Protocol No.: 07
Date: 07-May-2019
198
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
84 Cancer 
Facts 
& 
Figures 
2016. 
American 
Cancer 
Society. 
Available 
at 
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-
047079.pdf. Accessed: Sept 6, 2016.
85 Palefsky JM. Anal human papillomavirus infection and anal cancer in HIV-positive 
individuals: an emerging problem. AIDS. 1994;8(3):283-95.
86 Frisch M, Glimelius B, van den Brule AJ, et al. Sexually transmitted infection as a cause of 
anal cancer. N Engl J Med. 1997;337 (19):1350-8.
87 SEER Stat Fact Sheets: Anal Cancer. NIH Surveillance, Epidemiology and End Results 
Program. Available at http://seer.cancer.gov/statfacts/html/anus.html.; Accessed: Sept. 6, 
2016.
88 Glynne-Jones R, Nilsson PJ, Aschele C, Goh V, Peiffert D, Cervantes A, Arnold D. Anal 
cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2014;40(10):1165-76.
89 Long AP, Kroon BK, Gallee MP, et al. Pelvic lymph node dissection for penile carcinoma: 
extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement 
and survival. J Urol. 2007;177(3):947-52.
90 Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous 
cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 
700 patients. Eur Urol. 2008;54(1):161-8. Epub 2008 Apr 15.
91 Connell CF, Berger NA. Management of advanced squamous cell carcinoma of the penis. Urol 
Clin North Am. 1994;21(4):745-56.
92 Nicholson S, Hall E, Harland SJ, et al. Phase II trial of docetaxel, cisplatin and 5FU 
chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001). Br J Cancer. 
2013;109(10):2554-9. Epub 2013 Oct 29.
93 Haas GP, Blumenstein BA, Gagliano RG, et al. Cisplatin, methotrexate and bleomycin for the 
treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol. 
1999;161(6):1823-5.
94 Theodore C, Skoneczna I, Bodrogi I, et al. A phase II multicentre study of irinotecan (CPT 11) 
in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma 
(EORTC PROTOCOL 30992). Ann Oncol. 2008;19(7):1304-1307.
95 Di Lorenzo G, Federico P, Buonerba C, et al. Paclitaxel in pretreated metastatic penile cancer: 
final results of a phase 2 study. Eur Urol. 2011;60(6):1280-4.
96 Wang J, Pettaway CA, Pagliaro LC. Treatment for Metastatic Penile Cancer After First-line 
Chemotherapy Failure: Analysis of Response and Survival Outcomes. Urology. 
2015;85(5):1104-10.
Revised Protocol No.: 07
Date: 07-May-2019
199
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
97 Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, 
morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 
2010;27:20-7.
98 Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic 
accuracy in merkel cell carcinoma: Analysis of 5823 cases as the basis of the first consensus 
staging system. J Am Acad Dermatol 2010;63:751–61.
99 Howard RA, Dores GM, Curtis RE, et al. Merkel cell carcinoma and multiple primary cancers. 
Cancer Epidemiol Biomarkers Prev 2006;15:1545–9.
100 Ascoli V, Minelli G, Kanieff M, et al. Merkel cell carcinoma: A population-based study on 
mortality and the association with other cancers. Cancer Causes Control 2011;22:1521–7.
101 Gass JK, Chan SK, Rytina E, et al. Multiple primary malignancies in patients with merkel cell 
carcinoma. J Eur Acad Dermatol Venereol 2010;24:601–3.
102 Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel 
cell carcinoma. Science 2008;319:1096-100.
103 Sastre-Garau X, Peter M, Avril MF, et al. Merkel cell carcinoma of the skin: pathological and 
molecular evidence for a causative role of MCV in oncogenesis. J Pathol. 2009;218(1):48-56.
104 Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved 
survival in Merkel cell carcinoma of the skin. Clin Oncol 2007;25:1043-47. 
105 http://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf Accessed on 7 October 2014.
106 Crown J, Lipzstein R, Cohen S, et al. Chemotherapy of metastatic Merkel cell cancer. Cancer 
Invest. 1991;9:129-32.
107 Pectasides D, Moutzourides G, Dimitriadis M, et al. Chemotherapy for Merkel cell carcinoma 
with carboplatin and etoposide. Am J Clin Oncol. 1995 Oct;18:418-20.
108 Redmond J, Perry J, Sowray P, et al. Chemotherapy of disseminated Merkel-cell carcinoma. 
Am J Clin Oncol. 1991;14:305-7.
109 Rous P. A transmissible avian neoplasm. (sarcoma of the common fowl.). The Journal of 
experimental medicine 1910;12:696-705.
110 Martin D, Gutkind JS. Human tumor-associated viruses and new insights into the molecular 
mechanisms of cancer. Oncogene 2008;27 Suppl 2:S31-42.
111 Scheffner M, Huibregtse JM, Vierstra RD, et al. The HPV-16 E6 and E6-AP complex functions 
as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993;75:495-505.
112 Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. 
Nature reviews Cancer 2010;10:550-60.
Revised Protocol No.: 07
Date: 07-May-2019
200
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
113 Saha A, Robertson ES. Impact of EBV essential nuclear protein EBNA-3C on B-cell 
proliferation and apoptosis. Future microbiology 2013;8:323-52.
114 Herrero JA, Mathew P, Paya CV. LMP-1 activates NF-kappa B by targeting the inhibitory 
molecule I kappa B alpha. Journal of virology 1995;69:2168-74.
115 Dyson N, Bernards R, Friend SH, et al. Large T antigens of many polyomaviruses are able to 
form complexes with the retinoblastoma protein. Journal of virology 1990;64:1353-6.
116 Treisman R, Novak U, Favaloro J, et al. Transformation of rat cells by an altered polyoma 
virus genome expressing only the middle-T protein. Nature 1981;292:595-600.
117 Shuda M, Kwun HJ, Feng H, et al. Human Merkel cell polyomavirus small T antigen is an 
oncoprotein targeting the 4E-BP1 translation regulator. The Journal of clinical investigation 
2011;121:3623-34.
118 Lyngaa R, Pedersen NW, Schrama D, et al. T-cell responses to oncogenic merkel cell 
polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors. 
Clinical cancer research: an official journal of the American Association for Cancer Research 
2014;20:1768-78.
119 Li J, Zeng XH, Mo HY, et al. Functional inactivation of EBV-specific T-lymphocytes in 
nasopharyngeal carcinoma: implications for tumor immunotherapy. PloS one 2007;2:e1122.
120 Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple 
inhibitory receptors during chronic viral infection. Nature immunology 2009;10:29-37.
121 Carthon BC, Wolchok JD, Yuan J, Kamat A, et al. Preoperative CTLA-4 blockade: tolerability 
and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010 
May 15;16(10):2861-71. doi: 10.1158/1078-0432.CCR-10-0569. Epub 2010 May 11.
122 Lyngaa R1, Pedersen NW, Schrama D, et al. T-cell responses to oncogenic merkel cell 
polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors. 
Clin Cancer Res. 2014 Apr 1;20(7):1768-78.
123 Feichtenbeiner A1, Haas M, Büttner M, et al. Critical role of spatial interaction between CD8⁺
and Foxp3⁺ cells in human gastric cancer: the distance matters. Cancer Immunol Immunother. 
2014 Feb;63(2):111-9.
124 Paulson KG, Iyer JG, Simonson WT, et al. CD8+ lymphocyte intratumoral infiltration as a 
stage-independent predictor of Merkel cell carcinoma survival: a population-based study. Am 
J Clin Pathol. 2014 Oct;142(4):452-8.
125 Lipson EJ, Vincet JG, Loyo M, et al. Expression in the merkel cell carcinoma 
microenvironment: Association with inflammation, merkel cell polyomavirus, and overall 
survival. Cancer Immunol Res 2013;1:1–10. 
126 Bristol-Myers Squibb Investigator Brochure: Ipilimumab, BMS-734016, MDX010. 
Revised Protocol No.: 07
Date: 07-May-2019
201
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
127 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.
128 Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF 
mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and 
ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol, 2014. 32:5s 
(suppl; abstr LBA9003).
129 Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in 
untreated melanoma. N Engl J Med 2015; 372:2006-2017.
130 Scott JA, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung 
cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancel Oncol 2016; 
17:883-895.
131 Investigator Brochure, Anti-PD-1 Human Monoclonal Antibody, BMS-936558, Version No. 
12, 21-Jul-2014.
132 Triebel F, Jitsukawa S, Baixeras E, et al. LAG-3, a novel lymphocyte activation gene closely 
related to CD4. J. Exp. Med. 1990; 171:1393–1405.
133 Workman CJ, Wang Y, El Kasmi KC, et al. LAG-3 regulates plasmacytoid dendritic cell 
homeostasis. J Immunol;182(4):1885-91.
134 Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation 
gene-3 (CD223). J. Immunol. 2005; 174:688–695.
135 Camisaschi C, Casati C, Rini F, et al. LAG-3 expression defines a subset of CD4(+) CD25 
(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol. 2010; 
184:6545-6551.
136 Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004; 
21:503–513.
137 Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+T cell accumulation and 
effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 2007; 117:3383–
3392.
138 Lyford-Pike S, Peng S, Young GD, et al. Evidence for a Role of the PD-1: PD-L1 Pathway in 
Immune Resistance of HPV-Associated Head and Neck Squamous Cell Carcinoma. Cancer 
Res. 2013 Mar 15;73(6):1733-41.
139 Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 
synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 
2012;72:917-927.
140 Okazaki T, Okazaki IM, Wang J, et al. PD-1 and LAG-3 inhibitory co-receptors act 
synergistically to prevent autoimmunity in mice. J Exp Med. 2011; 208:395-407.
Revised Protocol No.: 07
Date: 07-May-2019
202
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
141 Bettini M, Szymczak-Workman AL, Forbes K, et al. Cutting edge: accelerated autoimmune 
diabetes in the absence of LAG-3. J Immunol. 2011;187:3493-3498.
142 Goding SR, Wilson KA, Xie Y, et al. Restoring Immune Function of Tumor-Specific CD4+ T 
Cells during Recurrence of Melanoma. J Immunol. 2013 Mar 27.
143 Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific 
CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl 
Acad Sci U S A. 2010;107:7875-7880.
144 Gandhi MK, Lambley E, Duraiswamy J, et al. Expression of LAG-3 by tumor-infiltrating 
lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-
cell function in Hodgkin lymphoma patients. Blood. 2006;108:2280-2289.
145 Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early 
lethality in mice deficient in CTLA-4. Science 1995;270:985-988.
146 Grosso JF, Goldberg MV, Getnet D, et al. Functionally distinct LAG-3 and PD-1 subsets on 
activated and chronically stimulated CD8 T cells. J Immunol. 2009; 182:6659-6669.
147 Saloura V, Zuo Z, Koeppen H, et.al. Correlation of T-cell inflamed phenotype with 
mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck 
cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr 6009).
148 Uozaki H, Fukayama M. Epstein-Barr virus and gastric carcinoma--viral carcinogenesis 
through epigenetic mechanisms. Int J Clin Exp Pathol 2008;1(3):198-216.
149 Sittig SP, Køllgaard T, Grønbæk K, et.al. Clonal expansion of renal cell carcinoma-infiltrating 
T lymphocytes. Oncoimmunology 2013, 2:E26014.
150 Giraldo NA, Becht E, Pagès F, Skliris G, et.al. Orchestration and Prognostic Significance of 
Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer. 
Clin Cancer Res. 2015, 21:3031-3040.
151 D'Incecco A, Andreozzi M, Ludovini V, et.al. PD-L1 and PD-1 expression in molecularly 
selected non-small-cell lung cancer (NSCLC) patients. Journal of Thoracic Oncology (2014) 
9 (Supplement 9): S7-S52.
152 Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 
antibody in patients with locally advanced or metastatic tumors. J Clin Oncol 2013;31(suppl; 
abstr 3000).
153 Investigator Brochure, Anti-Lag3 Human Monoclonal Antibody, BMS-986016, Version 
No. 4, 30 Aug 2016.
154 BMS-986016 Investigator Brochure, Version 4. Bristol-Myers Squibb Company; 2016. 
Document Control No. 930071620.
Revised Protocol No.: 07
Date: 07-May-2019
203
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
155 de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 
monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J 
Immunol. 2011;186(3):1840-1848.
156 Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to 
the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple 
myeloma. MAbs. 2015;7(2):311-321.
157 Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy 
in multiple myeloma. N Engl J Med. 2015;373(13): 1207-1219.
158 Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-
refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 
2016;387(10027):1551-1560.
159 McKeage K. Daratumumab: first global approval. Drugs. 2016;76(2):275-281.
160 Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and 
receptors. Leuk.Res. 2001;25:1-12
161 Vaisitti T, Aydin S, Rossi D et al. CD38 increases CXCL12-mediated signals and homing of 
chronic lymphocytic leukemia cells. Leukemia. 2010;24:958-969.
162 Malavasi F, Deaglio S, Damle R et al. CD38 and chronic lymphocytic leukemia: a decade later. 
Blood. 2011;118:3470-3478.
163 Overdijk MB, Verploegen S, Marijn B et al. Phagocytosis is a mechanism of action for 
daratumumab. ASH Annual Meeting Abstracts 2012;120:4054.
164 Jansen JHM, Boross P, Overdijk MB et al. Daratumumab, a human CD38 antibody induces 
apoptosis of myeloma tumor cells via fc receptor-mediated crosslinking. ASH Annual Meeting 
Abstracts 2012;120:2974
165 Krejcik J, Casneuf T, Nijhof IS et al. Daratumumab depletes CD38+ immune-regulatory cells, 
promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016. pii: 
blood-2015-12-687749. [Epub ahead of print].
166 Schadendorf D et al Efficacy and quality of life outcomes in patients with advanced melanoma 
(MEL) 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; August 31-September 3, 2016; Vienna, Austria.
167 Schadendorf D, et al. Pooled Analysis of Long-Term Survival Data from Phase II and Phase 
III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015; 33: 1889-
94.
168 Brahmer J, 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.
Revised Protocol No.: 07
Date: 07-May-2019
204
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
169 Felip E et al., Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
patients with previously treated advanced non-small lung cancer (NSCLC). Poster discussion 
presentation at the European Society of Medical Oncology Annual Meeting. 2017 Sep 8-12; 
Madrid, Spain. Poster 1301PD
170 Herbst RS et al. KEYNOTE-010: Durable clinical benefit in patients with previously treated, 
PD-L1-expressing NSCLC who completed pembrolizumab. Poster presentation at the World 
Conference on Lung Cancer 2016 Dec 4-7; Vienna, Austria.
171 Robert, C 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
172 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.
173 Robert C, Thomas L, Bondarenko et al. Ipilimumab plus dacarbazine for previously untreated 
metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26.
174 Hodi FS, O'Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with 
Metastatic Melanoma; N Engl J Med. 2010 Aug 19;363(8):711-23.
175 Lokhorst H., Laubach JP, Nahi, H, Plesner T, Gimsing P, Hansson M, et al. Dose-dependent 
efficacy of daratumumab (DARA) as monotherapy in patients with relapsed or refractory 
multiple myeloma (RR MM). J Clin Oncol 2014. 32:5s, 8513. 2014. 
176 Lonial S, Usmani S, Singha UK, Chari A, Bahlis NJ. Phase II study of daratumumab (DARA) 
monotherapy in patients with = 3 lines of prior therapy or double refractory multiple myeloma 
(MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33 (supplement):LBA8512
177 Nijhof IS, Groen RW, Noort WA et al. Preclinical evidence for the therapeutic potential of 
CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to 
lenalidomide and bortezomib. Clin.Cancer Res. 2014;21(12):2802-10.
178 Nijhof IS, Noort W, van Bueren J, et al. CD38-targeted immunochemotherapy of multiple 
myeloma: preclinical evidence for its combinatorial use in lenalidomide and bortezomib 
refractory/intolerant mm patients. Blood 2013;122:277.
179 van der Veer MS, de WM, van KB et al. Towards effective immunotherapy of myeloma: 
enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 
monoclonal antibody daratumumab. Haematologica. 2011;96:284-290.
180 Plesner T, Arkenau T, Lokhorst H et al. Preliminary safety and efficacy data of daratumumab 
in combination with lenalidomide and dexamethasone in relapsed or refractory multiple 
myeloma. Blood 2013;122:1986.
181 Plesner T., Arkenau T, Lokhorst, H et al. Safety and efficacy of daratumumab with 
lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Blood 
2014;124(21):84. 
Revised Protocol No.: 07
Date: 07-May-2019
205
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
182 Dimopoulos M, Oriol A, Nahi H, San Miguel JF, Bahlis NJ, Rabin N, and Orlowski R. An 
open-label, randomized phase 3 study of daratumumab, lenalidomide, and dexamethasone 
(DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple 
myeloma (RRMM): POLLUX. Haematologica 2016;EHA Abstr LB2238.
183 Palumbo A, Chanan-Khan A, Weisel K, Nooka, AK, and Masszi T. Phase III randomized 
controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib 
and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma 
(RRMM): CASTOR study. J Clin Oncol 2016;ASCO Abstr LBA4.
184 DARZALEX [package insert]. Janssen Biotech, Inc, Horsham PA; 2017.
185 Chapuy CI, Nicholson RT, Aguad MD et al: Resolving the daratumumab interference with 
blood compatibility testing. Transfusion 2015;55;1545–1554.
186 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. NEJM 2013;369:122-133.
187 Manuel M, Tredan O, Bachelot T, et al. Lymphopenia combined with low TCR diversity 
(divpenia) predicts poor overall survival 
in 
metastatic breast cancer patients. 
Oncoimmunology. 2012;1(4):432-440.
Revised Protocol No.: 07
Date: 07-May-2019
206
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
APPENDIX 1
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUSa
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.: 07
Date: 07-May-2019
207
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
APPENDIX 2
MANAGEMENT ALGORITHMS
Revised Protocol No.: 07
Date: 07-May-2019
208
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
209
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
210
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
211
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
212
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
213
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
214
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Revised Protocol No.: 07
Date: 07-May-2019
215
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
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.: 07
Date: 07-May-2019
216
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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.: 07
Date: 07-May-2019
217
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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.: 07
Date: 07-May-2019
218
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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.: 07
Date: 07-May-2019
219
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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.: 07
Date: 07-May-2019
220
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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.: 07
Date: 07-May-2019
221
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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 durationb met, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
b Minimum criteria for SD duration is 6 weeks.
Revised Protocol No.: 07
Date: 07-May-2019
222
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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.: 07
Date: 07-May-2019
223
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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. 
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
−
oral 
−
intravaginal 
−
transdermal 
Revised Protocol No.: 07
Date: 07-May-2019
224
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
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 
ovulationb
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
−
It is not necessary to use any other method of contraception when complete abstinence 
is elected. 
−
WOCBP participants who choose complete abstinence must continue to have 
pregnancy tests, as specified in Section 2. 
−
Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that the 
IMP and other study medications will not alter hormonal exposures such that contraception would be ineffective 
or result in increased exposures that could be potentially hazardous. In this case, alternative methods of 
contraception should be utilized.
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Revised Protocol No.: 07
Date: 07-May-2019
225
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Unacceptable Methods of Contraception
•
Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until 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 6.1.1 and Section 6.4.
Revised Protocol No.: 07
Date: 07-May-2019
226
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
APPENDIX 5
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 06, 18-Jul-2018
Rationale for Discontinuation of Nivolumab plus Daratumumab Combination Therapy
A decision to temporary hold on further enrollment was made on 26-May-2018 based on a 
communication that the Data Monitoring Committee (DMC) of a Phase Ib/II study in non-small cell lung 
cancer of daratumumab in combination with atezolizumab (an anti PD-L1 antibody from Roche) had 
recommended that study be terminated. The DMC of that study determined that there was no observed 
benefit within the combination arm of daratumumab plus atezolizumab over atezoluzimab monotherapy 
and in addition to the lack of benefit, the DMC noted a numerical increase in mortality-related events in 
the combination arm.
As such, BMS has decided to terminate the daratumumab arms in this study.
Rationale for Adding Cervical Cancer Cohort Expansion
The cervical cancer expansion cohort was added to further confirm the preliminary efficacy and 
safety signals of the combination B as first- or second-line treatment for recurrent or metastatic 
SCC of the cervix.
Rationale for Moving Neoadjuvant Cohort from Secondary to Exploratory Objective
This endpoint is primarily to explore the effect of treatment on immune cells and immune 
regulatory markers and generate hypothesis for further validation. Because it is measured to 
generate a hypothesis, is has been changed to an exploratory endpoint.
Summary of key changes for Revised Protocol 06
Section Number & Title
Description of 
Change
Brief Rationale
1.1.12
Rationale for Nivolumab plus Daratumumab 
Combination Therapy
1.1.13
Rationale for Nivolumab Combined with 
Daratumumab in Patients with HPV Positive and Negative or 
Unknown SCCHN
1.1.14
Rationale to Support Dose/Schedule of Nivolumab 
Combined with Daratumumab
1.5 Overall Risk/Benefit Assessment
3.1.1
Viral Status Determination Prior to Entry
4.7.7
Treatment of Study Drug-related Infusion Reactions
8.1 Sample Size Determination
Added rationale for 
discontinuing 
nivolumab plus 
daratumumab 
combination 
therapy.
Terminating the 
daratumumab 
combination arms.
1.3.2
Secondary Objectives
1.3.3
Exploratory Objective(s)
8.3.2
Secondary Endpoint(s)
8.3.3
Exploratory Endpoint(s)
8.4.2.2
Secondary Endpoints Methods
Moved neoadjuvant 
cohort from 
secondary to 
exploratory 
objective.
Reclassified endpoint 
from secondary to 
exploratory.
Revised Protocol No.: 07
Date: 07-May-2019
227
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 06
Section Number & Title
Description of 
Change
Brief Rationale
3.1 Study Design and Duration
Figure 3.1-3:
Study Design Schematic for the Metastatic 
Cohort Combination Therapies A and B and Combo B Cervical 
Cancer Expansion
3.3.1
Inclusion Criteria 2), a)
3.3.2
Exclusion Criteria m)
8.1 Sample Size Determination
Table 8.1-3:
Sample size in Recurrent/metastatic 
combination cohort
Table 8.1-6:
Two-sided 95% exact CI using Clopper-
Pearson method based on the number of observed responses out 
of 55 subjects
Table 8.1-7:
Two-sided 95% exact CI using Clopper-
Pearson method based on the number of observed responses out 
of 35 subjects
11 List of Abbreviations
Added description 
of cervical cancer 
expansion cohort.
Adding cervical 
cancer expansion arm 
to further confirm 
efficacy and safety 
signals.
3.1.1
Viral Status Determination Prior to Entry
3.1.4
Subjects in the Metastatic Combination Cohorts
8.1 Sample Size Determination
Noting closure of 
the anogenital HPV 
associated tumor 
cohorts.
Due to slow accrual 
and the current 
investigation of these 
tumor types in other 
BMS-sponsored 
studies, combination 
cohorts in this study 
will no longer include 
anogenital HPV 
associated tumor 
types.
Overall Rationale for the Revised Protocol 05, 18-Apr-2018
The revisions incorporated in Revised Protocol 05 allow for the concurrent enrollment of 
subjects with eligible tumor types in all metastatic Combination Cohorts A, B, and D. 
Combination cohorts in this study will no longer include the Epstein Barr Virus (EBV) positive 
gastric tumor type; however, subjects with this tumor type already enrolled may continue to 
receive study treatment as per protocol.
In addition, enrollment for Combination Cohort C will be closed. Enrollment for this cohort has 
been low, and this combination is being evaluated in other studies. Subjects who have already 
enrolled in this cohort will continue in the study as planned. In addition, crossover from other 
cohorts into Combo C will not be allowed.
Revised Protocol No.: 07
Date: 07-May-2019
228
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Current clinical and safety data for both BMS-986016 (Anti-LAG3) and daratumumab now 
available are included. 
A 24-month maximum duration of nivolumab treatment has also been implemented in this 
Revised Protocol. The optimal duration of immunotherapy is an important question and 
continues to be investigated. Clinical trials across different tumors types in the nivolumab and 
ipilimumab development program indicate that most of the responses occur early, with a median 
time to response of 2-4 months, and emerging data suggests that benefit can be maintained in the 
absence of continued treatment. A recent analysis in a melanoma study suggests the majority of 
patients who discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in 
the absence of further treatment. Furthermore, a limited duration of ipilimumab, including only 
four induction doses, resulted in long-term survival in patients with metastatic melanoma, with a 
sustained plateau in survival starting around 2 years after the start of treatment.
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years.  
Among 16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive >5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the overall survival (OS) 
curve begins to plateau after 2 years with an OS rate of 25% at 2 years and 18% at 3 years. These 
survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2-year OS rates 
of 23% and 29%, and 3-year OS rates of 16% to 18% for squamous and non-squamous NSCLC 
respectively).
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a  maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, p = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, p < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only two patients 
(4%) having confirmed progression after stopping at 2 years. 
Keynote-006 was a randomized phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the 
estimated risk of progression or death was 9% in these patients. 
Revised Protocol No.: 07
Date: 07-May-2019
229
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 2 
years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who 
completed 1 year of nivolumab therapy were randomized to either continue or stop treatment, 
with the option of retreatment upon progression. Among 163 patients still on treatment at 1 year 
and without progression, those who were randomized to continue nivolumab had significant 
improvement in progression-free survival (PFS) compared to those who were randomized to stop 
treatment, with median PFS (post-randomization) not reached vs 10.3 months, respectively; 
HR=0.42 (95% CI, 0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, 
there also was a trend for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 
0.33, 1.20]). Of note,  the PFS curves in both groups plateau approximately 1 year after 
randomization (i.e., 2 years after treatment initiation), suggesting that there may be minimal 
benefit in extending treatment beyond a total of 2 years.
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer-term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
•
Synopsis, Investigational Product;
•
Synopsis, Study Design
•
Section 3.1, Study Design and 
Duration
•
Section 3.1.1, Viral Status 
Determination Prior to Entry
Condensed text to better 
clarify the various populations 
in this study.
To provide clarity for the sites.
Revised Protocol No.: 07
Date: 07-May-2019
230
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
•
Synopsis, Investigational Product, 
Study Design, Schematics, Study 
Dosing Table 
•
Section 1.1.15, Rationale for 
Nivolumab Combination Therapy: 2-
Year Duration 
•
Section 3.1, Study Design and 
Duration
•
Section 3.1.3, Subjects in the 
Metastatic Monotherapy Cohort 
•
Section 3.1.4, Subjects in the 
Metastatic Combination Cohorts 
•
Section 4.5, Selection and Timing of 
Dose for Each Subject
Nivolumab program level 
revision limiting treatment to 
24 months
Instituted this maximum duration 
based on the data described 
above. 
•
Synopsis, Investigational Product, 
Objectives, Inclusion Criteria a)ii)(1); 
c)iv)(1) Study Design, Schematics; 
Statistical Considerations; 
•
Section 1.3.1, Primary Objectives 
•
Section 1.3.3, Exploratory 
Objective(s) 
•
Section 3.1, Study Design and 
Duration 
•
Section 3.1.4, Subjects in the 
Metastatic Combination Cohorts 
•
Section 3.3.1, Inclusion Criteria 
Inclusion Criteria 2 a)ii)(1); 2 c)iv)(1) 
•
Section 8.1, Sample Size 
•
Table 8.1-3, Sample size in 
Recurrent/metastatic combination 
cohort
•
Section 8.3, Exploratory Endpoint(s)
Enrollment of Epstein Barr 
Virus (EBV) gastric cancer 
into the metastatic 
combination therapies A and 
C has been closed. Accrual of 
EBV positive gastric cancer in 
the metastatic monotherapy 
cohort has been attained and is 
closed to enrollment.
Due to the low prevalence of 
EBV positive gastric tumor types 
and the current investigation of 
this tumor type in other BMS-
sponsored studies, combination 
cohorts in this study will no 
longer include EBV+ Gastric 
tumor type.
Revised Protocol No.: 07
Date: 07-May-2019
231
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
•
Synopsis Study Design; Statistical 
Considerations Table 4 
•
Section 3.1, Study Design and 
Duration 
•
Section 3.1.4, Subjects in the 
Metastatic Combination Cohorts
•
Section 4.4, Method of Assigning 
Subject Identification 
•
Section 8.1, Sample Size 
All Metastatic Combination 
Cohorts A B and D to enroll 
patients concurrently in 
eligible tumor types. All 
references to staggered 
enrollment or enrollment cap 
on any cohort has been 
removed. In addition, 
enrollment in Metastatic 
Combination Cohort C (all 
tumor types) is closed, 
including crossovers.
Concurrent enrollment in the 
metastatic combination cohorts 
enables accrual across all cohorts,
allows for the generation of 
clinical data, and provides an 
opportunity to bring effective 
treatments faster to patients with 
high unmet medical need.
•
Synopsis Sections:  Investigational 
Product, Study Design, Schematics, 
Study Dosing Table 
•
Section 1.5, Overall Risk/Benefit 
Assessment
•
Figure 3.1-5, Study Design Schematic 
for the Metastatic Cohort Combination 
Therapy CD: Tumor Type SCHHN 
HPV positive, negative or unknown I-
O naive 
•
Section 3.1.4, Subjects in the 
Metastatic Combination Cohorts 
•
Section 4.3, Storage and Dispensing 
•
Section 4.5, Selection and Timing of 
Dose for Each Subject and Table 4.5-1 
Study Drug Dosing 
•
Table 5.1-3, On-Treatment 
Assessments Metastatic Combination 
Therapy Cohorts (CA209358) 
•
Table 5.5-7: Pharmacokinetic
and Immunogenicity Sampling 
Schedule for Nivolumab (Nivolumab 
and Daratumumab Combination-
Combo D). 
Nivolumab will be 
administered before 
daratumumab when both study 
drugs are administered on the 
same study day (Combo D 
arm). Administration of 
daratumumab should follow 
instructions in the 
USPI/pharmacy manual. 
Specifications for 
administration of 
daratumumab previously 
presented have been deleted.
Daratumumab infusion requires 
longer infusion time and pre and 
post infusion medications to 
reduce the risk of infusion 
reactions. Nivolumab will be 
administered before daratumumab 
across studies that are evaluating 
the safety and efficacy of 
daratumumab in combination 
with nivolumab, in order enable 
management of daratumumab 
post infusion reactions.
•
Section 1.1.11, Rationale to Support 
Dose/Schedule of Nivolumab 
Combined with BMS -986016 
Added a section on Relatlimab 
Adverse Event Guidelines
To clarify for the sites that they 
should follow the Nivolumab 
Adverse Event Algorithms. 
•
Section 1.1.6, Rationale For Dose 
Selection for Nivolumab 
Added the rationale for the use 
of 480 mg dose of nivolumab 
and updated the rationale for 
the 240 mg dose.
To provide updated data and 
recent HA approvals of the dose 
rationales. 
•
Section 1.1.14, Rationale to Support 
Dose/Schedule of Nivolumab 
Update of safety and clinical 
data for daratumumab
Protocol now reflects current 
safety and clinical data for BMS-
Revised Protocol No.: 07
Date: 07-May-2019
232
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Combined with Daratumumab
986016.
•
Section 1.4.3.1, Non-clinical 
Pharmacology Studies Utilizing 
Murine Anti-PD-1 and Anti-Lag-3 
Antibodies
Added additional data.
To provide the most updated and 
complete non-clinical information 
available. 
•
Section 1.4.3.5, Clinical Safety 
Combination Therapy (Nivolumab 
plus Relatlimab)
Deleted repeated information 
and added a reference to 
Section 1.1.11 and the 
Investigator’s Brochure
To avoid repeated data in multiple 
places in the protocol. 
•
Section 1.5, Overall Risk/Benefit 
Assessment
Provided updated language 
regarding the nivolumab plus 
relatlimab combination. 
To provide the most updated 
information in the overall risk 
benefit section. 
•
Section 3.3.2, Exclusion Criteria
Added a criterion excluding 
treatment with botanical 
preparations 
To prevent drug-drug interactions. 
•
Section 3.4.1, Prohibited 
and/Restricted Treatments
Added botanical preparations 
as a prohibited medication. 
To prevent drug-drug interactions
•
Table 4.-1, Product Description: 
Treatment Period
Updated the potency for 
daratumumab (added 400-mg 
vials) and added a footnote to 
allow commercial product 
where allowed by local 
regulations. 
To provide flexibility in providing 
daratumumab. 
•
Section 4.7.3, Dose Delay Criteria
The nivolumab Dose Delay 
Criteria were updated. 
To align with the Summary of 
Product Characteristics. 
The daratumumab Dose Delay 
Criteria were updated.
To eliminate repetition and 
contradicting information. 
•
Section 4.7.5, Criteria to Resume 
Dosing
Removed one nivolumab 
criterion
To remove redundancies in other 
sections. 
Revised the criterion for 
participants in Combo C 
regarding troponin elevations
•
Section 4.7.6, Discontinuation Criteria
Revised the second bullet and 
first sub-bullet
To align with the Summary of 
Product Characteristics. 
•
Table 5.1-1:Screening Procedural 
Outline for All Subjects (CA209358)
Added to note section for 
collection of tumor tissue that 
fresh Biopsies are mandatory 
for neoadjuvant cohort 
patients.
Clarification
•
Table 5.1-2: On-Treatment 
Assessments Metastatic Monotherapy 
Cohort (CA209358)
Oxygen saturation testing 
removed from vital signs
This protocol now reflects the 
nivolumab program-wide removal 
of oxygen saturation testing.
•
Table 5.1-3: On-Treatment 
Assessments Metastatic Combination 
Oxygen saturation testing 
removed from vital signs and 
This protocol now reflects the 
nivolumab program-wide removal 
Revised Protocol No.: 07
Date: 07-May-2019
233
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
Therapy Cohorts (CA209358) 
provides the dosing windows 
for daratumumab. 
of oxygen saturation testing.
•
Table 5.1-4: On Treatment 
Assessments Neoadjuvant Cohort 
(CA209358)
•
Table 5.1-5: Eligibility Assessments 
and On-Treatment Assessments -
Subjects Receiving Study Drug Post-
Standard of Care (CA209358)
Oxygen saturation testing 
removed from vital signs
This protocol now reflects the 
nivolumab program-wide removal 
of oxygen saturation testing.
•
Table 5.1-6: Follow-Up Assessments -
All Subjects (CA209358) 
Clarification to timing of 
follow up visits for 
neoadjuvant cohort and 
correlation with case report 
form added to table footnote
Clarification.
•
Table 5.6.9-1: CA209358 Biomarker 
Sampling Schedule (Neo-Adjuvant 
Cohort) 
•
Table 5.6.9-2:
CA209358 
Biomarker Sampling Schedule 
(Metastatic Monotherapy Cohorts and 
Metastatic Cohort Combo A and B) 
•
Table 5.6.9-3:
CA209358 
Biomarker Sampling Schedule 
(Metastatic Combination Cohort 
Combo C and Combo D) 
Plasma samples (one sample 
at Cycle 1 Day 1) have been 
added for tumor and/or 
immune-related genomic 
analysis.
The plasma samples will be 
collected for ctDNA analysis to 
assess tumor mutations, tumor 
mutation burden, and other 
biomarkers.
•
Table 5.4.1-1: Schedule of Spiral 
CT/MRI Tumor Assessments for 
Metastatic Cohorts (Monotherapy and 
Combination Therapy), and Subjects 
Treated with Study Drug Post-
Standard of Care Adjuvant Treatment
Adjusted week numbers for 
assessments dates.
Original week numbers started at 
week 9 instead of week 8.
•
Section 8.2, Populations for Analysis
Definitions for all response 
evaluable subjects, all 
evaluable neoadjuvant 
subjects, and biomarker 
subjects have been added. 
Revised Protocol No.: 07
Date: 07-May-2019
234
Approved
8.0
v
Approved
1.0
v


Clinical Protocol
CA209358
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 05
Section Number & Title
Description of Change
Brief Rationale
All
The name of BMS-986016 
(relatlimab) has been added.
Provide familiarity with the name 
of BMS-986016 to investigators. 
All
All references to the 
metastatic or recurrent HPV 
positive tumors have been 
replaced with anogenital 
metastatic or recurrent HPV 
associated tumors (vulvar, 
vaginal, anal canal, penile).
Clarification to align with 
therapeutic area standard.
All
Additional editorial and 
format changes for
clarification and consistency.
Minor, therefore have not been 
summarized.
Revised Protocol No.: 07
Date: 07-May-2019
235
Approved
8.0
v
Approved
1.0
v

SAP_001.pdf: 
Official Title of Study: 
Non-Comparative, Open-Label, Multiple Cohort, Phase 1/2 Study of Nivolumab Monotherapy and 
Nivolumab Combination Therapy in Subjects With Virus-Positive and Virus-Negative Solid Tumors 
 
NCT Number: NCT02488759 
Document Date (Date in which document was last revised): Sep 7, 2021 


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
1
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
NON-COMPARATIVE, OPEN-LABEL, MULTIPLE COHORT, PHASE 1/2 STUDY OF 
NIVOLUMAB MONOTHERAPY AND NIVOLUMAB COMBINATION THERAPY IN 
SUBJECTS WITH VIRUS-POSITIVE AND VIRUS-NEGATIVE SOLID TUMORS
PROTOCOL CA209358
VERSION # 4.0
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
2
DOCUMENT HISTORY
Version Number
Author(s)
Description
1.0
Initial version
1.1
•
Add the definition of Relative Dose Intensity (%)
Table 7.4.1-1
•
Changed “sum of product diameters” to “sum of diameters” 
on page 23 and 26
2.0
•
Add the analysis for metastatic nivo and ipi combo cohort. 
•
Update the definition of PFS regarding No baseline tumor 
assessment.
2.1
•
Added the analysis for metastatic nivo and BMS-986016
combo cohort and metastatic nivo and daratumumab combo 
cohort.
•
Added definition of PFS after surgery for neoadjuvant 
subjects.
2.2
•
Removed metastatic combination gastric cohort.
•
Revised combo C cohorts
•
Updated naming of tumor types from “HPV associated 
tumors” to “Anogenital Cancers.
•
Updated Table 4.3.3-1
•
Updated section 7.3.2
•
Updated section 7.3.4
•
Updated Table 7.4.1-1
•
Updated section 7.5.1.2
3.0
•
Added cervical combo B expansion cohort.
•
Replaced exploratory endpoint for neoadjuvant cohort “PFS
after surgery/biopsy” with “RFS” in section 4.3.1 and related
analyses sections.
•
Moved secondary endpoint for neoadjuvant cohorts to
exploratoryendpoints section.
•
Added biomarker analysis for CPS.
•
Removed AE analysis by PD-L1 status.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
3
Version Number
Author(s)
Description
4.0
•
Clarified the timing of the primary analysis for metastatic 
cohort.
•
Updated the description of PK analysis and Immunogenicity 
sections that previously referenced CORE safety SAP.
•
Added final analysis at study closure. 
•
Added summary of continuous % residual viable tumor 
(%RVT) results and summary of surgery for neoadjuvant 
cohort. 
•
Clarified the derivation of completion rate in Outcome 
research analysis that it will be calculated using subjects 
assessed at assessment time point and it does not use outcome 
research analysis population. 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
4
TABLE OF CONTENTS
DOCUMENT HISTORY............................................................................................................2
TABLE OF CONTENTS............................................................................................................4
LIST OF TABLES......................................................................................................................7
LIST OF FIGURES ....................................................................................................................8
1
BACKGROUND AND RATIONALE......................................................................9
2
STUDY DESCRIPTION ........................................................................................10
2.1
Study Design ..........................................................................................................10
2.2
Treatment Assignment............................................................................................16
2.3
Blinding and Unblinding.........................................................................................17
2.4
Protocol Amendments.............................................................................................17
2.5
Data Monitoring and Other External Committees ...................................................20
3
OBJECTIVES ........................................................................................................20
3.1
Primary...................................................................................................................20
3.2
Secondary...............................................................................................................21
3.2.1
Metastatic Cohorts (Monotherapy and Combination Therapy)................................21
3.3
Exploratory.............................................................................................................21
3.3.1
Neoadjuvant Cohort ...............................................................................................21
3.3.2
Metastatic Cohorts (Monotherapy and Combination Therapy)................................22
4
ENDPOINTS..........................................................................................................23
4.1
Primary Endpoint....................................................................................................23
4.1.1
Neoadjuvant Cohort ...............................................................................................23
4.1.2
Metastatic Cohorts (Monotherapy and Combination Therapies).............................23
4.2
Secondary Endpoints ..............................................................................................23
4.2.1
Metastatic Cohorts (Monotherapy and Combination Therapies).............................23
4.3
Exploratory Endpoints............................................................................................24
4.3.1
Neoadjuvant Cohort only........................................................................................24
4.3.2
Metastatic Cohorts only..........................................................................................26
4.3.3
Neoadjuvant and Metastatic Cohorts......................................................................26
5
SAMPLE SIZE.......................................................................................................30
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................34
6.1
Study Periods..........................................................................................................34
6.1.1
Baseline Period ......................................................................................................34
6.1.2
Post Baseline Period...............................................................................................34
6.2
Treatment Regimens...............................................................................................35
6.3
Populations for Analyses ........................................................................................36
6.3.1
Study Cohorts.........................................................................................................36
6.3.2
Analysis Populations ..............................................................................................36
7
STATISTICAL ANALYSES..................................................................................37
7.1
General Methods ....................................................................................................37
7.2
Study Conduct........................................................................................................38
7.2.1
Accrual...................................................................................................................38
7.2.2
Relevant Protocol Deviations..................................................................................38
7.3
Study Population ....................................................................................................38
7.3.1
Subject Disposition.................................................................................................38
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
5
7.3.2
Demographics and Baseline Characteristics...........................................................38
7.3.3
Medical History......................................................................................................39
7.3.4
Prior Therapy.........................................................................................................39
7.3.5
Baseline Examinations............................................................................................40
7.4
Extent of Exposure .................................................................................................40
7.4.1
Administration of Study Therapy.............................................................................40
7.4.2
Modifications of Study Therapy ..............................................................................43
7.4.2.1
Dose Delays ...........................................................................................................43
7.4.2.2
Infusion Interruptions and Rate Changes................................................................44
7.4.2.3
Dose Reductions /Escalations.................................................................................45
7.4.3
Concomitant Medications.......................................................................................45
7.5
Efficacy..................................................................................................................45
7.5.1
Primary Analyses....................................................................................................45
7.5.1.1
Neoadjuvant Cohort: Rate of Surgery Delay...........................................................45
7.5.1.2
Metastatic Cohorts: Objective Response Rate.........................................................45
7.5.2
Secondary Analyses (Metastatic Cohorts Only).......................................................46
7.5.2.1
Duration of Response Based on Investigator Assessment ........................................46
7.5.2.2
Clinical Benefit Rate Based on Investigator Assessment..........................................46
7.5.2.3
Overall Survival .....................................................................................................46
7.5.2.4
Progression Free Survival ......................................................................................46
7.5.3
Exploratory Analyses..............................................................................................47
7.5.3.1
Neoadjuvant Cohort only........................................................................................47
7.5.3.2
Metastatic Cohorts only..........................................................................................47
7.5.4
Interim Analyses.....................................................................................................47
7.6
Safety.....................................................................................................................48
7.6.1
Deaths ....................................................................................................................48
7.6.2
Serious Adverse Events...........................................................................................48
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................48
7.6.4
Adverse Events Leading to Dose Delay of Study Therapy........................................48
7.6.5
Adverse Events .......................................................................................................48
7.6.6
Select Adverse Events .............................................................................................48
7.6.7
Immune Modulating Medication .............................................................................48
7.6.8
Multiple Events.......................................................................................................48
7.6.9
Clinical Laboratory Evaluations.............................................................................48
7.6.9.1
Hematology ............................................................................................................48
7.6.9.2
Serum Chemistry ....................................................................................................48
7.6.10
Immunogenicity ......................................................................................................48
7.6.11
Vital Signs and Pulse Oximetry...............................................................................49
7.7
Pregnancy...............................................................................................................49
7.8
Pharmacokinetics....................................................................................................49
7.9
Biomarkers .............................................................................................................49
7.9.1
PD-L1 Expression at baseline subgroups................................................................49
7.9.1.1
Analysis Methods....................................................................................................50
7.9.1.2
Distribution of PD-L1 Expression...........................................................................50
7.9.1.3
Association Between PD-L1 Expression and Efficacy Measures .............................50
7.9.2
Virus Status ............................................................................................................50
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
6
7.9.2.1
Association Between Virus Status and Efficacy Measures .......................................51
7.10
Outcome Research Analyses...................................................................................51
7.10.1
EORTC-QLQ-C30..................................................................................................51
7.10.2
EuroQol EQ-5D .....................................................................................................51
7.11
End of Study Analyses at Study Closure.................................................................52
8
CONVENTIONS....................................................................................................52
9
CONTENT OF REPORTS .....................................................................................53
10
REFERENCES.......................................................................................................53
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
7
LIST OF TABLES
Table 2.4-1:
Protocol Amendments ............................................................................17
Table 4.2-1:
Censoring scheme used in primary definition of PFS..............................24
Table 4.3-1:
Censoring scheme used in primary definition of RFS..............................25
Table 4.3.1-2:
Censoring scheme used in sensitivity analysis of RFS ............................25
Table 4.3-3:
Time Windows for EORTC-QLQ-C30 and EQ-5D Assessments............28
Table 5-1:
Probability of observing responses given true ORR for sample size 
of 23 subjects .........................................................................................31
Table 5-2:
Two-sided 95% exact CI using Clopper-Pearson method based on 
number of observed responses out of 23 subjects....................................31
Table 5-3:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 12 subjects ..............................31
Table 5-4:
Sample size in recurrent/metastatic combination cohort..........................32
Table 5-5:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 40 subjects ..............................33
Table 5-6:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based 
on the Number of Observed Responses out of 50 Subjects......................33
Table 5-7:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based 
on the Number of Observed Responses out of 35 Subjects......................33
Table 6.1-1:
Primary On-Treatment Definition For Safety in Treated Subjects ...........35
Table 7.4.2.1-1:
Length of Dose Delay.............................................................................43
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
8
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic for the Neoadjuvant Cohort:.............................11
Figure 2.1-2:
Study Design Schematic for the Metastatic Monotherapy Cohort............12
Figure 2.1-3:
Study Design Schematic for the Metastatic Cohort Combination 
Therapies A and B and Combo B SCC of the Cervix Expansion.............13
Figure 2.1-4:
Study Design Schematic for the Metastatic Cohort Combination 
Arm C ....................................................................................................14
Figure 2.1-5:
Study Design Schematic for the Metastatic Cohort Combination 
Therapy D: Tumor Type SCCHN HPV positive, negative or 
unknown I-O naive.................................................................................14
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
9
1
BACKGROUND AND RATIONALE
Study CA209358 is an open label, multiple-cohort, Phase 1/2 trial to investigate the safety and 
efficacy of nivolumab as a single agent and in combination with other therapy (ipilimumab, BMS-
986016, or daratumumab) in viral positive and viral negative tumor types - Epstein Barr Virus 
(EBV) positive gastric cancer, EBV positive and negative nasopharyngeal cancer (NPC), Human
Papilloma Virus (HPV) positive squamous cell cancer of the head and neck (SCCHN), HPV 
positive and negative cervical and other anogenital HPV associated cancers (vaginal, vulvar, anal 
canal, penile) and Polyomavirus positive merkel cell cancer.
There is a significant unmet medical need for subjects with virus positive tumors including 
nasopharyngeal carcinoma, gastric, Merkel cell carcinoma, cervical/vulvar/vaginal, or SCCHN as 
outlined in protocol (Protocol Section 1.1). Virus positive tumors may have distinct patterns of 
immune responses and tumor immune microenvironments (Protocol Section 1.1); therefore, a 
strong rationale exists to support blocking the PD-1 signaling pathway with the goal of improving 
patient outcomes in the metastatic/recurrent settings. 
One of the primary objectives of this protocol is to assess the safety and tolerability of 
administering 2 doses of nivolumab in the neoadjuvant setting, prior to surgical resection of 
disease. Based on the safety/tolerability profile as described in the protocol (Protocol Section
1.1.3), it is unlikely that subjects in the neoadjuvant cohort receiving 2 doses of nivolumab will 
experience a significant delay in surgery. CA209-358 will provide preliminary safety and 
biomarker data utilizing nivolumab in the neoadjuvant setting prior to surgery.
In the metastatic setting, subjects with virus-positive tumors generally have limited treatment 
options with high mortality rates, and NCCN guidelines recommend clinical trials as an option for 
each of the tumor types in this trial. 
This document contains descriptions of the statistical analyses that will be conducted for the 
Clinical Study Report (CSR) of study CA209358. This document also refers to Core Safety 
Statistical Analysis Plan1 that contains program level safety analyses descriptions.
Research Hypothesis:  
Research Hypothesis (A): Nivolumab, in the neo-adjuvant setting, will be safe and tolerable in 
subjects with select virus positive and virus-negative tumors.
Research Hypothesis (B):  Treatment with nivolumab alone or in combination with other therapy 
(ipilimumab, BMS-986016, or daratumumab) will lead to clinically meaningful tumor reductions, 
as measured by objective response rate and duration of response, in subjects with metastatic or 
unresectable tumors.
Schedule of Analyses:
Final analyses will be conducted by tumor types in each cohort
Neoadjuvant Cohort: 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
10
Analysis of PFS after surgery/biopsy will be conducted after a minimum of twelve months after 
the last subject’s surgery or biopsy in this cohort on each tumor type
Metastatic Cohorts: 
Primary endpoint for the metastatic cohorts is the investigator-assessed objective response rate 
(ORR) per RECIST 1.1.  The primary analysis will be conducted after one year follow up for the 
last subject’s first dose of study treatment. The timing of the primary analysis will allow to have 
mature OS data and will not affect the ORR results. In addition, safety analyses will be performed 
on each tumor type. Depending on enrollment rate, combination cohort could have a final analysis 
at the same time with monotherapy cohorts or later.
The final closure analysis will be conducted when a last subject is followed up for 122 days post 
last treatment dose for safety in accordance with the minimum safety follow up defined in the 
protocol. Updated safety analysis will be conducted.  No subsequent survival analysis will be 
performed after a post-treatment safety follow-up is completed and the study will be considered 
as closed. 
2
STUDY DESCRIPTION
2.1
Study Design
This is an open label, multiple-cohort, phase 1/2 trial to investigate the safety and efficacy of 
nivolumab as a single agent or in combination therapy in virus-positive and virus-negative solid 
tumors.
The tumor types for the neoadjuvant cohort are: 
(N-1): HPV positive SCCHN 
(N-2): HPV negative SCCHN
(N-3): GYN (Cervical, Vaginal, or Vulvar) Carcinoma
(N-4): Merkel Cell Carcinoma
The diseases or tumor types for the recurrent/metastatic monotherapy cohort are 
(M-1): EBV positive related Gastric cancer, 
(M-2): HPV positive SCCHN
(M-3): GYN (Cervical, Vaginal, or Vulvar) Carcinoma
(M-4): Merkel Cell carcinoma 
(M-5): Nasopharyngeal Carcinoma (NPC)
The diseases or tumor types for the recurrent/metastatic combination therapy cohort are 
(MC-1a): HPV positive Squamous Cell cancer of the Head and Neck (SCCHN) PD-1/PD-L1 
naive: combo A
(MC-2a): Cervical Carcinoma: combo A
(MC-2b): Cervical Carcinoma: combo B
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
11
(MC-exp): Squamous Cell Cancer of the Cervix: combo B expansion
(MC-3a): Other anogenital HPV associated cancers (vaginal, vulvar, anal canal, penile): 
combo A
(MC-3b): Other anogenital HPV associated cancers (vaginal, vulvar, anal canal, penile): 
combo B
(MC-4a): Merkel Cell Carcinoma: combo A
(MC-5a): Nasopharyngeal carcinoma (NPC): combo A 
(MC-6c): HPV positive Squamous Cell cancer of the Head and Neck (SCCHN) Prior PD-
1/PD-L1: combo C
(MC-7d): Squamous Cell cancer of the Head and Neck (SCCHN) I-O naive: combo D
The study design schematic is presented below.
The tumor types for the neoadjuvant cohort and the study design schematic for the neoadjuvant 
cohort (Figure 2.1-1) are presented below:
•
HPV positive SCCHN and HPV negative SCCHN
•
Cervical, Vaginal, Vulvar carcinoma
•
Merkel Cell Carcinoma
Figure 2.1-1:
Study Design Schematic for the Neoadjuvant Cohort:
The diseases or tumor types for the recurrent/metastatic monotherapy cohort and the study design 
schematic for the recurrent/metastatic monotherapy cohort is presented in (Figure 2.1-2) are 
presented below: 
•
EBV positive Gastric cancer,
•
HPV positive SCCHN
•
Cervical, vaginal, and vulvar carcinoma
•
Merkel Cell carcinoma 
•
Nasopharyngeal Carcinoma (NPC) 
Neoadjuvant
Nivo 240 mg
(2 doses)
1) Day 1
2) Day 15
Biopsy
Prior to 1st
dose
Biopsy or 
Surgical 
resection
(Day 29)
Investigator’s choice 
Standard of Care 
(SOC)
Nivo 240 mg Q2 weeks
Until 24 months maximum 
duration, PD, or Toxicity
Treatment
Follow-Up
Screening
Subsequent Treatment
Up to 5 weeks
TUMORS:
• GYN (cervical, vaginal, 
vulvar) - N = 21 
evaluable subjects
• MCC – N = 21 
evaluable subjects
• HPV (+) SCCHN – N = 
21 evaluable subjects
• HPV (-) SCCHN – N = 
21 evaluable subjects
•
F/U  visit 1+2
•
F/U post 
surgery (month 
4, 8, and 12)
•
Survival F/U
For Subjects with HPV: 
Virus selection required 
If unresectab erecurrent or 
metastatic disease within 1 
year after end of SOC 
If eligible
Min 12 weeks
10 subjects enrolled in each tumor - PAUSE –
Safety analyses
Additional 11 subjects enrolled if  ≤ 2/10 have 
surgery delayed > 4 weeks (due to nivo AE’s as 
specified in the label)
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
12
Figure 2.1-2:
Study Design Schematic for the Metastatic Monotherapy Cohort
The diseases or tumor types for the recurrent/metastatic combination therapy cohorts (Combo A, 
B and C) are listed below and the study design schematics for the recurrent/metastatic combination 
therapies A, B, and C are presented in Figure 2.1-3 and Figure 2.1-4. 
•
HPV positive SCCHN
−
Immuno-Oncology naive (anti-tumor vaccine and any T cell co-stimulation or checkpoint 
pathways therapy) (Combo A)
−
Prior PD-1/PD-L1 (Combo C) 
•
Cervical cancer (Combo A and B)
•
Anogenital HPV associated tumors (vaginal, vulvar, anal canal, penile) (Combo A and B)
•
Merkel Cell Carcinoma (Combo A)
•
Nasopharyngeal Carcinoma (NPC) (Combo A)
Metastatic 
Monotherapy 
Nivo monotherapy 240 mg
Q2 weeks
Until disease progression, toxicity, 
withdrawal of consent, or a maximum 
of 24 months
TUMORS:
• EBV (+) Gastric - N=12
• HPV(+) SCCHN - N=23
• GYN (cervical, vaginal, 
vulvar) - N=23
• MCC - N=23
• NPC  - N=23
Up to 5 weeks
Up to 2 priortreatments
≥ 1 target lesion
ECOG status: 0 or 1
• Imaging every 8 weeks starting at 
Week 8 for the first year of treatment
• Imaging every 12 weeks starting at 
year 2 and beyond
Min 12 weeks
survival
For Subjects with HPV (+) and 
EBV (+):  virus selection required
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
13
Figure 2.1-3:
Study Design Schematic for the Metastatic Cohort Combination 
Therapies A and B and Combo B SCC of the Cervix Expansion
;
Treatment
Follow-Up
Screening
Subsequent Treatment
Combo B Cervical Cancer 
expansion  
• Up to 2 prior treatments
• > 1 target lesion
• ECOG PS: 0-1
SCC OF THE CERVIX
• First-line treatment – 50 patients
• Second-line treatment – 20 
patients
Nivo + Ipi Combo
Combo B
Nivo-1mg/kg + Ipi-3mg/kg 
q3w x 4 followed by Nivo 
240mg q2w until disease 
progression, toxicity, 
withdrawal of consent, or a 
maximum of 24 months
• Imaging every 8 weeks 
starting at Week 8 for 
the first year of 
treatment
• Imaging every 12 weeks 
starting at year 2 and 
beyond
Min 12 
weeks
Survival
N = approx. 70 will be added to combo B to 
recieve treatment as first-line or second-line 
treatment
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
14
Figure 2.1-4:
Study Design Schematic for the Metastatic Cohort Combination Arm 
C
The disease or tumor type for the recurrent/metastatic combination D therapy cohort are listed 
below and the study design schematic for the recurrent/metastatic combination cohort for 
combination therapy D is presented in Figure 2.1-5.  
−
HPV positive or HPV negative or unknown SCCHN 
−
Immuno-Oncology therapy naive (anti-tumor vaccine and any T cell co-stimulation or 
checkpoint pathways therapy)
Figure 2.1-5:
Study Design Schematic for the Metastatic Cohort Combination 
Therapy D: Tumor Type SCCHN HPV positive, negative or unknown 
I-O naive.
Relatlimab(Anti-Lag-3) 80 
mg +
Nivolumab 240 mg q2W 
until, disease progression, 
toxicity, withdrawal of 
consent, or a maximum of 
24 months
• Imaging every 8 
weeks starting at 
Week 8 for the first 
year of treatment
• Imaging every 12 
weeks starting at 
year 2 and beyond
Treatment
Follow-Up
Screening
Subsequent Treatment
• Up to 2 prior treatments*
• > 1 target lesion
• ECOG PS: 0-1
TUMOR TYPE:
•HPV+ SCCHN (I-O experienced)**
Min 12 weeks
Survival
Combo C (Nivo + Relat) 
N = approx. 40
*Prior I-O therapy is permitted and is not counted toward the number of prior systemic treatment
**Include subjects that have had prior exposure to anti-PD-1, anti-PD-L1  or anti-CTLA-4 antibodies monotherapy or combination 
therapy
• Imaging every 8 weeks 
starting at Week 8 for the 
first year of treatment
• Imaging every 12 weeks 
starting at year 2 and 
beyond
Treatment
Follow-Up
Screening
Subsequent Treatment
• Up to 2 prior 
treatments
• > 1 target lesion
• ECOG PS: 0-1
TUMOR TYPES:
•SCCHN – HPV 
+/HPV – or HPV 
unknown
•I-O naïve
Min 12 weeks
Survival
N = approx. 40
Combo D
• Daratumumab 16 mg/kg q1W 
– Week 1 to 8; q2W –Week 9  
to 24 and q4W starting on 
Week 25 until toxicity, 
withdrawal of consent, or a 
maximum of 24 months
• Nivolumab 240 mg q2W –
starting on Week 3  and 480 
mg q4W starting  from Week 
25 until toxicity, withdrawal of 
consent, or a maximum of 24 
months
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
15
Neoadjuvant Cohort: Confirmation of viral status is required prior to study drug assignment for 
SCCHN subjects enrolled. Viral testing determined more than 35 days prior to first dose may be 
used. For SCCHN tumor types in the neoadjuvant cohort, 21 evaluable subjects with virus positive 
disease and 21 evaluable subjects with virus negative disease will be enrolled. No prior screening 
for GYN (cervical, vaginal, vulvar) or MCC cohorts is necessary due to the high prevalence of 
viral positivity and the technical aspects of the MCPyV assay. MCC and GYN (cervical, vaginal, 
or vulvar) cancers tumor types will contain 21 evaluable subjects each. Viral positivity will be 
tested retrospectively for MCC and GYN tumor types.  
Metastatic Monotherapy Cohort: Gastric and SCCHN subjects will be tested for viral status 
prior to study drug assignment. MCC, NPC, and GYN (cervical, vaginal, vulvar) subjects will not 
require viral screening prior to study entry. With the exception of gastric cancer (n=12), each 
specific tumor type in the metastatic monotherapy cohort will contain 23 subjects and will be 
treated with nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable 
toxicity. Viral positivity will be tested retrospectively for MCC, NPC, and GYN tumor types.
The study will enroll prospective subjects diagnosed with gastric cancer. Gastric subjects will 
provide pre-screening informed consent for determination of EBV+ viral status during the 
screening period and be registered in IRT. Viral testing will be performed locally or by a central 
laboratory and test results will be collected. After positive test result confirmation, consent for 
demographic and further eligibility will be collected. Subjects with EBV negative gastric cancer 
will be considered screen failures and will not be eligible for the study.
Metastatic Combination Therapy Cohort - Combo A, Combo B, and Combo C: SCCHN 
subjects will be tested for viral status prior to study drug assignment. Subjects with MCC, NPC, 
cervical cancer and other HPV associated tumors (vaginal, vulvar, anal canal, and penile) will not 
require viral screening prior to study entry. Viral positivity will be tested retrospectively for MCC, 
NPC, cervical cancer and anogenital HPV associated tumors (vulvar/vaginal/anal canal/penile) 
tumor types.
The HPV+ SCCHN, MCC, and NPC tumor types in the recurrent/metastatic cohort will each 
contain approximately 40 subjects that will be enrolled to the Combo A treatment arm. Patients 
with cervical cancer and anogenital HPV associated tumors (vulvar/vaginal/anal canal/penile) 
tumor types will be randomized in a 1:1 ratio to one of two dosing schema (Combo A or Combo 
B). Each dosing schema will contain approximately 40 subjects.
Subjects with HPV+ SCCHN with prior PD-1/PD-L1 treatment will be enrolled in Metastatic 
Combination Cohort (Combo C). Combo C will contain approximately 40 subjects. As of Revised 
Protocol 05, enrollment will close.
Approximately 40 I-O naive HPV positive, negative, or indeterminate SCCHN subjects will be 
enrolled to the Combo D treatment arm.  
The study will enroll prospective subjects diagnosed with SCCHN. SCCHN subjects will provide 
consent, via pre-screening informed consent, for determination of HPV viral status, if prior results 
are not available during the screening period and be registered in IRT (Combo A and C). Viral 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
16
testing will be performed locally or by a central laboratory and test results will be collected. After 
viral test result is confirmed positive, consent for demographic and further eligibility will be 
collected. If subjects decline pre-screening informed consent or are unwilling to undergo viral 
testing, they are eligible to enroll in Combo D. However, viral status should be determined 
retrospectively.
2.2
Treatment Assignment
After the subject’s informed consent has been obtained and eligibility is established, the subject 
will be enrolled and a number will be assigned through an interactive voice response system 
(IVRS). If the tumor group for which the subjects would be assigned to has not yet met the 
expected number of subjects for the study, the subject will be assigned a treatment vial number 
and will receive study treatment.
Neoadjuvant Cohort:
•
Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 
1 and Day 15 (before surgery).
Metastatic Monotherapy Cohort:
•
Nivolumab administered IV over 30 minutes at 240 mg every 2 weeks for a maximum of 
24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, 
whichever comes first.
Metastatic Combination Cohorts (Combinations A, B, C, and D):
•
Combo Arm A: Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks plus Ipilimumab 1 
mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease 
progression, unacceptable toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm B: Nivolumab 1 mg/kg IV over 30 minutes plus Ipilimumab 3 mg/kg IV over 
30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes 
every 2 weeks for a maximum of 24 months or until disease progression, unacceptable 
toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm C: Nivolumab 480 mg IV over 30 minutes plus BMS-986016 160 mg IV over 
60 minutes administered every 4 weeks for a maximum of 24 month, or until disease  
progression, unacceptable toxicity, or withdrawal of consent, whichever comes first. 
Subjects enrolled in Combo C prior to Revised Protocol 05 and on treatment with BMS-
986016 80 mg + Nivolumab 240 mg q2W will remain on this dose regimen for the duration 
of their time on treatment.
•
Combo Arm D: Daratumumab 16 mg/kg IV administered weekly for the first 8 weeks. 
Starting at Week 3, nivolumab 240 mg IV over 30 minutes will be administered every 2 
weeks. Nivolumab will be administered before the daratumumab infusion on study days 
when both study drugs are administered on the same day. Daratumumab 16 mg/kg will be 
administered every 2 weeks from Weeks 9-24. Starting at Week 25, nivolumab 480 mg IV 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
17
flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a 
maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of 
consent, whichever comes first. The infusion rates for the first, second, and subsequent 
daratumumab infusions should closely follow the specifications of the currently approved 
(USPI)/pharmacy reference manual.
2.3
Blinding and Unblinding
Not applicable. This is an open-label study.
2.4
Protocol Amendments
This SAP incorporates the following protocol amendments.
Table 2.4-1:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
Original Protocol
20-Oct-2015
Not applicable
Revised Protocol 01
(Incorporates Amendment 03)
23-Jul-2015
This global amendment was written primarily to address 
the following:
•
Addressed feedback 
 
regarding contraceptive language
In addition to the above changes, other minor changes have 
been made, including the following:
•
Corrected discrepancy in the protocol schema 
regarding the screening period duration
•
Clarified, updated, and corrected discrepancies 
pertaining to, information regarding virus testing 
throughout the protocol
•
Provided clarification regarding entry criteria related 
to specific tumor types
•
Provided specificity for entry criteria related to prior 
therapies
•
Provided specificity and updates related to biomarker 
sample 
requirements 
and 
biomarker 
testing 
methodologies
•
Corrected discrepancies regarding oxygen saturation 
testing
•
Updated safety laboratory testing requirements 
pertaining to  bicarbonate or total CO2 testing
•
Provided information regarding clinical interest 
related to objective response rate.
•
Corrected 
typographical 
and 
spelling 
errors 
throughout the document
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
18
Table 2.4-1:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
Revised Protocol 02
(Incorporates Amendment 07)
16-Oct-2015
This global amendment was written primarily to address 
the following:
•
Removed an exclusion criterion regarding prior 
surgeries that require general anesthesia and surgeries 
requiring local/epidural anesthesia. This change was 
made based on feedback provided by disease experts 
working on this trial
In addition to the above changes, other minor changes have 
been made, including the following 
•
Provided viral status determination clarifications
•
Removed a smoking history requirement for 
neoadjuvant cohort HPV positive SCCHN subjects
•
Edited the allowable window for safety lab testing 
prior to dosing
•
Omitted protocol content to reduce redundancy 
between sections explaining protocol discontinuation
•
Provided updates regarding dose delays in the 
neoadjuvant cohort
•
Added 
four 
month 
post-surgery 
follow-up 
assessments for neoadjuvant cohort subjects
•
Made updates regarding tumor scan assessment timing 
during follow-up period for neoadjuvant cohort
•
Corrected discrepant information regarding windows 
for protocol-specified cycles
•
Removed the requirement to discontinue tumor 
assessments one year after a complete response is 
determined 
•
Added a description regarding research related to ex 
vivo functional assays
•
Corrected 
typographical 
errors, 
and 
made 
administrative updates
Revised Protocol 03
(Incorporates Amendment 09)
16-Mar-2016
This global amendment was written primarily to address 
the following:
•
Addition of a metastatic combination cohort that will 
investigate the safety and efficacy of nivolumab in 
combination with ipilimumab in virus-positive and 
virus-negative solid tumors.
o
Updated the dose delay, resume and 
discontinuation criteria to include 
ipilimumab
o
Updated the sample size, interim analysis, 
and analysis populations to include the 
metastatic combination cohort
•
Clarified collection of tumor tissue samples
Approved
4.0
v
Approved
1.0
v


Statistical A nal ysis Pla n
C A 2 0 9 3 5 8
B M S- 9 3 6 5 5 8
ni v ol u ma b
1 9
T a ble 2. 4- 1: 
Pr ot oc ol A me n d me nts
A me n d me nts
D ate of Iss ue
S u m m ar y of M aj or C h a n ges
•
Pr o vi de d s pecificit y a n d u p dates relate d t o bi o mar ker 
sa m ple re q uire me nts a n d bi o mar ker testi n g 
met h o d ol o gies
I n a d diti o n t o t he a b o ve c ha n ges, ot her mi n or c ha n ges 
ha ve bee n ma de, i ncl u di n g t he f oll o wi n g:
•
Clarifie d d ose dela y, res u me a n d disc o nti n uati o n 
criteria
•
Clarifie d t hat t he a nal ysis will be perf or me d b y 
t u m or      t y pe i n eac h c o h ort
•
O mitte d pr ot oc ol c o nte nt t o re d uce re d u n da nc y 
bet wee n secti o ns e x plai ni n g pr ot oc ol disc o nti n uati o n
•
C orrecte d t y p o gra p hical err ors, a n d ma de 
a d mi nistrati ve u p dates
Re vise d Pr ot oc ol 0 4
(I nc or p orates A me n d me nt 1 3)
2 8- Oct- 2 0 1 6
T his gl o bal a me n d me nt was writte n pri maril y t o a d dress 
t he f oll o wi n g:
•
A d diti o n of t w o treat me nt ar ms, c o nsisti n g of 
ni v ol u ma b c o m bi ne d wit h B M S- 9 8 6 0 1 6 a ge nt a n d 
ni v ol u ma b c o m bi ne d wit h darat u m u ma b t o t he 
metastatic c o m bi nati o n c o h ort.
•
U p dates t o t he sa m ple sizes f or vari o us t u m or t y pes 
i n t he metastatic m o n ot hera p y a n d metastatic 
c o m bi nati o n t hera p y c o h orts f or c o m bi nati o ns A a n d 
B
•
A d diti o n of H P V p ositi ve a nal ca nal a n d pe nile 
ca ncers t o t he metastatic c o m bi nati o n c o h ort
•
Clarificati o n t hat res ults of Da y 2 9 t u m or bi o ps y 
f or ne oa dj u va nt c o h ort m ust be re vie we d b y 
pat h ol o gist a n d a c o p y of t he pat h ol o g y re p ort m ust 
be se nt t o B M S
•
Ni v ol u ma b pr o gra m le vel re visi o ns, i ncl u di n g 
al g orit h m u p date a n d c o ntrace pti o n re q uire me nts.
•
U p dates t o refere nces i n Secti o n 1 2 i n acc or da nce 
wit h i nf or mati o n a d de d t o t he pr ot oc ol 
I n a d diti o n t o t he a b o ve c ha n ges, ot her mi n or c ha n ges 
ha ve bee n ma de, i ncl u di n g c orrecti o n of t yp o gra p hical 
err ors, a n d a d mi nistrati ve u p dates.
Re vise d Pr ot oc ol 0 5
1 8- A pr- 2 0 1 8
•
A d de d 2 4- m o nt h ma xi m u m treat me nt d urati o n f or 
ni v ol u ma b.
•
Clarifie d sa m ple sizes f or ne oa dj u va nt t u m or t y pes.
•
All o w c o nc urre nt e nr oll me nt f or C o m bi nati o n 
C o h orts A, B, a n d D.
•
Re m o ve d gastric ca ncer fr o m C o m bi nati o n C o h orts.
•
E nr oll me nt t o C o m bi nati o n C is cl ose d (i ncl u di n g t o 
cr oss o vers).
A p p r o v e d 
4 . 0
v
A p p r o v e d
1 . 0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
20
Table 2.4-1:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
•
Added new safety data from BMS-986016 and 
daratumumab.
•
Changed order of nivolumab and daratumumab 
administration so that nivolumab is now administered 
before daratumumab.
•
Removed oxygen saturation testing from vital signs 
collection in all on-treatment groups.
•
Clarified imaging duration to be consistently starting 
at week 8.
•
Added 400-mg vials for daratumumab.
•
Updated naming of tumor types from “HPV 
associated tumors” to “Anogenital Cancers.”
Revised Protocol 06
18-Jul-2018
•
Terminated enrollment and treatment of 
daratumumab combination cohorts. 
•
Added a Combination B cohort expansion for SCC of 
the cervix.
•
Changed the neoadjuvant secondary endpoint to an 
exploratory endpoint.
•
Closed enrollment in the combination cohorts for 
anogenital HPV associate tumor types. 
Revised Protocol 07
07-May-2019
•
Incorporates Administrative Letter 02.
•
Changed exploratory objective and endpoint of 
progression-free survival to recurrence-free survival.
•
Updated inclusion/exclusion criteria from bulleted 
lists back to letters.
•
Updated language for EQ-5D-3L and EORTC-QLQ-
C30.
•
Added missing footnote identifier to Table 5.1-3.
2.5
Data Monitoring and Other External Committees
Not applicable.
3
OBJECTIVES
3.1
Primary
•
In the neoadjuvant cohort, to investigate the safety and tolerability of neoadjuvant nivolumab 
administration in the following tumor types:
-
HPV positive SCCHN 
-
HPV negative SCCHN
-
GYN (Cervical, Vaginal, Vulvar) Carcinoma
-
Merkel Cell Carcinoma
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
21
•
In the metastatic/recurrent nivolumab monotherapy cohort, to evaluate the investigator-
assessed objective response rate (ORR) of nivolumab monotherapy in subjects with the 
following diseases:
-
Metastatic or recurrent EBV positive related Gastric cancer, 
-
Metastatic or recurrent HPV positive SCCHN
-
Metastatic or recurrent GYN (Cervical, Vaginal, Vulvar) Carcinoma
-
Metastatic or recurrent Merkel Cell carcinoma 
-
Metastatic or recurrent Nasopharyngeal Carcinoma (NPC)
•
In the metastatic/recurrent combination therapy (nivolumab combined with either ipilimumab 
[Combo A or B], or BMS-986016 [Combo C]) cohort, to evaluate the investigator-assessed 
objective response rate (ORR) of nivolumab combination in subjects with the following 
diseases:
-
Metastatic or recurrent NPC
-
Metastatic or recurrent MCC
-
Metastatic or recurrent cervical cancers
-
Metastatic or recurrent HPV positive SCCHN (with primary exposure to anti-PD-1, 
anti-PD-L1 or anti-CTLA-4 antibody therapy [Combination C])
-
Other metastatic or recurrent anogenital HPV associated tumors (vulvar, vaginal, anal, 
canal, penile)
•
In the metastatic cohort nivolumab combined with daratumumab (Combo D) to evaluate the 
investigator-assessed objective response rate (ORR) in subjects with:
-
Metastatic or recurrent HPV positive, negative, or unknown SCCHN (without prior I-
O therapy exposure)
3.2
Secondary
3.2.1
Metastatic Cohorts (Monotherapy and Combination Therapy)
•
To evaluate the duration of response, progression-free survival and overall survival.
3.3
Exploratory
3.3.1
Neoadjuvant Cohort
•
To determine the percent change from baseline of immune cells and the percent change from 
baseline of select immune activation/inhibitory molecules of viral-specific T cells in tumor 
specific subsets of nivolumab treated subjects.
•
To evaluate the recurrence-free survival after neoadjuvant administration of nivolumab and 
surgery
•
To determine the percent change from baseline in tumor volume after two doses of neoadjuvant 
nivolumab.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
22
•
To determine pathologic complete response of tumors in subjects who receive surgical 
resection after two doses of neoadjuvant nivolumab in SCCHN, resectable Merkel Cell 
Carcinoma, and cervical, vaginal, or vulvar cancer.
•
To evaluate changes in anti-viral and anti-tumor immune responses at the tumor site, using 
proliferative and/or functional assays.
•
To investigate the potential association between selected biomarker measures in peripheral 
blood and tumor tissue, including PD-L1, with safety and clinical efficacy measures. 
•
To investigate the pharmacodynamic activity of nivolumab in the peripheral blood and tumor 
tissue as measured by gene expression, flow cytometry, immunohistochemistry and soluble 
factor assays. 
•
To study the effect of nivolumab on the viral antigen specific T cell responsiveness in the 
peripheral blood. 
•
To evaluate the potential association between the number of tumor mutations and neoantigens 
with clinical efficacy measures and determine if tumor antigen-specific T cells are present in 
the periphery.
•
To assess the subject’s overall health status as assessed by the EQ-5D. 
•
To evaluate cancer specific health related quality of life as assessed by EORTC QLQ-C30.
•
To characterize pharmacokinetics of nivolumab and explore exposure-response relationships.
•
To characterize the immunogenicity of nivolumab.
3.3.2
Metastatic Cohorts (Monotherapy and Combination Therapy)
•
To determine the safety and tolerability [defined as toxicity rates (worst CTC grade per subject) 
of adverse events and specific laboratory tests] of nivolumab monotherapy and combination 
therapy (ipilimumab, BMS-986016, or daratumumab) in subjects with metastatic or recurrent 
viral-mediated tumors.
•
To evaluate the pre and post treatment EBV DNA levels in subjects with EBV positive gastric 
cancer (monotherapy only) and nasopharyngeal carcinoma. 
•
To investigate the potential association between selected biomarker measures in peripheral 
blood and tumor tissue, including PD-L1, with safety and clinical efficacy measures. 
•
To investigate the pharmacodynamic activity of nivolumab monotherapy and combination 
therapy (ipilimumab, BMS-986016, or daratumumab) in the peripheral blood and tumor tissue 
as measured by gene expression, flow cytometry, immunohistochemistry and soluble factor 
assays. 
•
To study the effect of nivolumab monotherapy and combination therapy (ipilimumab, BMS-
986016, or daratumumab) on the viral antigen specific T cell responsiveness in the peripheral 
blood. 
•
To evaluate the potential association between the number of tumor mutations and neoantigens 
with clinical efficacy measures and determine if tumor antigen-specific T cells are present in 
the periphery.
•
To assess the subject’s overall health status as assessed by the EQ-5D. 
•
To evaluate cancer specific health related quality of life as assessed by EORTC QLQ-C30.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
23
•
To characterize pharmacokinetics of nivolumab monotherapy and combination therapy 
(ipilimumab, BMS-986016, or daratumumab) and explore exposure-response relationships.
•
To characterize the immunogenicity of nivolumab monotherapy and combination therapy 
(ipilimumab, BMS-986016, or daratumumab).
4
ENDPOINTS
4.1
Primary Endpoint
4.1.1
Neoadjuvant Cohort
•
The safety and tolerability objective will be measured by the incidence of drug-related select 
AEs and drug-related SAEs
•
Rate of surgery delay, which is defined as the proportion of subjects in the neoadjuvant cohort 
with surgery delayed > 4 weeks from the planned surgery date or planned start date for 
chemoradiation due to a drug-related AE will be reported for each tumor type.
4.1.2
Metastatic Cohorts (Monotherapy and Combination Therapies)
•
The investigator-assessed objective response rate (ORR)
ORR is defined as the number of subjects with a best overall response (BOR) of confirmed 
complete response (CR) or partial response (PR) divided by the number of treated subjects. 
The BOR is defined as the best response designation, as determined by the investigator, 
recorded between the date of treatment assignment and the date of objectively documented 
progression per RECIST 1.1 or the start date of subsequent anticancer therapy, whichever 
occurs first. CR or PR determinations included in the BOR assessment must be confirmed by 
a second scan no less than 4 weeks after the criteria for response are first met. For subjects 
without documented progression or subsequent therapy, all available response designations 
will contribute to the BOR assessment. For subjects who continue treatment beyond 
progression, the BOR should be determined based on response designations recorded up to the 
time of the initial RECIST 1.1-defined progression.
4.2
Secondary Endpoints
4.2.1
Metastatic Cohorts (Monotherapy and Combination Therapies)
•
Duration of response (DOR)  is computed for subjects with a BOR of PR or CR and is defined 
as the time from first confirmed response (CR or PR) to the date of the first documented tumor 
progression as determined using RECIST 1.1 criteria or death due to any cause, whichever 
occurs first. For subjects who neither progress nor die, the DOR will be censored on the date 
of their last evaluable tumor assessment. The magnitude of reduction in tumor volume is 
defined as the percent decrease in tumor volume from baseline to nadir, observed up until the 
time of the first documented tumor progression or death.
•
Clinical Benefit Rate (CBR) is defined as the number of participants with a best overall 
response (BOR) of confirmed complete response (CR) or partial response (PR) or stable 
disease (SD) divided by the number of treated subjects.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
24
•
Overall survival (OS) is defined as the time from first dosing date to the date of death. A subject 
who has not died will be censored at last known date alive. 
•
Investigator-assessed progression free survival (PFS) is defined as the time from first dosing 
date to the date of the first documented tumor progression, as determined by investigators (per 
RECIST 1.1), or death due to any cause. Subjects who had no baseline tumor assessment will 
be censored on the first dose date. Subjects who did not start subsequent anti-cancer therapy 
and die without a reported prior progression will be considered to have progressed on the date 
of their death. Subjects who did not progress or die will be censored on the date of their last 
tumor assessment. Subjects who did not have any on study tumor assessments and did not die 
will be censored on the date they were treated. Subjects who started any subsequent anti-cancer 
therapy without a prior reported progression will be censored at the last tumor assessment prior 
to or on the date of initiation of the subsequent anti-cancer therapy.
Table 4.2-1:
Censoring scheme used in primary definition of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments and no death
First Dosing date
Censored 
No on study tumor assessments and no 
death 
First Dosing date
Censored
Progression per RECIST 1.1 documented at 
scheduled visit or unscheduled visit and no 
new anticancer treatment started before
Date of the first documented tumor progression 
Progressed 
Subject progression free per RECIST 1.1 
and no new anticancer treatment started 
Date of last tumor assessment
Censored
New anticancer treatment started without a 
prior reported progression per RECIST 1.1 
or death  
Date of last tumor assessment prior or on the date 
of  initiation of the subsequent anti-cancer therapy
Censored 
Death without progression per RECIST 1.1
and no new anticancer treatment started
Date of death 
Progressed 
4.3
Exploratory Endpoints
4.3.1
Neoadjuvant Cohort only
•
The percent change from baseline of immune cells and the percent change from baseline of 
select immune activation/inhibitory molecules of viral-specific T cells in tumor specific 
subsets of nivolumab treated subjects will be evaluated. The percent change is the ratio of 
change from the baseline and baseline measurement.
•
Recurrence-free survival (RFS), which is defined as the time from surgery to the date or 
recurrence (local, regional, metastasis, locally advanced unresectable recurrence, clinical or 
radiographic progression occurs after surgery) as determined by investigators, or death due to 
any cause, whichever occurs first. (Note: a subject who dies without reported recurrence will 
be considered to have recurred on the date of death.) 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
25
Table 4.3-1:
Censoring scheme used in primary definition of RFS
Situation 
Date of Recurrence or Censoring 
Outcome 
Recurrence (local, regional, metastasis, 
locally advanced unresectable recurrence, 
clinical/radiographic progression occurs
after surgery)
Date of the earliest documented 
recurrence/progression after surgery
Event
Death without documented recurrence after 
surgery/biopsy
Date of death 
Event
No post-surgery disease assessment and no 
death
Date of surgery
Censored
No recurrence and no death
Date of last evaluable disease assessment
Censored
New anticancer therapya started without 
recurrence or death
Date of last evaluable disease assessment prior to 
or on the same date of initiation of subsequent 
therapy
Censored
a Protocol allowed adjuvant therapy in SOC follow up phase is not counted as subsequent therapy. 
Table 4.3.1-2:
Censoring scheme used in sensitivity analysis of RFS
Recurrence (local, regional, metastasis, 
locally advanced unresectable recurrence, 
clinical/radiographic progression occurs 
after surgery)
Date of the earliest documented 
recurrence/progression after surgery 
Event 
Death without documented recurrence after 
surgery/biopsy 
Date of death 
Event 
No post-surgery disease assessment and no 
death
Date of surgery
Censored
No recurrence and no death
Last known alive date
Censored
New anticancer therapya started without 
recurrence or death
Date of last evaluable disease assessment prior to 
or on the same date of initiation of subsequent 
therapy
Censored
a Protocol allowed adjuvant therapy in SOC follow up phase is not counted as subsequent therapy. 
•
Safety endpoints (Section 7.6)
•
The percent change in tumor volume from baseline after two doses of neoadjuvant nivolumab 
is defined as the ratio of the change in tumor volume and the baseline tumor volume.
•
The proportion of treated subjects who experiences pathologic complete response will be used 
to determine pathologic response rate of tumors after two doses of neoadjuvant nivolumab in 
HPV positive and negative SCCHN, resectable Merkel Cell Carcinoma, and HPV positive 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
26
cervical, vaginal, or vulvar cancer. Pathological complete response (pCR) is defined as the 
absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete 
resected tumor specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy.
4.3.2
Metastatic Cohorts only
•
The safety and tolerability objective will be measured by the incidence of adverse events, 
serious adverse events, deaths and laboratory abnormalities.
•
Pre and post treatment EBV DNA levels will be collected in the subjects with EBV positive 
gastric cancer (monotherapy only) and nasopharyngeal carcinoma. The change in EBV DNA 
levels will be used to determine the effect of BMS-936558 (nivolumab).
•
Efficacy endpoints in GYN tumor type (monotherapy only) will also be reported in two 
subgroups, Cervical and Vaginal/Vulvar, when data allows.
4.3.3
Neoadjuvant and Metastatic Cohorts
•
PD-L1 Expression:
PD-L1 expression missing: Subjects without an available tumor biopsy specimen for PD-L1 
evaluation will be considered as PD-L1 expression missing. 
For subjects with an available tumor biopsy specimen(s), the following will be considered:
PD-L1 expression is quantified and reported by two methods: tumor proportion score (TPS) 
and combined positive score (CPS). TPS is defined as the percent of tumor cells membrane 
staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay. CPS 
is evaluated based on the number of viable tumor cells that exhibit PD-L1 membrane staining 
and associated immune cell (lymphocytes and macrophages) that exhibit PD-L1 membrane 
and/or cytoplasmic staining. This is referred as quantifiable PD-L1 expression. If the PD-L1 
staining could not be quantified, it is further classifies as:
o
Indeterminate: PD-L1 staining hampered for reasons attributed to the biology of the tumor 
tissue sample and not because of improper sample preparation or handling 
o
Not evaluable: Tumor tissue sample was not optimally collected or prepared (e.g. PD-L1 
expression is neither quantifiable nor indeterminate). Not evaluable can be determined 
from H&E process before the tumor biopsy specimen is sent for PD-L1 evaluation or from  
the H&E process during PD-L1 evaluation.
If more than one tumor biopsy specimen is available, PD-L1 expression is determined from 
the most recently collected specimen before first dose date with a quantifiable result. If all 
specimens for a given subject are either indeterminate or not evaluable, then the PD-L1 
expression will be considered indeterminate as long as at least one specimen is indeterminate. 
Otherwise, PD-L1 expression will be considered not evaluable.
•
Pharmacokinetics:
The PK objective will be measured from serum concentration. Samples will be collected to 
characterize pharmacokinetics of nivolumab and to explore exposure-safety and exposure-
efficacy relationships. 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
27
•
Biomarkers:
Biomarkers potentially associated with clinical endpoints will be measured by analyzing tumor 
and blood samples. Biomarker endpoints include, but are not limited to, single-nucleotide 
polymorphisms (SNPs), proteins in tumor specimens and serum, and immune cell populations. 
•
Immunogenicity:
Serum samples collected will be analyzed by a validated immunogenicity assay. Selected 
serum samples may be analyzed by an exploratory orthogonal method that measures anti-
nivolumab. Potential results generated from any orthogonal method are intended as 
informational for technology exploration purposes and will not be reported.
In addition, ad hoc serum samples designated for pharmacokinetic or biomarker assessments 
may also be used for immunogenicity analysis if required (e.g., insufficient volume for 
complete immunogenicity assessment or to follow up on suspected immunogenicity related 
AE).
•
EQ-5D:
Subjects’ overall health status will be assessed using the EuroQoL Group’s self-reported health 
status measure (EQ-5D-3L). EQ-5D essentially has 2 components: the EQ-5D descriptive 
system and the EQ visual analogue scale (EQ-VAS).
The EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no 
problems, some problems, severe problems. Once the data have been collected and a database 
created, a scoring function can be used to assign a value (i.e., EQ-5D index score) to self-
reported health states from a set of population-based preference weights.
The EQ VAS records the subject’s self-rated health state on a 100-point vertical, visual 
analogue scale (0 = worst imaginable health state; 100 = best imaginable health state).
•
EORTC-QLQ-C30:
Health-related quality of life (HRQoL) will be assessed using the European Organization for 
Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire Version 3. It is a 30-
item instrument that has gained wide acceptance in oncology clinical studies.  The EORTC 
QLQ-C30 is composed of multi-item and single scales. These include five functional scales 
(physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and 
vomiting and pain) and a global health status/QOL scale and six single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single 
items meet the standards for reliability. The reliability and validity of the questionnaire is 
highly consistent across different language-cultural groups2. Except for the overall health 
status and global quality of life items, responses for all items are 4-point categorical scales 
ranging from 1 (Not at all) to 4 (Very much). The overall health status/quality of life 
responses are 7-point Likert scales.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
28
Data will be scored according to the algorithm described in the EORTC QLQ-C30 scoring 
manual, as follows:
Functional scales:
-
Physical functioning: (1 - ((Q1+Q2+Q3+Q4+Q5)/5-1)/3) * 100
-
Role functioning: (1 - ((Q6+Q7)/2-1)/3) * 100
-
Emotional functioning: (1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100
-
Cognitive functioning: (1 - ((Q20+Q25)/2-1)/3) * 100
-
Social functioning: (1 - ((Q26+Q27)/2-1)/3) * 100
Global health status:
-
Global health status/QoL: ((Q29+Q30)/2-1)/6 * 100
Symptom scales/items:
-
Fatigue: ((Q10+Q12+Q18)/3-1)/3 * 100
-
Nausea and vomiting: ((Q14+Q15)/2-1)/3 * 100
-
Pain: ((Q9+Q19)/2-1)/3 * 100
-
Dyspnea: (Q8-1)/3 * 100
-
Insomnia: (Q11-1)/3 * 100
-
Appetite loss: (Q13-1)/3 * 100
-
Constipation: (Q16-1)/3 * 100
-
Diarrhea: (Q17-1)/3 * 100
-
Financial difficulties: (Q28-1)/3 * 100
Missing values will be imputed for missing items by “assuming that the missing items have 
values equal to the average of those items which are present” for any scale in which at least 
half the items are completed. A scale in which less than half of the items are completed will 
be treated as missing. This is the method proposed in the scoring manual. A questionnaire 
will be considered as received if at least one of the 15 scales is non-missing (after 
imputation).
All questionnaires completed at baseline and on-study will be assigned to a time-point 
according to the windowing criteria in Table 4.3-3 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 observation will be treated as missing for that time-point.
Table 4.3-3:
Time Windows for EORTC-QLQ-C30 and EQ-5D Assessments
Nominal Time-Point
Time Window
Nivolumab Monotherapy Metastatic Cohorts
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
29
Table 4.3-3:
Time Windows for EORTC-QLQ-C30 and EQ-5D Assessments
Nominal Time-Point
Time Window
Baseline
Prior to first dose on Day 1
Week 9
Day 2 thru Day 85, inclusive
Every 8 Weeks up to week 25
Nominal Day (+28 days/-27 days, inclusive)
Week 33
Nominal Day 225 (+42 days/-27 days, inclusive)
Every 12 weeks thereafter
Nominal Day (+42 days/-41 days, inclusive)
Follow-up 1
Any data associated with Follow-up X01 visit
Follow-up 2
Survival Follow-up Visits (applies to EQ-5D only)
Any data associated with Follow-up X02 visit
Survival Follow-up Visit 1
Any data associated with Survival Follow-up Visit 1
Survival Follow-up Visit 2
Any data associated with Survival Follow-up Visit 2
...
...
Nivolumab Monotherapy Neoadjuvant Cohorts
Baseline
Prior to first dose on Day 1
Week 3
Day 2 thru Day 28 or the day before surgery/biopsy 
date, whichever is earlier, inclusive.
SOC Follow-up 1 
SOC Follow-up 2 
Any data associated with Follow-up E01 visit
Any data associated with Follow-up E02 visit
Post SOC Week 1
Post SOC Day 1 (prior to first dose of post SOC Nivo)
Post SOC Week 9
Post SOC Day 2 thru Post SOC Day 85, inclusive
Post SOC Week 17
Post SOC Day 86 thru Post SOC Day 141, inclusive
Post SOC Week 25
Post SOC Day 142 thru Post SOC Day 197, inclusive
Post SOC Week 33
Post SOC Day 198 thru Post SOC Day 267, inclusive
Every 12 weeks thereafter
Nominal Post SOC Day (+42 days/-41 days, inclusive)
Follow-up 1
Any data associated with Follow-up X01 visit
Follow-up 2
Any data associated with Follow-up X02 visit
Survival Follow-up Visits (applies to EQ-5D only)
Survival Follow-up Visit 1
Any data associated with Survival Follow-up Visit 1
Survival Follow-up Visit 2
Any data associated with Survival Follow-up Visit 2
...
...
Nivolumab combination therapy A, C, D treatment group
Same as Nivolumab Monotherapy Metastatic Cohorts 
Approved
4.0
v
Approved
1.0
v


Statistical A nal ysis Pla n
C A 2 0 9 3 5 8
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 0
T a ble 4. 3- 3: 
Ti me Wi n d o ws f or E O R T C- Q L Q- C 3 0 a n d E Q- 5 D Assess me nt s
N o mi n al Ti me- P oi nt
Ti me Wi n d o w
Ni v ol u m a b c o m bi n ati o n t her a p y B tre at me nt gr o u p
Baseli ne
Wee k 1 0
Wee k 1 9
Wee k 2 7
Wee k 3 5
Wee k 4 7
E ver y 1 2 wee ks t hereafter
Pri or t o first d ose o n Da y 1
Da y 2 t hr u Da y 9 9, i ncl usi ve
Da y 1 0 0 t hr u Da y 1 5 5, i ncl usi ve
Da y 1 5 6 t hr u Da y 2 1 1, i ncl usi ve
Da y 2 1 2 t hr u Da y 2 6 7, i ncl usi ve
N o mi nal Da y 3 2 3 ( + 4 2 da ys/- 5 5 da ys, i n cl usi ve)
N o mi nal Da y ( + 4 2 da ys/- 4 1 da ys, i ncl usi ve)
F oll o w- u p 1
A n y data ass ociate d wit h F oll o w- u p  X 0 1 visit
F oll o w- u p 2
S ur vi val F oll o w- u p Visits (a p plies t o E Q- 5 D  o nl y)
A n y data ass ociate d wit h F oll o w- u p X 0 2 visit
S ur vi val F oll o w- u p Visit 1
A n y data ass ociate d wit h S ur vi val F oll o w- u p Visit 1
S ur vi val F oll o w- u p Visit 2
A n y data ass ociate d wit h S ur vi val F oll o w- u p Visit 2
...
...
5 
S A M P L E SI Z E 
S a m ple size deter mi nati o n is n ot base d o n statistical p o wer calc ulati o n.
1)  Ne o a dj u v a nt C o h ort:
T he S C C H N t u m or t y pes will c o ntai n 2 1 H P V- p ositi ve a n d 2 1 H P V- n e gati ve e val ua ble s u bjects. 
M C C a n d H P V p ositi ve cer vical, va gi nal, or v ul var ca ncers t u m or  t y pes will c o ntai n 2 1 e val ua ble 
s u bjects eac h. A sa m ple size of 2 1 ca n detect, wit h m ore t ha n 66 % a n d 8 9 % pr o ba bilit y, a saf et y 
e ve nt t hat occ urs at a n i nci de nt rate of 5 % a n d 1 0 %, res pecti vel y. Ass u mi n g 1 0 %, 1 5 %, a n d 2 0 % 
f or pat h ol o gic c o m plete res p o nse rate, a sa m ple size of 2 1 ca n detect, m ore t ha n 8 9 %, 9 7 % a n d 
9 9 % pr o ba bilit y, at leas t o ne pat h ol o gic c o m plete res p o nse res pecti vel y.
1)  Rec urre nt/ M et ast atic M o n ot her a p y C o h ort:
H P V + S C C H N, G Y N, M C C a n d N P C t u m or t y p e i n t he rec urre nt/ metastatic c o h ort w ill c o ntai n 
2 3 s u bjects.  T a ble 5- 1 s h o ws t he pr o ba bilities of o bser vi n g 0, 1 or 2 res p o n ders a n d 
3 res p o n ders 
ass u mi n g 5 %, 2 0 % a n d 3 0 % tr ue res p o nse rate of O R R.  s h o ws t he t w o si de d 9 5 % e xact CI usi n g 
Cl o p per- Pears o n met h o ds base d o n o bser ve d 3, 4 a n d 5 res p o n ders  o ut of 2 3 s u bjects.
E B V + Gastric t u m or t y pe will c o ntai n a p pr o xi matel y 1 2 s u bjects,  d ue t o t he l o w pre vale nce. Ta ble  
5- 3   s h o ws  t he  precisi o n  of  t he  esti mati o n  of  O R R  base d  o n  t he t w o-si d e d  9 5 %  e xact  CI  usi n g 
Cl o p per Pears o n met h o ds base d o n 1, 2, 3, 4 a n d 5 res p o n ders o u t of 1 2 s u bjects. Ass u mi n g t he 
A p p r o v e d 
4 . 0
v
A p p r o v e d
1 . 0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
31
true ORR is 25%, 12 subjects can provide approximately 84% probability to observe at least 2 
responders.
Table 5-1:
Probability of observing responses given true ORR for sample size 
of 23 subjects
True ORR
Probability of observing 0,1 or 2 
responses
Probability of observing 
≥3 responses
5%
89.5%
10.5%
20%
13.3%
86.7%
30%
1.6%
98.4%
Table 5-2:
Two-sided 95% exact CI using Clopper-Pearson method based on 
number of observed responses out of 23 subjects
The number of observed 
responses
3
4
5
Observed Response Rate
3/23 (13.0%)
4/23 (17.4%)
5/23 (21.7%)
95% exact CI
(2.8%, 33.6%)
(5.0%, 38.8%)
(7.5%, 43.7%)
Table 5-3:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 12 subjects
Number of 
observed 
responses
1
2
3
4
5
Observed 
Response Rate
1/12 (8.3%)
2/12 (16.7%)
3/12 (25.0%)
4/12 (33.3%)
5/12 (41.7%)
95% exact CI 
(%)
(0.2, 38.5)
(2.1, 48.4)
(5.5, 57.2)
(9.9, 65.1)
(15.2, 72.3)
2) Recurrent/Metastatic Combination Cohort:
The HPV+SCCHN, MCC, and NPC tumor types in the recurrent/metastatic cohort will each 
contain approximately 40 subjects that will be enrolled to the Combo A treatment arm. Patients 
with cervical cancer and other HPV associated tumors (vulvar/vaginal/anal canal/penile) tumor 
type will be randomized in a 1:1 ratio to one of two dosing schema (Combo A or Combo B). 
Approximately 40 subjects will be randomized into each dosing schema. With Revised Protocol 
06, no new subjects will be randomized in the anogenital HPV associated tumors cohorts.
Additionally, the metastatic cervical Combination B cohort will be expanded to treat 
approximately 50 subjects as first-line treatment for their recurrent/metastatic disease if unfit or 
unsuitable to receive platinum-based therapy and approximately 20 subjects as second-line 
treatment for their recurrent/metastatic SCC of the cervix to confirm the efficacy signal. With 
Approved
4.0
v
Approved
1.0
v


Statistical A nal ysis Pla n
C A 2 0 9 3 5 8
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 2
C o m b o B a n d t he C o m b o B e x pa nsi o n, t here s h o ul d be a t ot al of a p pr o xi matel y 7 5 s u bjects wit h 
first-li ne treat me nt a n d a p pr o xi matel y 3 5 s u bjects wit h sec o n d-li ne treat me nt of cer vical ca ncer 
(a p pr o xi matel y 1 1 0 cer vical s u bjects t otal). 
T he H P V + S C C H N wit h pri or P D- 1/ P D- L 1 treat me nt t u m or t y pe will be e nr olle d i n Metastatic 
C o m bi nati o n C o h ort ( C o m b o C). C o m b o C w ill c o ntain a p pr o xi matel y 4 0 s u bjects. H o we ver, at 
Re vise d Pr ot oc ol 0 5, n o ne w s u bjects will be e nr olle d i n t his c o h ort. 
A p pr o xi matel y  4 0  H P V  ne gati ve  a n d  H P V  i n deter mi nate  I- O  nai ve  S C C H N  s u bjects  will  b e 
e nr olle d  t o  t he  C o m b o  D  tr eat me nt  ar m.  Wit h  Re vise d  Pr ot oc ol  0 6,  n o  ne w  s u bjects  w ill  b e 
e nr olle d i n t his c o h ort.
S a m ple sizes of eac h treat me nt ar m i n eac h t u m or t y pe are s u m marize d i n Ta ble 5- 4. 
T a ble 5- 4: 
S a m ple size i n rec urre nt/ met ast atic c o m bi n ati o n c o h or t
C o m b o A
Ni v o- 3 m g/ k g q 2 w 
+ I pi- 1 m g/ k g q 6 w
C o m b o B
Ni v o- 1 m g/ k g + I pi-
3 m g/ k g q 3 w x 4 
f oll o we d b y Ni o v 
2 4 0 m g q 2 w
C o m b o C
Ni v o + B M S-
9 8 6 0 1 6
C o m b o D
Ni v o + D ar a
Cer vical
4 0
1 1 0 a
A n o ge nital H P V 
ass ociate d t u m ors 
( va gi nal/ v ul var/a nal 
ca nal/ pe nile)
4 0
4 0
M C C
4 0
N P C
4 0
H P V + S C C H N
(I/ O nai ve)
4 0 
H P V + S C C H N 
( Pri or P D- 1/ P D- L 1)
4 0
I- O Nai ve S C C H N
4 0
a
I ncl u des 4 0 fr o m C o m bi nati o n B a n d 7 0 fr o m C o m bi nati o n B e x pa nsi o n.
I n t his st u d y, a n O R R i n e xcess of 1 0 % will be c o nsi dere d of cli nical i nt erest. Ass u mi n g t he tr ue 
O R R is 2 5 %, 4 0 s u bjects i n eac h t u m or t y pe ca n pr o vi de a p pr o xi matel y 7 9. 8 % p o wer t o reject t he 
n ull h y p ot hesis t hat t he tr ue O R R is
1 0 %, c o nsi deri n g a t w o-si d e d al p ha of 5 %. I n a d diti o n, Ta ble  
5- 5   s h o ws  t he  precisi o n of  t he  esti mati o n  of  O R R  base d  o n  t he t w o-si d e d  9 5 %  e xact  CI  usi n g 
Cl o p per Pears o n met h o ds base d o n 8, 9, 1 2, 1 6 a n d 2 0 res p o n ders o ut of 4 0 s u bjects. At o bser ve d 
m ore t ha n or e q ual t o 9 res p o n ders, i. e., O R R ≥2 2. 5 %, t he l o wer b o u n d of t he 9 5 % CI e xcl u des 
1 0 %.
Ta ble  5- 6   s h o ws t he  precisi o n  of  t he  esti mati o n  of  O R R  base d  o n t he t w o-si d e d  9 5 %  e xact  CI 
usi n g Cl o p per- Pears o n met h o ds base d o n 2 0, 2 2, 2 6, 3 0, 3 3, a n d 3 5 res p o n ders o ut of 5 0 s u bjects. 
A p p r o v e d 
4 . 0
v
A p p r o v e d
1 . 0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
33
At observed more than or equal to 22 responders, i.e., ORR ≥44%, the lower bound of the 95% 
CI excludes 30%; at observed more than or equal to 26 responders, i.e., ORR ≥52%, the lower 
bound of the 95% CI excludes 37%.
Table 5-7 shows the precision of the estimation of ORR based on the two-sided 95% exact CI 
using Clopper-Pearson methods based on 3, 5, 8, 10, 12 and 14 responders out of 35 subjects. At 
observed more than or equal to 8 responders, i.e., ORR ≥22.9%, the lower bound of the 95% CI 
excludes 10%.
Due to the low prevalence of EBV+ Gastric tumor types and the current investigation of this tumor 
type in other BMS-sponsored studies, combination cohorts in this study will no longer include 
EBV+ Gastric tumor type.
Table 5-5:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 40 subjects
Number of 
observed 
responses
8
9
12
16
20
Observed 
Response Rate
8/40 (20.0%)
9/40 (22.5%)
12/40 (30.0%)
16/40 (40.0%)
20/40 (50.0%)
95% exact CI 
(%)
(9.1, 35.6)
(10.8, 38.5)
(16.6, 46.5)
(24.9, 56.7)
(33.8, 66.2)
Table 5-6:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 50 Subjects
Number of 
observed 
responses
20
22
26
30
33
35
Observed 
Response 
Rate
20/50
(40.0%)
22/50
(44%)
26/50
(52%)
30/50
(60%)
33/50
(66%)
35/50
(70%)
95% exact CI 
(%)
(26.4, 54.8)
(30.0, 58.8)
(37.4, 66.3)
(45.2, 73.6)
(51.2, 78.8)
(55.4, 82.1)
Table 5-7:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 35 Subjects
Number of 
observed 
responses
3
5
8
10
12
14
Observed 
Response 
Rate
3/35
(8.6%)
5/35
(14.3%)
8/35
(22.9%)
10/35
(28.6%)
12/35
(34.3%)
14/35
(40%)
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
34
Table 5-7:
Two-sided 95% Exact CI Using Clopper-Pearson Method Based on 
the Number of Observed Responses out of 35 Subjects
Number of 
observed 
responses
3
5
8
10
12
14
95% exact CI 
(%)
(1.8,23.1)
(4.8, 30.3)
(10.4, 40.1)
(14.6, 46.3)
(19.1, 52.2)
(23.9,57.9)
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline Period
Baseline evaluations or events are defined as evaluations or events that occur before the date and 
time of the first dose of study treatment.
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 are 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) are defined as 
evaluations with a date on or prior to the day of first dose of study treatment
If there are multiple valid assessments, the assessment that is closest to a day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 
assessments are collected at the same date (and time if collected), the assessment with the latest 
database entry date (and time if collected) will considered as baseline. 
6.1.2
Post Baseline Period
On-treatment AEs are 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). An AE will be counted as on-treatment if the event 
occurred within 30 (or 100) days of the last dose of study treatment. Specifically, re-initiation 
study treatment is excluded for the purpose of determining the last dose of study treatment as part 
of the definition of on-treatment; separate safety analyses for re-initiation therapy may be 
performed. 
On-treatment evaluations (laboratory tests, pulse oximetry, and vital signs) are defined as 
evaluations taken after the day (and time, if collected and not missing) of first dose of study 
treatment. An evaluation will be counted as on-treatment if it occurred within 30 (or 100) days of 
the last dose of study treatment.
Late emergent drug-related AEs are defined as drug-related AEs with an onset date greater than 
100 days after the last dose of study treatment in subjects off study treatment.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
35
Table 6.1-1:
Primary On-Treatment Definition For Safety in Treated Subjects
Cohort
Option for Re-Initiation
On-Treatment Definition
Neoadjuvant 
Yes
On or after first dose of nivolumab and within 30 
(or 100) days after last dose of nivolumab prior to 
re-initiation dosing
Metastatic
No
On or after first dose of study treatment and within 
30 (or 100) days after the last dose of study 
treatment
6.2
Treatment Regimens
Neoadjuvant Cohort:
•
Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 
1 and Day 15 (before surgery).
Metastatic Monotherapy Cohort:
•
Nivolumab administered IV over 30 minutes at 240 mg every 2 weeks for a maximum of 
24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, 
whichever comes first.
Metastatic Combination Cohort (Combinations A, B, C, and D):
•
Combo Arm A: Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks plus Ipilimumab 1 
mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease 
progression, unacceptable toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm B: Nivolumab 1 mg/kg IV over 30 minutes plus Ipilimumab 3 mg/kg IV over 
30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes 
every 2 weeks for a maximum of 24 months or until disease progression, unacceptable 
toxicity, or withdrawal of consent, whichever comes first.
•
Combo Arm C: Nivolumab 480 mg IV over 30 minutes plus BMS-986016 160 mg IV over 
60 minutes administered every 4 weeks for a maximum of 24 month, or until disease 
progression, unacceptable toxicity, or withdrawal of consent, whichever comes first. 
Subjects enrolled in Combo C prior to Revised Protocol 05 and on treatment with BMS-
986016 80 mg + Nivolumab 240 mg q2W will remain on this dose regimen for the duration 
of their time on treatment.
•
Combo Arm D: Daratumumab 16 mg/kg IV administered weekly for the first 8 weeks. 
Starting at Week 3, nivolumab 240 mg IV over 30 minutes will be administered every 2 
weeks. Nivolumab will be administered before the daratumumab infusion on study days 
when both study drugs are administered on the same day.  Daratumumab 16mg/kg will be 
administered every 2 weeks from Weeks 9-24. Starting at Week 25, nivolumab 480 mg IV 
flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
36
maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of 
consent, whichever comes first. The infusion rates for the first, second, and subsequent 
daratumumab infusions should closely follow the specifications of the currently approved 
(USPI)/pharmacy reference manual.183
6.3
Populations for Analyses
6.3.1
Study Cohorts
The tumor types for the neoadjuvant cohort are: 
(N-1): HPV positive SCCHN 
(N-2): HPV negative SCCHN
(N-3): GYN (Cervical, Vaginal, Vulvar) Carcinoma
(N-4): Merkel Cell Carcinoma
The diseases or tumor types for the recurrent/metastatic monotherapy cohort are 
(M-1): EBV positive related Gastric cancer, 
(M-2): HPV positive SCCHN
(M-3): GYN (Cervical, Vaginal, Vulvar) Carcinoma
(M-4): Merkel Cell carcinoma 
(M-5): Nasopharyngeal Carcinoma (NPC)
The diseases or tumor types for the recurrent/metastatic combination therapy cohort are 
(MC-1a): HPV positive Squamous Cell cancer of the Head and Neck (SCCHN) PD-1/PD-L1 
naive: combo A
(MC-2a): Cervical Carcinoma: combo A
(MC-2b): Cervical Carcinoma: combo B
(MC-exp): Squamous Cell Cancer of the Cervix: combo B expansion
(MC-3a): Anogenital HPV associated tumors (vaginal/vulvar/anal canal/penile) Carcinoma: 
combo A
(MC-3b): Anogenital HPV associated tumors (vaginal/vulvar/anal canal/penile) Carcinoma: 
combo B
(MC-4a): Merkel Cell Carcinoma: combo A
(MC-5a): Nasopharyngeal carcinoma (NPC): combo A 
(MC-6c): HPV positive Squamous Cell cancer of the Head and Neck (SCCHN) Prior PD-
1/PD-L1: combo C
(MC-7d): Squamous Cell cancer of the Head and Neck (SCCHN) I-O naive: combo D
6.3.2
Analysis Populations
Within each tumor type in each cohort the following populations will be defined.
•
Enrolled subjects: All subjects who signed an informed consent form and were registered into 
the IVRS.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
37
•
Treated subjects: All subjects who received at least one dose of nivolumab. This is the 
primary population for efficacy and safety analyses.
•
Response evaluable subjects: All treated subjects who have a BOR of CR, PR, SD, Non-
CR/Non-PD or PD, and target lesion(s) assessed at baseline, and one of the following: i) at 
least one on-study timepoint (before sub-sequent therapy) with all baseline target lesion(s) 
assessed; ii) clinical progression or death before any on-study tumor assesment.
•
Evaluable neoadjuvant subjects: All treated subjects in neoadjuvant cohorts (N-1, N-2, N-3, 
N-4) who have available paired tissue samples at screening and Day 29.
•
Pathologic response evaluable subjects: All treated subject in neoadjuvant cohorts who 
received study treatment surgery and have known pathological response based on Day 29 TN 
classification.
•
Outcomes research subjects: All treated subjects who have an assessment at baseline and at 
least one post baseline assessment.
•
Pharmacokinetic subjects: All treated subjects have available serum concentration data.
•
Immunogenicity subjects: All treated subjects with baseline and at least 1 post baseline 
immunogenicity assessment.
•
PD-L1 tested subjects:  All subjects who had a tumor tissue sample available for assessment 
of PD-L1 expression at baseline.
•
Treated PD-L1 tested subjects:  All PD-L1 tested subjects who received at least one dose of 
study treatment.
•
PD-L1 evaluable subjects:  All treated PD-L1 tested subjects with quantifiable PD-L1 
expression.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, the following subsections describe tabulations of discrete variables, by 
the frequency and proportion of subjects falling into each category. Percentages given in these 
tables will be rounded and, therefore, may not always sum to 100%. Continuous variables will be 
summarized using the mean, standard deviation, median, minimum and maximum values. If a 
missing category is not being presented in the data display, only those subjects with non-missing 
values for the parameter being assessed are included in the percentage calculation.
Time to event distribution (e.g. progression free survival, overall survival, time to response, and 
duration of response) will be estimated using Kaplan Meier techniques. When appropriate, the 
median along with the corresponding log-log transformed 95% CI will be estimated. Rates at fixed 
time points will be derived from the Kaplan Meier estimate and corresponding confidence intervals 
will be derived based on Greenwood formula3 for variance derivation and on log-log 
transformation applied on the survivor function S(t) 4.
Confidence intervals for binomial proportions will be derived using the Clopper-Pearson method5.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
38
All analyses will be performed separately for each tumor type upon completion of follow-up for 
the primary endpoint in each tumor type. Safety analyses will also be performed for each tumor 
type.
7.2
Study Conduct
7.2.1
Accrual
The following will be presented on the enrolled population:
•
Number of subjects accrued by country and investigational site
•
Number of subjects accrued by month
7.2.2
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations. Non-
programmable relevant eligibility and on-treatment protocol deviations, as well as significant (both 
programmable and non-programmable) eligibility and on-treatment protocol deviations will be 
reported through 
 listings.
At entrance:
•
Subjects with baseline ECOG performance status > 1
•
Subjects without measurable disease at baseline (only for metastatic cohort)
•
Subjects with baseline tumor diagnosis of a tumor type that is not planned in the cohort that 
the subject was enrolled in.
On-study:
•
Subjects receiving anti-cancer therapy (chemotherapy, hormonal therapy, immunotherapy, 
standard or investigational agents for treatment of cancer) while on study therapy. 
A summary table will be produced separately for each tumor type in all treated subjects. A by 
subject listing will be produced.
7.3
Study Population
7.3.1
Subject Disposition
The total number of subjects enrolled (treated or not) will be presented along with the reason for 
not being treated. This analysis will be performed on all enrolled population only.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated. Reason for discontinuation will be derived from subject status CRF page. This analysis 
will be performed only on all treated population.
A subject list for all treated subjects will be provided showing the subject’s enrollment date, first 
and last dosing date, off study date and reason for going off-study.
7.3.2
Demographics and Baseline Characteristics
Descriptive statistics will be summarized the following baseline characteristics for all treated 
subjects. All baseline presentations will identify subjects with missing measurements. In 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
39
tabulations of categorical variables, percentages are based on subjects with measurements. Listings 
will also be provided.
•
Age group 1 (descriptive statistics); Age categories (< 65, ≥ 65 and < 75, ≥75)
•
Age group 2 (descriptive statistics): Age categories (18-64, 65-84, >= 85) 
•
Weight (descriptive statistics)
•
Gender (Male, Female)
•
Race (White, Black, Asian, and Other) 
•
Region (US/Canada, Europe, Rest of the World)
•
ECOG PS (0/1)
•
Time from initial disease diagnosis to treatment (< 1 year, 1 - < 2 year, 2 - < 3 year, 
3 - < 4 year, 4 - < 5 year, ≥ 5 year) 
•
Time from initial disease diagnosis to study entry (<=1 year, >1 year)
•
All lesions (Investigator Tumor Assessments at Baseline): sites of diseases, number of disease 
sites per subject
•
Target Lesions (Investigator Tumor Assessments at Baseline): Presence of target lesions, site 
of target lesion, sum of diameters of target lesions.
•
Virus status (Positive / Negative) in tumor types (M-3) GYN (Cervical, vaginal, and vulva)
Carcinoma, (MC-2a, MC-2b, MC-exp) Cervical Carcinoma, (MC-3a, MC-3b) anogenital 
HPV associated tumors (vaginal/vulvar/anal canal/penile), (M-4, MC-4a) Merkel Cell 
Carcinoma and (M-5, MC-5a) Nasopharyngeal Carcinoma (NPC), SCCHN (MC-7d), for 
which the virus status are tested retrospectively. 
•
Smoking status (never, current, former, unknown) for SCCHN cohorts N-1, N-2, M-2, M5, 
MC-1a, MC-5a, MC-6c, MC-7d
•
Disease location for SCCHN subjects (oral cavity, hypopharynx, oropharynx, larynx, other)
•
Disease location for MCC subjects (primary only, lymph nodes only, primary and lymph 
nodes, visceral)
7.3.3
Medical History
General medical history will be listed by subject. 
7.3.4
Prior Therapy
The following will be summarized by tumor type for all treated population:
•
Prior therapy (1, 2, 3, ≥ 4)
•
Best response to most recent prior regimen (CR/PR vs. SD vs. PD)
•
Prior metastatic therapy (yes/no)
•
Prior neo-adjuvant therapy (yes/no)
•
Prior adjuvant therapy (yes/no)
•
Number of prior systemic cancer therapy in metastatic settings (0, 1, 2)
•
Time from completion of most recent prior regimen to progression (<= 3, <3 - <=6, <6 - <=12, 
>12 months)
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
40
•
Time from completion of most recent prior regimen to study entry (<= 3, <3 - <=6, <6 - <=9, 
<9 - <=12, >12 months)
•
Prior surgery related to cancer (yes or no)
•
Prior radiotherapy (yes or no)
•
Prior/current non-study medication classified by anatomic and therapeutic classes.
Medication will be reported using the generic name. A listing by subject will also be provided.
7.3.5
Baseline Examinations
Percentage of subjects with abnormal baseline physical examination will be tabulated by 
examination criteria and tumor type for all treated subjects.
7.4
Extent of Exposure
The extent of exposure will be characterized according to the number of subjects exposed, and the 
duration of exposure. Analyses in this section will be performed on all Treated Subjects for each 
tumor type in different cohorts.
7.4.1
Administration of Study Therapy
The following parameters will be summarized (descriptive statistics) by tumor type:
•
Number (%) of treated subjects exposed for specified periods of time such as less than 1 week, 
1 week to 1 month, 1 month to 6 months by treatment.
•
Number of doses received (summary statistics)
•
Cumulative dose 
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 
- < 110%; ≥ 110%.
•
Duration of treatment: duration of treatment will be presented using a Kaplan-Meier curve 
whereby the last dose date will be the event date for subjects who discontinued study therapy.  
Subjects who are still on study therapy will be censored on their last dose date.  Median 
duration of treatment and associated 95% CI will be provided.
•
A by-subject listing of dosing of study medication (record of study medication, infusion details
and dose change) and a listing of batch number will be also provided.
•
A by-subject listing of extent of exposure (weight, number of doses, date of first and last dose, 
cumulative dose, duration of treatment, and reason for discontinuation) will be provided.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
41
Table 7.4.1-1:Administration of study therapy: definition of parameters
Nivolumab monotherapy
Nivolumab
Dosing schedule per protocol
240 mg every 2 weeks 
Cumulative Dose
Cum dose (mg) is sum of the doses (mg) administered to a subject during the 
treatment period.
Duration of treatment 
Last dose date - Start dose date +1
Relative Dose Intensity (%)
Cum dose /[(Last dose date - Start dose date + 14) x 240/14] x 100
Nivolumab combined with Ipilimumab: Combo A
Nivolumab
Ipilimumab
Dosing Schedule per Protocol
3 mg/kg every 2 weeks
1 mg/kg every 6 weeks 
Dose
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most recent 
weight (kg). Dose administered in 
mg at each dosing date and weight 
are collected on the CRF
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most recent 
weight (kg). Dose administered in 
mg at each dosing date and weight 
are collected on the CRF
Cumulative Dose
Cum Dose (mg/kg) is the sum of the 
doses administered to a subject.
Cum Dose (mg/kg) is the sum of the 
doses administered to a subject.
Relative Dose Intensity (%)
Cum dose /[(Last dose date - Start
dose date + 14) x 3/14] x 100
Cum dose /[(Last dose date - Start
dose date + 42) x 1/42] x 100
Duration of Treatment
Last dose date - Start dose date +1
Last dose date - Start dose date +1
Nivolumab combined with Ipilimumab: Combo B
Nivolumab
Ipilimumab
Dosing Schedule per Protocol
1 mg/kg every 3 weeks for 4 doses 
followed by 240 mg every 2 weeks
3 mg/kg every 3 weeks for 4 doses
Dose
Dose (mg) is defined as Total Dose 
administered (mg). Dose 
administered in mg at each dosing 
date is collected on the CRF
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most recent 
weight (kg). Dose administered in 
mg at each dosing date and weight 
are collected on the CRF
Cumulative Dose
Cum Dose (mg) is the sum of the 
doses administered to a subject.
Cum Dose (mg/kg) is the sum of the 
doses administered to a subject.
Cycle Duration(i) (wk)
(Dose date(i+1) - Dose date(i))/7
N/A
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
42
Nivolumab combined with Ipilimumab: Combo B
Nivolumab
Ipilimumab
For the last dose N, if N<=4, cycle 
duration (N) (wk)=3; if N >4, cycle 
duration (N) (wk)=2.
Cycle Intensity(i) (mg/kg/wk)
Dose(i)/Cycle Duration(i)
N/A
Relative Cycle Intensity (i) (%)
(Cycle Intensity(i)/intended dose per 
week) * 100
N/A
Relative Dose Intensity (%)
Sum of all Relative Cycle Intensities 
divided by N
Cum dose /[(Last dose date - Start
dose date + 21) x 3/21] x 100
Duration of Treatment
Last dose date - Start dose date +1
Last dose date - Start dose date +1
Volume infused, volume prepared, and weight are collected on the CRF. Nominal nivolumab dose collected in IVRS. 
i = 1, 2,...,N, where N = number of infusions. Cycle Duration (N) = 3 weeks for nominal 1 mg/kg nivolumab doses for 
first 4 doses and 2 weeks for nominal 240 mg after 4th dose. Intended dose per week is xx mg (0.33 mg/kg times 
subject’s weight in kg) for nominal 1 mg/kg nivolumab doses in the first 4 doses and 120 mg for nominal 240 mg 
nivolumab doses after 4th dose.
Nivolumab combined with BMS-986016: Combo C
Nivolumab
BMS-986016
Dosing Schedule per Protocol
240 mg every 2 weeks
80 mg every 2 weeks
Dose
Dose (mg) is defined as Total Dose 
administered (mg). Dose 
administered in mg at each dosing 
date is collected on the CRF
Dose (mg) is defined as Total Dose 
administered (mg). Dose 
administered in mg at each dosing 
date is collected on the CRF
Cumulative Dose
Cum Dose (mg) is the sum of the 
doses administered to a subject.
Cum Dose (mg) is the sum of the 
doses administered to a subject.
Relative Dose Intensity (%)
Cum dose /[(Last dose date - Start 
dose date + 14) x 240/14] x 100
Cum dose /[(Last dose date - Start 
dose date + 14) x 80/14] x 100
Duration of Treatment
Last dose date - Start dose date +1
Last dose date - Start dose date +1
Nivolumab combined with Daratumumab: Combo D
Nivolumab
Daratumumab
Dosing Schedule per Protocol
240 mg q2 weeks (starting at Week 
3); 480 mg q4 weeks starting at 
Week 25
16 mg/kg q1 week (Weeks 1-8), q2 
weeks (Weeks 9-24); q4 weeks 
starting at Week 25
Dose
Dose (mg) is defined as Total Dose 
administered (mg). Dose 
administered in mg at each dosing 
date is collected on the CRF
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most recent 
weight (kg). Dose administered in 
mg at each dosing date and weight 
are collected on the CRF
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
43
Nivolumab combined with Daratumumab: Combo D
Nivolumab
Daratumumab
Cumulative Dose
Cum Dose (mg) is the sum of the 
doses administered to a subject.
Cum Dose (mg/kg) is the sum of the 
doses administered to a subject.
Cycle Duration(i) (wk)
(Dose date(i+1) - Dose date(i))/7
For the last dose N, if N<=11, cycle 
duration (N) (wk)=2; if IN>11, cycle 
duration (N) (wk)=4.
(Dose date(i+1) - Dose date(i))/7
For the last dose N, if N<=8, cycle 
duration (N) (wk)=1; if  16>=N>8,  
cycle duration (N) (wk)=2; if N>16, 
cycle duration (N) (wk)=4.
Cycle Intensity(i) (mg/kg/wk)
Dose(i)/Cycle Duration(i)
Dose(i)/Cycle Duration(i)
Relative Cycle Intensity (i) (%)
(Cycle Intensity(i)/intended dose per 
week) * 100
(Cycle Intensity(i)/intended dose per 
week) * 100
Relative Dose Intensity (%)
Sum of all Relative Cycle Intensities 
divided by N
Sum of all Relative Cycle Intensities 
divided by N
Duration of Treatment
Last dose date - Start dose date +1
Last dose date - Start dose date +1
Volume infused, volume prepared, and weight are collected on the CRF. Nominal nivolumab dose collected in IVRS. 
For nivolumab, i = 1, 2,...,N, where N = number of infusions. Cycle Duration (N) = 2 weeks for nominal 240 mg 
nivolumab doses for first 11 doses and 4 weeks for nominal 480 mg after 12th dose. Intended dose per week is 120 
mg for nominal 240 mg or nominal 480 mg.
For Daratumumab, i = 1, 2, ..., N, where N = number of infusions. Cycle Duration (N) = 1 week for first 8 doses, 2 
weeks for 9th~16th doses and 4 weeks after 17th dose for nominal 16 mg/kg daratumumab doses. Intended dose per 
week is 16mg/kg for the first 8 doses, 8mg/kg for 9th~16th doses and 4 mg/kg after 17th dose.
7.4.2
Modifications of Study Therapy
7.4.2.1
Dose Delays
Treatment may be delayed for up to a maximum of 6 weeks from the last dose. 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 studies drugs must be delayed 
until treatment can resume. Length of delay for study treatment is summarized in Table 7.4.2.1-1.
Dose delays will be divided into following categories: 4 - < 8 days, 8 - < 15 days, 15 - < 43, ≥ 43 
days. Reason for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized by tumor type:
•
Number of subjects with at least one dose delayed, number of dose delayed per subject, length 
of delay and reasons for dose delay
Table 7.4.2.1-1:
Length of Dose Delay
Nivolumab monotherapy
Nivolumab Dose Delay
duration of previous cycle in days - 14
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
44
Table 7.4.2.1-1:
Length of Dose Delay
Nivolumab monotherapy
Nivolumab combined with Ipilimumab: Combo A
Nivolumab Dose Delay
duration of previous cycle in days - 14
Ipilimumab Dose Delay
duration of previous cycle in days - 42
Nivolumab combined with Ipilimumab: Combo B
Nivolumab Dose Delay
(duration of previous cycle in days - 21) for the first 4 
doses
(duration of previous cycle in days - 14) starting from 
the 5th dose
Ipilimumab Dose Delay
(duration of previous cycle in days - 21) for the first 4 
doses
Nivolumab combined with BMS-986016: Combo C
Nivolumab Dose Delay
duration of previous cycle in days - 14
BMS-986016 Dose Delay
duration of previous cycle in days - 14
Nivolumab combined with Daratumumab: Combo D
Nivolumab Dose Delay
(duration of previous cycle in days - 14) for the first 11 
doses
(duration of previous cycle in days - 28) starting from 
the 12th dose
Daratumumab Dose Delay
(duration of previous cycle in days - 7) for first 8 
doses, 
(duration of previous cycle in days - 14) for 9th~16th 
doses,
(duration of previous cycle in days - 28) after 17th 
doses.
7.4.2.2
Infusion Interruptions and Rate Changes
Each nivolumab, or ipilimumab infusion 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 cohort, tumor type and treatment:
•
Number of subjects with at least one dose infusion interruption, number of infusion 
interruptions per subject and the reason for interruption.
•
Number of subjects with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per subject and the reason for reduction
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
45
7.4.2.3
Dose Reductions /Escalations
There will be no dose escalations or reductions of nivolumab allowed. 
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 WHO Drug Dictionary.
The following summary tables will be provided by tumor type: 
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term).
A by-subject listing will accompany the table.
7.5
Efficacy
Analyses from this section will be produced separately for each tumor type in different cohorts, 
except where otherwise indicated. In (M-3, N-3) GYN (Cervical, vaginal, and vulvar) Carcinoma, 
all analyses will also be conducted in two subgroups, Cervical and Vaginal/Vulvar. 
7.5.1
Primary Analyses
7.5.1.1
Neoadjuvant Cohort: Rate of Surgery Delay
Rate of surgery/biopsy delay will be summarized using all treated subjects. The Clopper-Pearson 
method will be used to estimate the two-sided 95% confidence intervals.
Surgical summary (e.g., type of surgery, median time from last dose to surgery, reasons for surgical 
delay/cancellation, and any other details) will be also provided if the data are collected and 
available. 
7.5.1.2
Metastatic Cohorts: Objective Response Rate 
The ORR based on investigator assessment (Per RECIST 1.1) will be summarized. The Clopper-
Pearson method will be used to estimate the two-sided 95% confidence intervals. 
BOR will be summarized by response category.
To assess consistency of ORR, investigator-assessed ORR (primary analysis) will be summarized 
for the following subgroups by tumor type:
•
Age (descriptive statistics); Age categories (< 65, ≥ 65 and < 75, ≥75)
•
Gender (Male, Female)
•
Race (White, Black, Asian, and Other) 
•
Region (US/Canada, Europe, Rest of the World)
•
ECOG PS (0/1)
•
Time from initial disease diagnosis to study entry (<= 1 year, > 1 year) 
•
Prior therapy (surgery, radiotherapy, and systemic cancer therapy)
•
Prior lines of therapy (1, 2, 3, >=4)
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
46
•
Number of prior therapy in metastatic settings (0, >=1)
•
Prior platinum (yes, no) for SCCHN, GYN, cervical, anogenital HPV associated tumors
•
Prior bevacizumab (yes, no) for SCCHN, GYN, cervical, anogenital HPV associated tumors
•
Time from completion of most recent prior regimen to study entry (<= 3, <3 - <=6, <6 - <=9, 
<9 - <=12, >12 months)
•
All lesions (Investigator tumor assessments at Baseline): sites of diseases, number of disease 
sites per subject
•
Target Lesions (Investigator tumor assessments at Baseline): presence of target lesions, site of 
target lesion, sum of diameters of target lesions.
•
Virus status (Positive / Negative) in tumor types (M-3) GYN (cervical, vaginal, and vulva) 
Carcinoma, (MC-2a, MC-2b, MC-exp) Cervical Carcinoma, (MC-3a, MC-3b) Anogenital 
HPV associated tumors (vaginal/vulvar/anal canal/penile), (M-4, MC-4a) Merkel Cell 
Carcinoma and (M-5,MC-5a) Nasopharyngeal Carcinoma (NPC), for which the virus status 
are tested retrospectively. 
7.5.2
Secondary Analyses (Metastatic Cohorts Only)
7.5.2.1
Duration of Response Based on Investigator Assessment
DOR will be summarized for subjects who achieve confirmed PR or CR using the Kaplan-Meier 
product-limit method. Median values of DOR, along with two-sided 95% CI using the log-log 
transformation will also be calculated by cohort. In addition, the percentage of responders still in 
response at different time points (3, 6, and 12 months) will be presented based on the KM plot.
7.5.2.2
Clinical Benefit Rate Based on Investigator Assessment
CBR based on investigator assessment (Per RECIST 1.1) will be summarized by binomial 
response rates and their corresponding two-sided 95% exact CIs using Clopper-Pearson method.
7.5.2.3
Overall Survival
OS curves for each tumor type will be estimated using the Kaplan-Meier (KM) product limit 
method. Median OS and the corresponding two-sided 95% confidence intervals using the log-log 
transformation will be computed. Survival rates at 3, 6, 12, 18, 24, 36, 48, and 60 months will be 
estimated using KM estimates on the OS curve for each tumor type. Minimum follow-up must be 
longer than the time point to generate the rate. Associated two-sided 95% CIs will be calculated.
7.5.2.4
Progression Free Survival
PFS curves for each tumor type will be estimated using the Kaplan-Meier (KM) product limit 
method. Median PFS and the corresponding two-sided 95% confidence intervals using the log-log 
transformation will be computed. Survival rates at 3, 6, 9, 12 months will be estimated using KM 
estimates on the PFS curve for each tumor type. Minimum follow-up must be longer than the time 
point to generate the rate. Associated two-sided 95% CIs will be calculated.
The source of progression (death vs. progression) will be summarized.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
47
The status of subjects who are censored in the PFS Kaplan-Meier analysis will be tabulated using 
following categories:
•
Still on-treatment
•
Received subsequent anti-cancer therapy (stem cell transplant, other)
•
Progression-free in follow-up
•
Off-study (lost to follow-up, withdrew consent, other).
7.5.3
Exploratory Analyses
7.5.3.1
Neoadjuvant Cohort only 
•
The percent change from baseline of immune cells and the percent change from baseline of 
select immune activation/inhibitory molecules of viral-specific T cells in tumor specific 
subsets of treated subjects will be evaluated. Change from baseline will be summarized using 
descriptive statistics (n, mean, standard deviation, median, first and third quartiles, minimum, 
maximum).
•
The following analyses will be conducted for RFS in primary analysis and sensitivity analysis. 
RFS curves for each tumor type will be estimated using the Kaplan-Meier (KM) product limit 
method. Median RFS and the corresponding two-sided 95% confidence intervals using the log-
log transformation will be computed. Survival rates at 3, 6, 9, 12 months will be estimated 
using KM estimates on the RFS curve for each tumor type. Minimum follow-up must be longer 
than the time point to generate the rate. Associated two-sided 95% CIs will be calculated.
Primary RFS analysis should use censoring scheme listed in Table 4.3-1. Sensitivity RFS 
analysis should use censoring scheme listed in Table 4.3.1-2.
•
The percent change in tumor volume from baseline after two doses of neoadjuvant nivolumab 
will be summarized using descriptive statistics (n, mean, standard deviation, median, first and 
third quartiles, minimum, maximum).
•
Pathological complete response (pCR) rate will be summarized using all treated subjects who 
received surgery by a binomial response rate. The Clopper-Pearson method will be used to 
estimate the two-sided 95% confidence intervals. Summary of continuous % residual viable 
tumor (%RVT) results will be provided descriptively if the data is available. 
7.5.3.2
Metastatic Cohorts only 
•
Change in EBV DNA levels in subjects with EBV positive gastric cancer (monotherapy only)
and nasopharyngeal carcinoma will be summarized using descriptive statistics (n, mean, 
standard deviation, median, first and third quartiles, minimum, maximum).
7.5.4
Interim Analyses
Under the circumstance that data of some tumor types mature faster than others or a strong signal 
is observed in some tumor types, interim analyses may be performed prior to the completion of 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
48
the study in order to facilitate program decisions and to support presentations or publication. These 
interim analyses will not impact the study duration and the trial will continue as planned.
7.6
Safety
For all safety related analyses, refer to the Core Safety SAP6. Safety will be summarized for: all 
treated, by tumor type; all dose escalation subjects, by tumor type.
7.6.1
Deaths
See Core Safety SAP. 
7.6.2
Serious Adverse Events
See Core Safety SAP. 
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP. 
7.6.4
Adverse Events Leading to Dose Delay of Study Therapy
See Core Safety SAP. 
7.6.5
Adverse Events
See Core Safety SAP. 
7.6.6
Select Adverse Events
See Core Safety SAP. 
7.6.7
Immune Modulating Medication
See Core Safety SAP.
7.6.8
Multiple Events
See Core Safety SAP. 
7.6.9
Clinical Laboratory Evaluations
7.6.9.1
Hematology
See Core Safety SAP. 
7.6.9.2
Serum Chemistry
See Core Safety SAP.
7.6.10
Immunogenicity
Immunogenicity data generated from this study may be combined with data from other studies 
to further explore the incidence of immunogenicity following administration of nivolumab as 
monotherapy or in combination with ipilimumab, relatlimab or daratumumab. Selected serum
samples may be analyzed by an exploratory method that measures anti-nivolumab, anti-
ipilimumab, anti-BMS-986016 (relatlimab), or anti-daratumumab antibodies. Please also see 
section 7.8. These analyses, if conducted, will be reported separately. Immunogenicity will be 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
49
reported for anti-drug antibody (ADA) positive status (such as persistent positive, neutralizing 
positive, only last sample positive, baseline positive and other positive) and ADA negative 
status, relative to baseline, by cohort and treatment, if applicable. Further details on 
immunogenicity background and rationale, definitions, population for analyses and endpoints 
are described in Core Safety SAP.
7.6.11
Vital Signs and Pulse Oximetry
See Core Safety SAP. 
7.7
Pregnancy
See Core Safety SAP. 
7.8
Pharmacokinetics
The nivolumab, ipilimumab, relatlimab, or daratumumab concentration data obtained in this study 
may be combined with data from other studies in the clinical development program to develop a 
population PK model. This model may be used to evaluate the effects of intrinsic and extrinsic 
covariates on the PK of respective drug. Immunogenicity data generated from this study may also 
be added as one of the covariates of the model. In addition, exposure-response analyses with 
selected efficacy and safety endpoints may be conducted. Results of population PK and exposure 
response-analyses, if conducted using the concentration data (for nivolumab, ipilimumab, 
relatlimab, or daratumumab) from this study, will be reported separately. 
7.9
Biomarkers
Analyses for PD-L1 and virus status are described below. Methodology for biomarkers other than 
PD-L1 and virus status will be detailed in a separate biomarker SAP. 
7.9.1
PD-L1 Expression at baseline subgroups
The following PD-L1 expression subgroups will be considered by tumor type.
For TPS:
•
Each baseline quantifiable PD-L1 expression status subgroup:
−
PD-L1 ≥ X%
−
PD-L1 < X%
−
Where X% is predefined as 1% and 5% if not otherwise specified.
•
Baseline PD-L1 expression not evaluable or indeterminate subgroup.
•
Baseline PD-L1 expression not reported.
For CPS:
•
Each baseline quantifiable CPS status subgroup:
−
CPS ≥ X
−
CPS < X
−
Where X is predefined as 1 and 10 if not otherwise specified.
•
Baseline CPS not evaluable or indeterminate subgroup.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
50
•
Baseline CPS not reported.
7.9.1.1
Analysis Methods
Analyses of PD-L1 will include:
•
Examine the distribution of TPS and CPS
•
Assess potential associations between TPS or CPS and efficacy measures
7.9.1.2
Distribution of PD-L1 Expression
Descriptive statistics of PD-L1 expression and PD-L1 status (for both TPS and CPS) will include:
•
Listing of all PD-L1 IHC data using all PD-L1 tested subjects.
•
Summary of tumor specimen acquisition and characteristics using all treated and PD-L1 tested
subjects.
•
Summary statistics of PD-L1 expression by tumor type using all treated and PD-L1 tested
subjects.
•
Waterfall plot of PD-L1 expression at baseline by tumor type using all treated and PD-L1 tested 
subjects.  
•
Frequency of PD-L1 expression status by tumor type using all treated and PD-L1 tested 
subjects, including indeterminate and not evaluable if over 5% of subjects in the population 
fall in this category.
7.9.1.3
Association Between PD-L1 Expression and Efficacy Measures
Analyses will be performed using all treated and PD-L1 tested subjects, if not otherwise specified, 
for the followings: 
•
BOR, PFS, OS, DOR and pCR will be summarized using frequency and percentage for each 
tumor type, by baseline PD-L1 status (both TPS and CPS). Objective response rate and 
pathologic complete response rate, with exact 95% CIs will be computed using the Clopper-
Pearson method.
•
Box plots of PD-L1 expression versus response status will be generated for each tumor type
using all PD-L1 evaluable subjects.
•
Waterfall plot of best reduction from baseline target lesion will be generated for each tumor 
type by PD-L1 status (both TPS and CPS) at baseline using all PD-L1 evaluable subjects.
7.9.2
Virus Status
•
The following virus status subgroups will be considered by tumor type for cohorts (N-3) GYN 
(Cervical, vaginal, and vulva) Carcinoma, (N-4) Merkel Cell Carcinoma, (M-3) GYN 
(Cervical, vaginal, and vulva) Carcinoma, (MC-2a, MC-2b, MC-exp) Cervical Carcinoma, 
(MC-3a, MC-3b) anogenital HPV associated tumors (vaginal/vulvar/anal canal/penile), (M-
4, MC-4a) Merkel Cell Carcinoma and (M-5,MC-5a) Nasopharyngeal Carcinoma (NPC), for 
which the virus status are tested retrospectively. .
•
Virus status tested
−
Virus positive
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
51
−
Virus negative
•
Virus status not tested
7.9.2.1
Association Between Virus Status and Efficacy Measures
•
BOR, PFS, OS, DOR and pCR will be summarized using frequency and percentage for each 
tumor type, by virus status. Objective response rate and pathologic complete response rate, 
with exact 95% CIs will be computed using the Clopper-Pearson method.
•
Waterfall plot of best reduction from baseline target lesion will be generated for each tumor 
type by virus status.
7.10
Outcome Research Analyses
7.10.1
EORTC-QLQ-C30 
Unless otherwise specified, the analysis of EORTC QLQ C-30 will be performed in all treated 
subjects who have an assessment at baseline and at least one subsequent assessment. Analyses will 
be performed by tumor type.
Baseline measures will be summarized using descriptive statistics (n, mean, standard deviation, 
95% confidence intervals, median, first and third quartiles, minimum, maximum) for each scale, 
based on subjects with a baseline measurement.
Change from baseline will be summarized using descriptive statistics (n, mean, standard deviation, 
95% confidence intervals, median, first and third quartiles, minimum, maximum) for each scale at 
each assessment time point. In addition, the percentage of subjects demonstrating a clinically 
meaningful deterioration (defined as a 10-point change from baseline) will be presented for each 
scale at each assessment timepoint. Percentages will be based on number subjects assessed at 
baseline and at assessment time point.
For all assessment timepoints, mean scores and mean score changes from baseline (n, mean, 
standard deviation, 95% confidence intervals, median, 25th and 75th percentiles, minimum, 
maximum) will be reported.
EORTC-QLQ-C30 questionnaire completion rate is defined as the proportion of subjects who 
answered the questionnaires out of number subjects assessed at assessment time 
point. Completion rate will be calculated and summarized for each assessment time point.
A by subject listing of QLQ-C30 with each QLQ-C30 item, functional scales, symptoms scales 
and global health status will be provided.
7.10.2
EuroQol EQ-5D
Unless otherwise specified, the analysis of EQ-5D7 will be performed in all treated subjects who 
have an assessment at baseline and at least one subsequent assessment. Analyses will be performed 
by tumor type.
Subject’s overall health state on a visual analog scale (EQ-VAS) and EQ-5D index using UK 
weighting algorithm at each assessment time point will be summarized using descriptive statistics 
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
52
(n, mean, standard deviation, 95% confidence intervals, median, 25th and 75th percentiles, 
minimum, maximum).
Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment time 
point will be summarized by level of problem. Percentages will be based on number subjects 
assessed at assessment time point.
For all assessment timepoints, mean scores and mean score changes from baseline (n, mean, 
standard deviation, 95% confidence intervals, median, 25th and 75th percentiles, minimum, 
maximum) will be reported.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, self-
care, usual activities, pain/discomfort and anxiety/depression), health state (5 dimensions digits 
combined in a 5-digit number), EQ-5D index using UK weighting algorithm and EQ-VAS will be 
provided. 
More results of EQ-5D-Index will be presented separately and will be described in the WWHEOR 
SAP.
7.11
End of Study Analyses at Study Closure
Subjects who remaining on study treatment following primary analysis will be followed for safety 
as defined in the protocol. The end of study analyses will be performed for the selected safety data 
and the duration of treatment using all enrolled subjects.
The following data will be reported:
•
Subject disposition
•
Duration of treatment
•
Death
•
Adverse events
•
Serious adverse events
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 Specification8. Missing and partial Non-Study Medication Domain 
dates will be imputed using the derivation algorithm described in 4.3.3 of BMS Non-Study 
Medication Domain Requirements Specification9.
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 date alive   day and the maximum 
will be considered as the death date.
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
53
•
If the month or the year is missing, the death date will be imputed as the last known date alive 
day
•
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 day
For date of progression, 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.
*In cases where 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.
For other partial/missing dates, the following conventions may be 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 from first diagnosis to first dosing date, duration of response, and time to 
response) will be calculated as follows:
                       Duration = (Last date - first date + 1)
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 described in this SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables and listings.
10
REFERENCES
1
Core Safety Statistical Analysis Plan for CA209 v4, Bristol-Myers Squibb.
2
Aaronson N.K., Ahmedzai S., et al. The European Organisation for Research and Treatment 
of Cancer QLQ-30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst, 85: 365-376, 1993.
3
Greenwood, M. The errors of sampling of the survivorship tables, Reports on Public Health 
and Statistical Subjects, 33, Appendix 1, HMSO, London, 1926
Approved
4.0
v
Approved
1.0
v


Statistical Analysis Plan
CA209358
BMS-936558
nivolumab
54
4
Kalbfleisch, J. D. and Prentice, R. L. (1980), The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons.
5
Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 26: 404-423, 1934.
6    Core Safety Statistical Analysis Plan for CA209, Bristol-Myers Squibb.
7
Dolan P. Modeling valuations for EuroQol health states. Medical Care 1997;35: 1095-1108
7 Adverse Event Domain Requirements Specification. Bristol-Myers Squibb Co. PRI. Version 
2.1. April 23, 2012.
8
Non-Study Medication Domain Requirements Specification. Bristol-Myers Squibb Co. PRI. 
Version 2.2 April 24, 2012.
Approved
4.0
v
Approved
1.0
v