Clinical trial NCT01714739
Conditions: CANCER,NOS
Sponsor: Bristol-Myers Squibb
Start date: 2012-10-07; Completion date: 2019-12-13
Enrollment: 337 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the safety and tolerability and preliminary anti-tumor activity of lirilumab (BMS-986015) given in combination with nivolumab (BMS-936558) and to identify dose limiting toxicities (DLTs) and the maximally tolerated dose (MTD) of the combination. In addition, to assess the combinations of lirilumab and nivolumab or lirilumab and nivolumab plus ipilimumab (BMS-734016) in subjects with advanced (metastatic and/or unresectable) refractory solid tumors.

Detailed description:

Arms: arm 1: Dose Escalation and Initial Signal Detection in Multiple Solid Tumors - Nivolumab with Lirilumab arm 2: In platinum-refractory recurrent or metastatic SCCHN - Nivolumab with or without Lirilumab arm 3: Additional Signal Detection in Solid Tumors - Nivolumab with Lirilumab (Study Part 4 Removed; No Subjects Enrolled) arm 4: Safety Lead-In and Additional Signal Detection in Solid Tumors -- Nivolumab Plus Ipilimumab with Lirilumab (Study Part 6 Removed; No Subjects Enrolled)
Interventions: intervention 1: Lirilumab intervention 2: Nivolumab intervention 3: Ipilimumab
Intervention descriptions: intervention 1: Specified dose on specified days. intervention 2: Specified dose on specified days. intervention 3: Specified dose on specified days.

Protocol documents:
Prot_000.pdf: 
Official Title of Study: 
A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or Lirilumab 
Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors 
NCT Number: NCT01714739 
Document Date (Date in which document was last revised): May 8, 2018 


Page:
1
Protocol Number:
CA223001
IND Number:
115,879
EUDRACT Number
2016-001359-36
Date:
11-Jun-2012
Revised Date:
08-May-2018
Clinical Protocol CA223001
A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or 
Lirilumab Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors
Revised Protocol Number: 12
Incorporates Administrative Letters 04 & 05
Study Director
Medical Monitor
Telephone (office): 
Telephone (office): 
Fax: 
Fax: 
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
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.
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Revised Protocol No.: 12
2
Date: 08-May-2018
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
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Revised Protocol No.: 12
3
Date: 08-May-2018
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 12
08-May-2018
The primary purpose of this revised protocol is to close the future 
enrollment in Part 3 and Part 5 and removal of Part 4 and Part 6 from the 
protocol study design. Additional revisions based on the lack of clear 
evidence of clinical benefit will include removal of overall survival visits 
for all subjects, additional subjects entering treatment beyond 
progression, retreatment at the time of disease progression as well as 
select sample collection and study visits.
Administrative 
Letter 05
30-Aug-2017
Medical Monitor update
Administrative 
Letter 04
30-May-2017
Medical Monitor and Study Director update
Revised 
Protocol 11
28-Feb-2017
Incorporates Amendment 15
Amendment 15
28-Feb-2017
Updated the cohort size and subject allocation for the Signal Detection 
Cohort Expansion (Part 4) and the cohort size, randomization scheme, 
treatment regimen, and inclusion criteria for the Signal Detection in 
Squamous Cell Carcinoma of the Head and Neck (SCCHN) with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5).
Throughout the protocol, administrative changes, clarifications and 
typographical corrections, and updates for consistency were made.
Revised 
Protocol 10
12-Dec-2016
Incorporates Amendment 13
Amendment 13
12-Dec-2016
Indicated that the Dose Escalation and Cohort Expansion (Part 1) and the 
SCCHN Cohort Expansion (Part 2) have both completed enrollment and 
are not applicable starting with Amendment 13 and all subsequent 
amendments and that their specific eligibility criteria are not applicable. 
Added 4 new study parts:
•
The SCCHN Randomized Cohorts (Part 3)
•
The Signal Detection Cohort Expansion (Part 4)
•
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5)
•
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Updated for all new cohorts listed above, including updates to study 
rationale, background, safety text, eligibility criteria, study objectives, 
study design, discontinuation criteria, and statistical analyses. Added that 
enrollment for the SCCHN Cohort Expansion (Part 2) will stop when the 
SCCHN Randomized Cohorts (Part 3) open. Clarified that subjects on 
nivolumab will be allowed to continue study therapy after initial 
investigator-assessed Response Evaluation Criteria in Solid Tumors 
version 1.1 defined progression if they are assessed to be deriving 
clinical benefit and tolerating study drug. Aligned applicable text to 
current Bristol-Myers Squibb (BMS) standards. Aligned introductory and 
product development background sections to current Investigator’s 
Brochures. Updated relevant text from the Dose Escalation and Cohort 
Expansion (Part 1; completed) and The SCCHN Cohort Expansion 
(Part 2; completed) per recent clarification that lirilumab dosing should 
begin 30 minutes after dosing of nivolumab and moved order of infusion 
text into Section 4.1, Study Treatments. Added new headings or 
reorganized sections of text related to the Dose Escalation and Cohort 
Expansion (Part 1; completed) and the SCCHN Cohort Expansion 
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Revised Protocol No.: 12
4
Date: 08-May-2018
Document
Date of Issue
Summary of Change
(Part 2; completed) for clarification. Removed sentence stating subjects 
who have received nivolumab are not eligible to enroll (maintained 
exclusion for subjects in any prior clinical study with ipilimumab or 
nivolumab). Clarified that biopsy sites no longer need to be distinct from 
evaluable lesions. Clarified which parts of the study may have an interim 
analysis done. Added “and suggest preliminary signs of clinical activity” 
to the hypothesis. For all study parts, Vz will be used instead of Vss. 
Throughout the protocol, administrative changes, clarifications and 
typographical corrections, and updates for consistency were made.
Revised 
Protocol 09
29-Jul-2016
Incorporated Amendment 12
Amendment 12
29-Jul-2016
Added 150-day follow-up
Revised
Protocol 08
22-Jul-2016
Incorporates Amendment 11
Amendment 11
22-Jul-2016
Updated statistical language for SCCHN Expansion Cohort (Part 2),
Updated WOCBP, Updated management algorithms in Appendix 3.
Revised 
Protocol 07
12-Apr-2016
Incorporates Amendment 10
Amendment 10
12-Apr-2016
Added European Union Drug Regulating Authorities Clinical Trials 
(EUDRACT) Number, updated protocol title, added BMS Belgium 
address, updated objectives, updated hepatitis language, moved male 
condoms and spermicide to Less Effective Methods of Contraception, 
updated Table 5.7d, updated statistical sections, updated Appendix 1. 
Revised 
Protocol 06
11-Jan-2016
Incorporates Amendment 09
Amendment 09
11-Jan-2016
Correction to Inclusion Criteria (Target Population) numbering/lettering.
Revised 
Protocol 05
02-Nov-2015
Incorporates Amendment 07
Amendment 07
02-Nov-2015
The purpose of this amendment is to add additional subjects to the 
SCCHN cohort in order to further explore the safety and efficacy of the 
compound. Some administrative corrections were also updated.
Revised 
Protocol 04
24-Jul-2014
Incorporates Amendment 06
Amendment 06
24-Jul-2014
Updated inclusion and exclusion criteria, clarification of diagnostic 
imaging scan criteria and collection timelines, and addition of 
pharmacokinetic anti-killer cell immunoglobulin-like receptors (KIR), 
pharmacokinetic anti-programmed cell death 1 (PD-1), anti-drug-
antibody (ADA) anti-KIR, and ADA anti-PD-1 collection points.
Revised 
Protocol 03
06-Feb-2014
Incorporates Amendment 05
Amendment 05
06-Feb-2014
Updated safety information for nivolumab and lirilumab. In the dose 
escalation cohorts, increased the number of subjects that may be enrolled 
at each Dose Level from 12 to 15 in order to obtain additional data. 
Additional tumor types of SCCHN and hepatocellular carcinoma added 
to dose cohort expansions. The colorectal cancer cohort was modified to 
enroll only subjects with non-microsatellite-instability-high tumors. 
Gehan 2-stage approach for efficacy assessment of these tumor types 
added. Cohort expansions of ovarian and renal cell carcinoma deleted. 
Expanded the biomarker collection to the head and neck dose cohort 
expansion. Inclusion criteria for all cohort expansions updated. Increased 
number of subjects in non-small cell lung cancer and melanoma cohorts. 
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Revised Protocol No.: 12
5
Date: 08-May-2018
Document
Date of Issue
Summary of Change
Updates to vital sign assessments, clarifications of efficacy criteria, and 
ADA endpoints were added. Rationale for circulating tumor DNA 
analysis and assessment schedule added.
Revised 
Protocol 02
08-Apr-2013
Incorporates Amendment 04
Amendment 04
08-Apr-2013
Updated generic drug names to lirilumab for BMS-986015 and 
nivolumab for BMS-936558. Revised contraception requirements for 
Appendix 1. New laboratory requirements for after Cycle 1 Day 1. 
Revised 
Protocol 01
04-Sep-2012
Incorporates Amendment 03
Amendment 03
04-Sep-2012
Revised dose escalation design 3 + 3 + 3. Revised permanent 
discontinuation criteria (Section 4.9.4). Revised eligibility to require 
subjects to have normal thyroid function and at least 1 prior therapy in 
the advanced/metastatic setting.
Original 
Protocol
11-Jun-2012
Not applicable.
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
OVERALL RATIONALE FOR REVISED PROTOCOL 12:
The primary purpose of this revised protocol is to close the future enrollment in Part 3 and Part 5 
and removal of Part 4 and Part 6 from the protocol study design. At the time of Amendment 13, 
preliminary data from an initial cohort of subjects in this study suggested a signal of potential 
efficacy (ORR of 24% [7/29]) in recurrent or metastatic SCCHN subjects with disease progression 
on or after platinum-based therapy. Subsequent efficacy analysis of additional SCCHN subjects 
treated with the combination of lirilumab and nivolumab did not demonstrate a differential efficacy 
signal as compared to nivolumab monotherapy treatment in a similar population of SCCHN 
subjects. Therefore, with Revised Protocol 12, enrollment in Parts 3 and 5 is closing and Parts 4 
and 6 are removed from the protocol. As the combination of lirilumab and nivolumab continues to 
be well tolerated, individual subjects who continue to have clinical benefit with the combination 
of lirilumab and nivolumab without an increase in adverse events will be permitted to remain on 
study treatment until protocol-specified discontinuation criteria are met. 
Additional revisions based on the lack of a differential efficacy signal will include removal of 
overall survival visits for all subjects, additional subjects entering treatment beyond progression,
retreatment at the time of disease progression as well as select sample collection and study visits.
Subjects will be permitted up to a maximum of 2 years of treatment as specified in the individual 
study parts.
Sections in the synopsis have been updated to align with the protocol section changes listed 
below.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
Section 1.2.3, The Signal Detection Cohort 
Expansion (Part 4); Section 1.2.5, The 
Signal Detection in Previously Untreated 
MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6); Section 
1.3.1.3, Primary Objective for the Signal 
Detection Cohort Expansion (Part 4); 
Section 1.3.1.5, Primary Objective for the 
Signal Detection in Previously Untreated 
MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6); Section 
1.3.2.3, Secondary Objectives for the 
Signal Detection Cohort Expansion (Part 
4); Section 1.3.2.5, Secondary Objectives 
for the Signal Detection in Previously 
Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 6);
 
Existing text under 
these sections is now 
replaced with a 
statement “Removed 
with Revised protocol 
12” as Part 4 and Part 6 
are no longer part of 
this study.
Existing text under 
these sections is 
removed to reflect the 
modified protocol 
design for the removal 
of Part 4 and Part 6
after implementation 
of this revised 
protocol. 
Revised Protocol No.: 12
Date: 08-May-2018
6
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
 
 
 
 Section 
3.1.4, The Signal Detection Cohort 
Expansion (Part 4); Section 3.1.6, The 
Signal Detection in Previously Untreated 
MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6); Section 
5.1.3, The Signal Detection Cohort 
Expansion (Part 4); Section 8.1.5, The 
Signal Detection Cohort Expansion (Part 
4); Section 8.1.7, The Signal Detection in 
Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 6); Section 8.3.1.3, The Signal 
Detection Cohort Expansion (Part 4); 
Section 8.3.1.5, The Signal Detection in 
Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 6); Section 8.3.2.3, The Signal 
Detection Cohort Expansion (Part 4); 
Section 8.3.2.5, The Signal Detection in 
Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 6); 
 
 
 
 
 
Section 8.4.7, Outcomes Research 
Analyses
Section 1.4.4, Lirilumab: Clinical 
Pharmacology and Safety
Section has been 
updated for number of 
subjects and also 
clarified most common 
related AEs.
The updates were 
made to align with the 
current Lirilumab 
Investigator Brochure.
Revised Protocol No.: 12
Date: 08-May-2018
7
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
Section 1.4.13.2, Rationale for Schedule, 
Dose, and Tumor Types for the SCCHN 
Randomized Cohorts (Part 3 - closed to 
enrollment) and the Signal Detection 
Cohort Expansion (Part 4 - removed): Flat 
Doses; Section 1.4.16, Rationale for Use of 
Blood and Tumor Tissue in Biomarker 
Studies; Section 3.5.1, Treatment Beyond 
Disease Progression; Section 4.1, Study 
Treatments; Section 4.3, Selection and 
Timing of Dose for Each Subject; Section 
4.4, Blinding/Unblinding; Section 4.9.5, 
Guidelines for Permanent Discontinuation; 
Section 5.3.1, Microsatellite Instability 
Testing; Section 5.4, Efficacy 
Assessments;
 
 
 
 Section 8.3, 
Endpoint Definitions; Section 8.4.4, 
Pharmacokinetic Analyses
These sections have 
been updated to remove 
the text related to Part 4 
and Part 6.
Related text for Part 4 
and Part 6 under these 
sections are removed 
to reflect the modified 
protocol design for the 
removal of Part 4 and 
Part 6 after 
implementation of this 
revised protocol.
Section 1.4.19, Rationale for Two Year 
Duration of Treatment
New section added.
New text added to 
provide the rationale 
for limiting treatment 
duration for all study 
parts in the study.
Section 1.5, Overall Risk/Benefit 
Assessment
Modified the text under 
this section to reflect 
the closing of Part 3 
and Part 5 enrollment 
and removal of Part 4 
and Part 6 from the 
protocol.
Existing text in this 
section is updated to 
reflect the modified 
protocol design for
closing future 
enrollment in Part 3 
and Part 5 and 
removal of Part 4 and 
Part 6 after 
implementation of this 
revised protocol.
Revised Protocol No.: 12
Date: 08-May-2018
8
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
Section 3.1, Study Design and Duration; 
Figure 3.1 1: Overall Study Design for All 
Study Arms (Study CA223001)
Modified the text under 
this section to reflect 
the closing of Part 3 
and Part 5 enrollment 
and removal of Part 4 
and Part 6 from the 
protocol.
Study Schema was 
updated.
Existing text and 
figure (study design) 
in this section is 
updated to reflect the 
modified protocol 
design for closing 
future enrollments in 
Part 3 and Part 5 and 
removal of Part 4 and 
Part 6 after 
implementation of this 
revised protocol.
Section 3.1.1, The Dose Escalation and 
Cohort Expansion (Part 1; Completed); 
Section 3.1.2, The SCCHN Cohort 
Expansion (Part 2; Completed); Section 
3.1.5, The Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed 
to enrollment)
Text regarding 
retreatment at the time 
of disease progression 
during the follow-up 
periods was removed. 
Revision was made to 
remove the 
retreatment option 
based on the lack of a 
differential efficacy 
signal. 
Section 3.1.1, The Dose Escalation and 
Cohort Expansion (Part 1; Completed); 
Figure 3.1.1-1: Study Period Schematic for 
the Dose Escalation and Cohort Expansion 
(Part 1; Completed); Section 3.1.2, The 
SCCHN Cohort Expansion (Part 2; 
Completed); Figure 3.1.2 1: Study Period 
Schematic for Part 2 (Completed); Section 
3.1.3, The SCCHN Randomized Cohorts 
(Part 3 closed to enrollment); 
Figure 3.1.3-2: Study Period Schematic for 
the SCCHN Randomized Cohorts (Part 3); 
Section 3.1.5, The Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed 
to enrollment); Figure 3.1.5 2: Study 
Period Schematic for the Signal Detection 
in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5); 
Section 3.7, Post-treatment Study Follow-
up
Added a statement to 
indicate that survival 
follow-up no longer 
applicable after 
implementation of this 
revised protocol 12. 
Revision was made to 
remove the overall 
survival visits for all 
subjects based on the 
lack of a differential 
efficacy signal. 
Revised Protocol No.: 12
Date: 08-May-2018
9
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
Section 3.5.1, Treatment Beyond Disease 
Progression
Added statement: 
“With Revised Protocol 
12, no additional 
subjects are permitted 
to enter Treatment 
Beyond Disease 
progression. At the 
time of initial 
progressive disease, 
subjects will be 
required to discontinue 
study treatment and 
enter clinical follow-
up”
The statement was 
added to reflect the 
modified protocol 
design upon approval 
of this revised 
protocol.
Section 5.3 Safety Assessments; Tables 
Table 5.1.1 2: On-treatment Procedural 
Outline the Dose Escalation and Dose 
Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; 
Completed) (CA223001); Table 5.1.1 3: 
Follow-up Procedural Outline the Dose 
Escalation and Dose Expansion (Part 1; 
Completed) and the SCCHN Cohort 
Expansion (Part 2; Completed) 
(CA223001); Table 5.1.2 2: On-treatment 
Procedural Outline the SCCHN 
Randomized Cohorts (Part 3 - closed to 
enrollment) (CA223001); Table 5.1.2 3:
Follow-up Procedural Outline the SCCHN 
Randomized Cohorts (Part 3-closed to 
enrollment) (CA223001); Table 5.1.4 2:
On-treatment Procedural Outline the Signal 
Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 5 - closed to enrollment) 
(CA223001); Table 5.1.4 3: Follow-up 
Procedural Outline the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed 
to enrollment) (CA223001)
Added clarification 
statement indicating 
non-serious AEs will 
also be collected until 
the start of subsequent 
anti-cancer therapy. 
The statement was 
added to discontinue 
AE collection at the 
start of subsequent 
anti-cancer therapy.
Revised Protocol No.: 12
Date: 08-May-2018
10
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
Section 5.6, Biomarker Assessments; Table 
5.7.3.3 4: Biomarker Assessment 
Schedule: the SCCHN Cohort Expansion 
(Part 2; completed); 
 
 
Table 5.7.3.3 7: 
Pharmacokinetics, Immunogenicity, and 
Biomarker Assessment Schedule: the 
Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5 - closed for 
enrollment) and in the Signal Detection in 
Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 6 - removed)
Added statement that 
no further biomarker 
samples are to be 
collected upon 
implementation of this 
revised protocol 12. 
The statement was 
added to reflect the 
modified protocol 
design upon approval 
of this revised 
protocol.
Section 5.7.3.3, Pharmacokinetics, 
Immunogenicity (Anti-drug antibodies) 
and Biomarker Assessment Schedules; 
Table 5.7.3.3 4: Biomarker Assessment 
Schedule: the SCCHN Cohort Expansion 
(Part 2; completed); 
 
 
Table 5.7.3.3 7: 
Pharmacokinetics, Immunogenicity, and 
Biomarker Assessment Schedule: the 
Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5 - closed for 
enrollment) and in the Signal Detection in 
Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination 
(Part 6 - removed)
Added statement “PK 
and ADA samples will 
continue to be collected 
but will not be 
analyzed except as 
clinically indicated in 
specific cases such as 
Grade 3/4 toxicity, 
infusion reactions, etc.”
Clarification statement 
was added.
Section 5.8, Outcomes Research 
Assessments
Added statement that 
no additional quality of 
life questionnaire 
(QLQ) are to be 
collected upon 
The statement was 
added to reflect the 
modified protocol 
design upon approval 
of this revised 
protocol.
Revised Protocol No.: 12
Date: 08-May-2018
11
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12
Section Number & Title
Description of Change
Brief Rationale
implementation of this 
revised protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
12
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
SYNOPSIS
Clinical Protocol CA223001
Title of Study: Protocol CA223001: A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab
(Anti-PD-1) or Lirilumab Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors
Investigational Product(s), Dose and Mode of Administration, and Duration of Treatment with Investigational
Product(s): Subjects will receive intravenous (IV) doses of lirilumab (BMS-986015) every 4 weeks (Q4W),
nivolumab (BMS-936558) every 2 weeks (Q2W), ipilimumab (BMS-734016) every 6 weeks (Q6W), and/or placebo
for lirilumab Q4W until the end of the defined treatment period for the applicable study part.
Study Phase: 1/2
Research Hypothesis:
Please note that the Dose Escalation and Cohort Expansion (Part 1) and the Squamous Cell Carcinoma of the Head 
and Neck (SCCHN) Cohort Expansion (Part 2) have both completed enrollment and not applicable starting with 
Amendment 13 and all subsequent amendments or revised protocols. For preliminary safety and efficacy results, see 
Section 1 “Clinical Experience with Lirilumab and Nivolumab Combination Treatment” of the protocol body. With 
Revised Protocol 12, Parts 3 and 5 are closed to enrollment and Parts 4 and 6 are removed.
•
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the SCCHN Cohort Expansion 
(Part 2; Completed): It is anticipated that the combination of anti-killer cell immunoglobulin-like receptors
(KIR) antibody (lirilumab) and anti-programmed cell death 1 (anti-PD-1) antibody (nivolumab) will demonstrate
adequate safety and tolerability at pharmacologically relevant doses and suggest preliminary signs of clinical 
activity so as to permit further clinical testing.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment): It is anticipated that treatment with 
nivolumab alone or in combination with lirilumab will lead to clinically meaningful tumor reductions, as 
measured by objective response rate (ORR), in subjects with platinum-refractory recurrent or metastatic SCCHN
who are programmed cell death ligand 1-positive (PD-L1+) (PD-L1+ is defined as PD-L1 expressed in ≥1% of 
tumor cells).
•
The Signal Detection Cohort Expansion (Part 4): Removed with Revised Protocol 12.
•
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed 
to enrollment): It is anticipated that the triplet regimen of anti-KIR antibody (lirilumab), anti-PD-1 antibody 
(nivolumab), and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody (ipilimumab) to treat subjects with 
platinum-refractory recurrent or metastatic SCCHN will demonstrate adequate safety and tolerability at 
pharmacologically relevant doses for further clinical testing.
•
The Signal Detection in Previously Untreated Metastatic Melanoma (MEL) with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 6): Removed with Revised Protocol 12.
Primary Objective:
•
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the SCCHN Cohort Expansion 
(Part 2; Completed): To assess the safety and tolerability of lirilumab given in combination with nivolumab and 
to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of the combination in subjects 
with advanced (metastatic and/or unresectable) solid tumors. To assess the safety and preliminary anti-tumor 
activity of the combination of lirilumab and nivolumab in subjects with advanced solid tumors.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment): To estimate the ORR of lirilumab given in 
combination with nivolumab in subjects with recurrent or metastatic SCCHN that has relapsed or progressed 
within 6 months of the last dose of a platinum-containing therapy and whose tumors express PD-L1.
•
The Signal Detection Cohort Expansion (Part 4): Removed with Revised Protocol 12. 
•
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed 
to enrollment): To assess the safety and preliminary anti-tumor activity of the combination of lirilumab with 
nivolumab and ipilimumab in subjects with platinum-refractory recurrent or metastatic SCCHN.
•
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6): Removed with revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
13
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Secondary Objective(s):
•
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the SCCHN Cohort Expansion (Part 
2; Completed)
−
To characterize the pharmacokinetics (PK) of lirilumab and nivolumab when co-administered.
−
To monitor immunogenicity of lirilumab and nivolumab when administered as combination therapy.
−
To assess the pharmacodynamic effect in tumor tissue on tumor-infiltrating lymphocyte (TIL) subsets from 
MEL and SCCHN subjects treated with lirilumab given in combination with nivolumab.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)
−
To estimate disease control rate (DCR), duration of response (DOR), and time to response of lirilumab given 
in combination with nivolumab.
−
To assess depth of response of lirilumab given in combination with nivolumab and of nivolumab 
monotherapy.
−
To assess the overall survival (OS) of lirilumab given in combination with nivolumab and nivolumab 
monotherapy. 
−
To assess the progression-free survival (PFS) of lirilumab given in combination with nivolumab and
nivolumab monotherapy.
−
To estimate the ORR by investigator assessment of lirilumab given in combination with nivolumab and 
nivolumab monotherapy.
−
To assess the safety of lirilumab given in combination with nivolumab in subjects with SCCHN.
•
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12
•
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed 
to enrollment)
−
To estimate DOR of lirilumab given in combination with nivolumab and ipilimumab. 
−
To assess depth of response of lirilumab given in combination with nivolumab and ipilimumab. 
−
To characterize the PK and immunogenicity of lirilumab in combination with nivolumab and ipilimumab.
−
To investigate the immunomodulatory properties of lirilumab in combination with nivolumab and 
ipilimumab, and to evaluate potential baseline and on-treatment biomarkers in peripheral blood and tumor 
for association with efficacy in subjects with platinum-refractory recurrent or metastatic SCCHN.
−
To explore biomarkers of lirilumab in combination with nivolumab and ipilimumab in subjects with 
platinum-refractory recurrent or metastatic SCCHN.
•
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6)
Removed with Revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
14
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
•
Primary Endpoints:
•
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the SCCHN Cohort Expansion 
(Part 2; Completed):
−
The primary endpoints are safety measures (the Dose Escalation and Cohort Expansion [Part 1] the SCCHN 
Cohort Expansion [Part 2]), and assessment of preliminary anti-tumor activity (for the SCCHN Cohort 
Expansion [Part 2]).
♦
For the SCCHN Cohort Expansion (Part 2), assessment of preliminary anti-tumor activity will be based 
on using immune-mediated Response Evaluation Criteria in Solid Tumors (irRECIST) for the purposes 
of subject management. Timepoint tumor response evaluations will be recorded on the case report form 
(CRF) based on investigators’ assessments using irRECIST criteria. Statistical analysis and reporting 
will be based primarily on RECIST v1.1 criteria.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment):
−
The primary endpoint is ORR in subjects randomized to lirilumab plus nivolumab.
♦
Tumor assessments are scheduled to be performed at Week 8 (± 7 days) from first dose date, every 
8 weeks (Q8W; ± 7 days) until Week 48, and then every 12 weeks (Q12W; ± 7 days) until progressive 
disease (PD) or treatment discontinuation, whichever occurs earlier.
Revised Protocol No.: 12
Date: 08-May-2018
15
Approved
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Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
•
The Signal Detection Cohort Expansion (Part 4):
Removed with Revised Protocol 12. 
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed 
to enrollment):
−
The primary endpoints are safety measures and assessment of preliminary anti-tumor activity.
♦
The assessment of preliminary anti-tumor activity will be based on using RECIST v1.1. Timepoint tumor 
response evaluations will be recorded on the CRF based on investigators’ assessments using RECIST 
v1.1 criteria. Statistical analysis and reporting will be based primarily on RECIST v1.1 criteria. 
Investigator-assessed BOR based on RECIST v1.1 will be listed.
•
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6) :
Removed with revised Protocol 12.
•
Secondary Endpoints:
•
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the SCCHN Cohort Expansion 
(Part 2; Completed):
−
The secondary endpoints are PK, anti-drug antibodies [ADAs], and biomarkers.
♦
The secondary endpoint of occurrence of specific ADAs to lirilumab and nivolumab will be determined 
from measurements on Weeks 1, 3, 5, 13, 17, 33, 49, 65, and 81; end of treatment; and all 3 clinical 
follow-up visits (please see Table 5.7.3.3-1, Table 5.7.3.3-2, Table 5.7.3.3-3, and Table 5.7.3.3-4 in the 
protocol body).
♦
Biomarker endpoint measures will be taken from a minimum of 10 MEL cohort expansion subjects and 
a minimum of 10 SCCHN (the Dose Escalation and Dose Expansion [Part 1; completed]) cohort 
expansion subjects or other additional subjects included in the biomarker analysis data sets. 
♦
Biomarker endpoint measures will be taken from a minimum of 15 subjects in the SCCHN Cohort 
Expansion (Part 2) or other additional subjects included in the biomarker analysis data sets.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment):
−
The secondary endpoints are DCR, DOR, time to response, depth of response, OS, PFS, ORR by investigator 
assessment, and safety measures.
♦
Tumor assessments are scheduled to be performed at Week 8 (± 7 days) from first dose date, Q8W
(± 7 days) until Week 48, and then Q12W (± 7 days) until PD or treatment discontinuation, whichever 
occurs earlier.
•
The Signal Detection Cohort Expansion (Part 4):
−
Removed with revised Protocol 12.
•
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed 
to enrollment):
−
The secondary endpoints are DOR, depth of response, PK, ADAs, immunomodulatory properties, and 
biomarkers.
♦
Tumor assessments are scheduled to be performed at Week 8 (± 7 days) from first dose date, Q8W 
(± 7 days) for 1 year (48 weeks), and then Q12W (± 7 days) until PD or treatment discontinuation, 
whichever occurs earlier.
♦
The secondary endpoint of occurrence of specific ADAs to lirilumab, nivolumab, and ipilimumab, will 
be determined from measurements specified in Table 5.7.3.3-7 of the protocol body).
♦
Biomarker endpoint measures will be included from all subjects in the biomarker analysis data sets.
•
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6):
Removed with revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
16
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Study Design:
This is a Phase 1/2 study that will be conducted in 6 parts. 
•
Part 1 (completed): The Dose Escalation and Cohort Expansion of the study will consist of a dose escalation 
assessment of the safety and tolerability of lirilumab administered in combination with nivolumab in subjects 
with advanced solid tumors and 5 cohort expansions at either the MTD, maximum administered dose (MAD), or 
at an alternative dose as determined by the investigators and the Sponsor. 
•
Part 2 (completed): The SCCHN Cohort Expansion will be an additional cohort expansion at Dose Level 4 in 
subjects with platinum-refractory recurrent or metastatic SCCHN. The SCCHN Cohort Expansion (Part 2) of this 
study will close to enrollment as the SCCHN Randomized Cohorts (Part 3) open.
•
Part 3 (closed to enrollment): The SCCHN Randomized Cohorts will involve a single-blinded, randomized cohort 
expansion of lirilumab in combination with nivolumab vs nivolumab monotherapy in subjects with platinum-
refractory recurrent or metastatic SCCHN who are PD-L1+. 
•
Part 4 (removed): The Signal Detection Cohort Expansion will be an additional cohort expansion of nivolumab 
and lirilumab at a flat dose in subjects with sqNSCLC, ESCC, BC, and other squamous histologies (including 
squamous cell cancers of the skin, cervix, vulva, vagina, penis, anorectal, and of unknown primary site) and in 
subjects with SCCHN who have received prior PD-1/PD-L1 directed therapy.
•
Part 5 (closed to enrollment): The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination will be an open-label safety and signal detection cohort with a triplet regimen of lirilumab in 
combination with nivolumab and ipilimumab in subjects with platinum-refractory recurrent or metastatic 
SCCHN.
•
Part 6 (removed): The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination will be a safety and signal detection cohort with a first-line triplet regimen of lirilumab 
in combination with nivolumab and ipilimumab in subjects with previously untreated metastatic MEL.
Subjects will not be allowed to crossover between any parts or allowed to crossover to other Bristol-Myers Squibb 
studies, including CA209714 and CA209651 for SCCHN. 
Revised Protocol No.: 12
Date: 08-May-2018
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Figure 1:
Overall Study Design for All Study Arms (CA223001)
a Treatment period is until PD, treatment discontinuation, or a maximum of up to 2 years of treatment as specified in 
the individual study parts, whichever occurs earlier.
b Subjects must have PD-L1+ tumors. PD-L1+ is defined as PD-L1 expressed in >1% of tumor cells.
c 150 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug 
(± 5 days) if date of discontinuation of study drug is greater than 150 days after last dose.
d No longer required with Revised Protocol 12.
CRC=colorectal cancer; HCC=hepatocellular carcinoma; R=randomization.
In all parts, subjects will complete up to 4 study periods: Screening (up to 28 days for the Dose Escalation and Cohort 
Expansion [Part 1; completed] and the SCCHN Cohort Expansion [Part 2; completed] and up to 35 days for all other 
study parts), Treatment (as defined below), Clinical follow-up (150 days), Survival follow-up (up to 3 years following 
the first dose of study drug). Survival follow-up is no longer required with Revised Protocol 12 and no further visits 
should be conducted.
The treatment period will last until PD, treatment discontinuation or a maximum of up to 2 years of treatment, as 
specified in the individual study parts whichever occurs earliest. For subjects receiving lirilumab and nivolumab 
combination therapy in the Dose Escalation and Cohort Expansion (Part 1; completed), the SCCHN Cohort Expansion 
(Part 2; completed), and the SCCHN Randomized Cohorts (Part 3; Arm A only), each 8-week treatment cycle is 
composed of 4 doses of nivolumab and 2 doses of lirilumab. Nivolumab will be administered on Days 1, 15, 29, and 
43 of each 8-week treatment cycle, and lirilumab will be administered on Days 1 and 29 of each 8-week treatment 
cycle. For subjects receiving nivolumab monotherapy (Arm B of the SCCHN Randomized Cohorts [Part 3] only), 
each 8-week treatment cycle is composed of 4 doses of nivolumab and 2 doses of placebo for lirilumab. Nivolumab 
will be administered on Days 1, 15, 29, and 43 of each 8-week treatment cycle, and placebo for lirilumab will be 
administered on Days 1 and 29 of each 8-week treatment cycle. For subjects receiving lirilumab in combination with 
nivolumab and ipilimumab in the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5), nivolumab will be administered Q2W, ipilimumab will be administered Q6W, and lirilumab 
will be administered Q4W in each 12-week cycle. 
Revised Protocol No.: 12
Date: 08-May-2018
18
Approved
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Safety lead-in: Initially approximately 10 subjects will be enrolled in the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5). Any findings will be discussed between the BMS Medical Monitor 
and investigators and an agreement will be reached as to whether a lower dose or an alternate dose schedule should 
be examined or whether any additional treatment guidelines should be implemented prior to enrollment of additional 
subjects on study.
Following each treatment cycle (for all assigned treatments), the decision to treat a subject with additional cycles of 
study therapy will be based on tumor assessment (evaluation performed between Days 49 and 56 and completed before 
the first dose in the next 8 week cycle for all study parts except the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination [Part 5], which is performed Q8W and completed before study therapy is 
continued. Treatment decisions related to subject management will be based exclusively on irRECIST for the Dose 
Escalation and Cohort Expansion (Part 1; completed) and the SCCHN Cohort Expansion (Part 2; completed) (see 
protocol body Section 1.4.14 for the rationale and Appendix 2 for definitions); with Amendment 13, all other study 
parts will use only RECIST v1.1 (see protocol body Sections 3.1.3, 3.1.4, 3.1.5, and 3.1.6 for details). 
Subjects will generally be allowed to continue study therapy until the first occurrence of any of the following: 
a)
Achievement of irCR-confirmed (the Dose Escalation and Cohort Expansion [Part 1; completed] and the SCCHN 
Cohort Expansion [Part 2; completed]) or CR-confirmed the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination [Part 5]).
b)
Completion of a maximum of up to 2 years of the study treatment; 12 cycles in Parts 1, 2 and 3, and 8 cycles in 
Part 5. 
c)
irPD (the Dose Escalation and Cohort Expansion [Part 1; completed] and the SCCHN Cohort Expansion [Part 2; 
completed]) or PD confirmed or unconfirmed (the SCCHN Randomized Cohorts [Part 3], and the Signal 
Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination [Part 5],).
d)
Clinical deterioration suggesting that no further benefit from treatment is likely.
e)
Intolerability to therapy.
f)
Meeting criteria for discontinuation of study therapy as outlined in protocol body Sections 3.5 and 4.9.5. 
For all study parts, the subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30,
60, 100, and 150 to monitor for adverse events (AE)s.
Survival follow-up is no longer required with Revised Protocol 12 and no further visits should be conducted.
The Dose Escalation (Part 1; Completed): A 3 + 3 + 3 design will be used to assess the safety of lirilumab given in
combination with nivolumab. The dosages during dose escalation are provided in Table 1. The DLT observation period
will last for 8 weeks or until the completion of Cycle 1, whichever is longer. Three subjects will be treated initially at
each Dose Level. If 0 DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at the next higher
Dose Level. If 1 of 3 subjects experiences a DLT, that cohort will be expanded to 6 subjects. If 1 of 6 subjects
experiences a DLT, a new cohort of 3 subjects will be treated at the next higher Dose Level. If 2 of 6 DLT subjects
experience a DLT, that cohort will be expanded to 9 subjects. If 2 of 3, 3 of 6, or 3 of 9 subjects experience DLTs
within a cohort, then that Dose Level will be determined to have exceeded the MTD. If no MTD is reached through
Cohort 4, then additional cohorts at 6 mg/kg lirilumab and 10 mg/kg lirilumab, given in combination with 3 mg/kg
nivolumab, may be considered based on the aggregate safety experience during dose escalation and in consultation
and agreement between investigators and Sponsor via a protocol amendment.
After determining the MTD, MAD, or completion of dose escalation without identifying the MTD and to further
explore pharmacodynamic/biomarker objectives, 3 to 12 additional subjects may be enrolled in each Dose Level for
a total of up to 15 subjects at any Dose Level (original 3 to 12 subjects from dose escalation plus additional subjects
required to have a total cohort size of 15).
No intra-subject dose escalation or reduction is allowed. Subjects who withdraw from the study during the DLT period
for reasons other than a DLT may be replaced within the same Dose Level. For the purpose of making decisions on
dose escalation from a safety perspective, subjects will be considered evaluable if they have received 3 out of the 4
scheduled nivolumab doses through the 8-week observation period only if the 1 missed dose was secondary to non-
Revised Protocol No.: 12
Date: 08-May-2018
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
medical reasons. In addition, subjects with dosing delays of ≥3 weeks in Cycle 1 for non-DLT events will be
considered not evaluable for making decisions on dose escalation and should be replaced.
Dose escalation will be based on the number of DLTs experienced during Cycle 1.
The initial 6 subjects at each Dose Level will have peripheral blood evaluations for pharmacodynamic markers.
Table 1:
Dosages During Dose Escalation
Dose Level
Number
Total Subjectsa
Lirilumab
(IV; mg/kg)
Nivolumab
(IV; mg/kg)
1
n = approximately 3 to 15
0.1
3
2
n = approximately 3 to 15
0.3
3
3
n = approximately 3 to 15
1
3
4
n = approximately 3 to 15
3
3
Total
n = approximately 12 to 60
a 3 to 12 subjects will be enrolled during dose escalation. Additional subjects may be added to each Dose Level after
completion of the dose escalation period of the study for a total of up to 15 subjects per Dose Level.
All available clinical and laboratory data and the nature, time of onset, and time to resolution of DLTs observed during
dose escalation will be reviewed to determine whether an alternative dose schedule should be examined after
consultation between the investigators and the Sponsor, if needed. If agreed upon, the alternative schedule will be
identified by a protocol amendment.
The Cohort Expansion (Part 1; Completed): The purpose of the cohort expansions is to gather additional safety,
tolerability, preliminary efficacy, and pharmacodynamic information regarding the combination of lirilumab and
nivolumab. Once the safety profile of all doses tested has been characterized and the MTD of combined administration
of lirilumab and nivolumab has been defined, the cohort expansions will be initiated at the MTD, the MAD, or an
alternate dose, if recommended by the investigators and the Sponsor. Treatment doses in the cohort expansion groups
will not exceed the MAD. Five cohort expansions will be restricted to the tumor types listed in Table 2. The non-small
cell lung cancer (NSCLC) and MEL cohorts, which have demonstrated activity with nivolumab monotherapy, will be
used to assess increased activity of the combination therapy. The colorectal cancer (CRC), SCCHN, and hepatocellular
carcinoma (HCC) cohorts will explore activity of the combination therapy in tumors with unknown or historically low
responses to nivolumab monotherapy. Continuous evaluation of toxicity events in the cohort expansions will be
performed throughout enrollment in the cohort expansions. If the rate of DLTs exceeds 33%, then the findings will be
discussed and further enrollment may be interrupted. If a cohort expansion is discontinued due to toxicity, a new
cohort may be initiated at a previously tested lower Dose Level.
In each of the NSCLC and MEL cohorts, approximately 35 subjects will be enrolled to allow for a more precise
estimate of the ORR in these tumors following combination treatment. The sample size for the other 3 cohorts will be
guided by the Gehan design. In order to determine if a target response rate (eg, 25% to 30%) is likely, an initial number
of subjects (eg, 9) will be treated at first (Stage I) in a cohort, as outlined in Table 2. In the tumor cohort in which no
responses are observed, it will be concluded that the true response rate is unlikely to be greater than or equal to the
target rate and no more subjects will be enrolled in that cohort. Otherwise, in the cohorts in which at least 1 response
among the Stage I subjects is observed, up to 9 additional subjects will be treated for a total of 18 subjects per tumor
type, as guided by Table 3. In Stage I, approximately 9 subjects will be enrolled per tumor type. The number of
subjects enrolled in Stage II per tumor cohort will be guided by the number of responders observed in Stage I and the
required precision of the ORR estimate. This is summarized in Table 3 below, using a precision of 12% around the
ORR point estimate.
Revised Protocol No.: 12
Date: 08-May-2018
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 2:
Tumor Types Eligible for Cohort Expansion
Tumor Type
Stage I Subjects
Stage II Subjects
Total Subjects
NSCLC
N/A
N/A
Approx. 35
MEL
N/A
N/A
Approx. 35
CRC
9
4 to 9
Approx. 9 to 18
SCCHN
9
4 to 9
Approx. 9 to 18
HCC
9
4 to 9
Approx. 9 to 18
Totals
Approx. 97 to 124
Approx. = approximately; N/A = not applicable.
The actual sample size per cohort in Stage II to achieve desired precision (standard error) of 12% for the ORR estimate,
as guided by the Gehan design, depends on the number of responses observed in Stage I (see Table 3), assuming a
target ORR of 25% to 30%.
Table 3:
Cohort Expansion Sample Sizes by n of Responses in Stage I for CRC, SCCHN, and 
HCC Tumors
Stage I Number of
Responses in the First
9 Subjects
Stage II na
Total n/Cohort
0
0
9
1
4
13
2
8
17
3
9
18
4
8
17
5
5
14
6
0
9
a Based on 12% precision for the ORR estimates and a target ORR of 25% to 30%.
DLT: This section only applies to the Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort 
Expansion (Part 2), which have both completed enrollment and therefore this section and its subsections are not 
applicable starting with Amendment 13 and all subsequent amendments or revised protocols. For the purpose of 
guiding dose escalation, hepatic, non-hematologic, and hematologic DLTs will be defined separately (protocol body 
Section 4.8) and will be determined based on the incidence, intensity, and duration of AEs that are related to study 
drug and that occur within 56 days (8 weeks, through the completion of Cycle 1) of initiation of study drug in the 
Dose Escalation and Cohort Expansion (Part 1; completed). The severity of AEs will be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). For 
the purposes of subject management, DLTs will lead to dose interruption regardless of the cycle in which a DLT 
occurs (see protocol body Section 4.9.3 for specific guidelines).
The SCCHN Cohort Expansion (Part 2; Completed): To further explore emerging efficacy and safety data in
subjects with SCCHN; an additional cohort of approximately 35 subjects will be treated at Dose Level 4 (see Table 
1). The null hypothesis that the true ORR is 25% will be tested against a 1-sided alternative: ORR = 40%. The null 
hypothesis will be rejected if 12 or more responses are observed in 35 subjects. This design gives a 1-sided type I error 
Revised Protocol No.: 12
Date: 08-May-2018
21
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Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
rate of 0.15 and a power of 0.81. See Section 1 “Clinical Experience with Lirilumab and Nivolumab Combination 
Treatment” in the protocol body for preliminary safety and efficacy results.
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment): This is a parallel study of lirilumab in 
combination with nivolumab vs nivolumab monotherapy in subjects with platinum-refractory recurrent or metastatic 
SCCHN. This will be a single-blind, placebo-controlled, randomized, expansion study. Patients will be tested for PD-
L1 status and enrolled if PD-L1 is expressed in ≥1% of tumor cells. Randomization will occur within approximately 
35 days after screening. A total of approximately 225 subjects will be randomized in a 2:1 ratio to the 2 treatment 
arms (Arm A [flat dose of 240 mg lirilumab Q4W and flat dose of 240 mg nivolumab Q2W] and Arm B [placebo for 
lirilumab Q4W and flat dose of 240 mg nivolumab Q2W monotherapy]). The treatment period will last until PD, 
treatment discontinuation, or a maximum of up to 12 cycles of treatment, whichever occurs earlier.
The Signal Detection Cohort Expansion (Part 4): Removed with Revised Protocol 12. 
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment): This is an open-label Phase 2, cohort expansion study of lirilumab in combination with nivolumab and 
ipilimumab in subjects with platinum-refractory recurrent or metastatic SCCHN. Enrollment will occur within
approximately 35 days after screening. Approximately 40 subjects will be treated with nivolumab 3 mg/kg IV Q2W, 
ipilimumab 1 mg/kg IV Q6W, and lirilumab 3 mg/kg IV Q4W. The treatment period will last until PD, treatment 
discontinuation, or a maximum of up to 8 cycles of treatment, whichever occurs earlier.
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab Combination 
(Part 6): Removed with revised Protocol 12. 
Duration of Study: The screening period will last up to 28 days for the Dose Escalation and Cohort Expansion (Part 1; 
completed) and the SCCHN Cohort Expansion (Part 2; completed) and up to 35 days for all the other study parts. The
treatment period will last up to a maximum of 2 years or until PD or treatment discontinuation, whichever occurs 
earlier. The clinical follow-up period will last 150 days. Survival follow-up is no longer required with Revised Protocol 
12 and no further visits should be conducted. With revised protocol 12, the total time on study for any individual
subject will not exceed approximately 2.5 years. The total duration of the study is expected to be 4.5 years from the
time of the first visit of the first subject to the required clinical follow-up of the last subject enrolled.
Number of Subjects: Up to approximately 740 subjects will be dosed pending results from the various 2-stage design 
components of the study. Additional subjects may also be enrolled if necessary to ensure an adequate number of higher
PD-L1 expressers.
Study Population:
The study population will include men and women who are more than 18 years old, have histologic confirmation of a
solid malignancy that is advanced (metastatic and/or unresectable), have measurable disease, and meet all eligibility
criteria. As of Protocol Amendment 13, subjects undergoing biopsy do not need to have a biopsy lesion that is distinct 
from an index lesion.
•
For the Dose Escalation (Part 1; Completed): Subjects with any tumor type (with the exception of primary
central nervous system tumors and hematologic malignancies) are eligible to enroll.
•
For the Cohort Expansion (Parts 1 and 2; Completed): Subjects must have 1 of the following tumor types to
be eligible: NSCLC; MEL, CRC, SCCHN, or HCC. All subjects will be given the option of undergoing
pre-treatment, on-treatment, and post-treatment biopsies if they can be performed with acceptable clinical risk.
For subjects with MEL and SCCHN, a minimum of 10 treated subjects in each cohort will be required to undergo
pre-treatment and on-treatment biopsies during cohort expansion. Post-treatment biopsies (following completion
of all study therapy) will be optional. In addition, optional biopsies may be obtained from subjects who have
clinically meaningful events, such as response, disease progression, or AEs of interest. Consent for biopsies must
be obtained. Biopsy sites for these subjects must be distinct from evaluable lesions and must not have been
irradiated prior to entry.
•
For the SCCHN Cohort Expansion (Part 2; Completed) and the SCCHN Randomized Cohorts (Part 3 -
closed to enrollment): Subjects must have histologically confirmed platinum-refractory recurrent or metastatic
SCCHN (oral cavity, pharynx, larynx), Stage 3/4 and not amenable to local therapy with curative intent (surgery
or radiation therapy with or without chemotherapy) and in the SCCHN Randomized Cohorts (Part 3) only must 
have tumors that are PD-L1+ on fresh biopsies by immunohistochemistry (IHC) testing performed by the central 
Revised Protocol No.: 12
Date: 08-May-2018
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laboratory during the screening period. For SCCHN Cohort Expansion (Part 2; completed) only, a minimum of
15 subjects will be required to undergo mandatory pre-treatment and on-treatment biopsies at acceptable clinical
risk as judged by the investigator. For the SCCHN Randomized Cohorts (Part 3), all subjects will be required to 
provide fresh biopsies at baseline and on-treatment if a subject has accessible lesions and if the risks associated 
with obtaining biopsies are deemed acceptable.
•
For the Signal Detection Cohort Expansion (Part 4): Removed with Revised Protocol 12. 
•
For the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 -
closed to enrollment): Subjects must have histologically confirmed platinum-refractory metastatic or recurrent 
SCCHN (oral cavity, oropharynx, hypopharynx, and larynx). Subjects must have tumor progression or recurrence 
after prior platinum-containing systemic therapy for recurrent or metastatic disease. In addition, subjects who 
have progressed within 6 months of platinum-based therapy used as part of concurrent chemoradiation (definitive 
or adjuvant therapy) are also eligible. All subjects will be required to provide fresh biopsies at baseline and 
on-treatment if a subject has accessible lesions and if the risks associated with obtaining biopsies are deemed 
acceptable. 
•
For the Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6): Removed with Revised Protocol 12. 
Study Assessments:
•
Safety Outcome Measures: AEs will be assessed continuously during the study and for 150 days after the last
treatment or until the start of subsequent anti-cancer therapy.AEs will be coded using the most current version of
the Medical Dictionary for Regulatory Activities (MedDRA) and reviewed for potential significance and
importance. Subjects should be followed until all treatment-related AEs have recovered to baseline or are deemed
irreversible by the investigator. Safety evaluation will also be based on clinical laboratory tests collected to assess
laboratory abnormalities as well as results of vital sign measurements, electrocardiograms (ECGs), physical
examinations, and imaging studies. Both AEs and laboratory tests will be graded using NCI CTCAE v4.0.
•
Efficacy Measures: Disease assessment with computed tomography and/or magnetic resonance imaging, as 
appropriate, will be performed at baseline and Q8W until disease progression, at the completion of clinical follow-
up, or until subjects withdraw from the study. Disease assessments at other timepoints may be performed if the 
investigator is concerned about tumor progression. Tumor responses will be derived for appropriate populations 
of subjects as defined by RECIST v1.1 (see protocol body Appendix 3) from tumor measurements. For the Dose 
Escalation and Cohort Expansion (Part 1; completed) and the SCCHN Cohort Expansion (Part 2; completed), 
investigator-assessed responses and treatment decisions related to subject management will be based on irRECIST 
(see protocol body Appendix 2); all other study parts will use only RECIST v1.1. Radiographic assessments may 
be submitted to the third-party radiology vendor for any part of the study. Tumor assessments should be submitted 
to the third-party radiology vendor as they are performed on an ongoing basis. Submission of radiographic scans 
to the third-party vendor is no longer required with Revised Protocol 12.
−
In Parts 1 and 2, changes in tumor measurements and tumor responses will be assessed by the investigator 
using irRECIST criteria. Investigators will also report the number and size of new lesions that appear while 
on-study. The timepoint tumor assessments will be reported on the CRF based on investigators’ assessment 
using irRECIST criteria. The SCCHN Randomized Cohorts (Part 3), and the Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), however, will use only RECIST v1.1 for 
all assessments. Please refer to Appendix 3 for specifics of RECIST v1.1 and Appendix 2 for specifics of 
irRECIST criteria to be utilized in this study.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment):
−
The primary endpoint is ORR based on assessment in all subjects randomized to lirilumab plus nivolumab.
Tumor progression or response endpoints will be assessed using RECIST v1.1 criteria. All randomized 
subjects will be monitored by radiographic assessment every 8 weeks (± 7 days) beginning from the first
dose date until Week 48 and Q12W (± 7 days) thereafter until PD or treatment discontinuation (whichever 
occurs later), to determine changes in tumor size.
−
Secondary efficacy endpoints of the SCCHN Randomized Cohorts (Part 3) are DCR, DOR, time to response, 
depth of response, OS, PFS, ORR according to investigator-assessed response, and safety measures.
•
The Signal Detection Cohort Expansion (Part 4):
−
Removed with Revised Protocol 12. 
Revised Protocol No.: 12
Date: 08-May-2018
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•
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6): 
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Removed with Revised Protocol 12. 
•
PK Measures: Serum samples for lirilumab, nivolumab, and/or ipilimumab PK assessments will be collected for 
all subjects in both dose escalation and cohort expansion. Detailed schedules of PK evaluation is provided in 
Section 5.7.3.3. PK of nivolumab, lirilumab, and ipilimumab will be derived from serum concentration vs time. 
The PK parameters to be assessed wherever feasible include: maximum observed concentration (Cmax), time of 
maximum observed concentration, area under the plasma concentration-time curve (AUC) from time zero to time 
of last quantifiable concentration, AUC from time zero extrapolated to infinite time, trough observed serum 
concentration, AUC in 1 dosing interval (AUC[TAU]), clearance, volume of distribution of the terminal phase, 
and half-life. Nivolumab, lirilumab, and ipilimumab end of infusion and trough (trough observed concentration) 
concentrations will be calculated at specified visits whenever feasible.
•
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment): Outcomes Research Assessments 
Measures: EQ-5D-3L, EORTC-QLQ-C30, EORTC-QLQ-H&N35, and healthcare resource utilization 
questionnaire. Removed with Revised Protocol 12.
•
Immunogenicity Measures: Serum samples to evaluate development of positive ADA response to lirilumab and
nivolumab will be collected from all subjects pre-dose at specified timepoints.
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Statistical Methods:
•
Sample Size Determination:
−
The Dose Escalation and Cohort Expansion (Part 1; Completed):
♦
See Section 1 “Clinical Experience with Lirilumab and Nivolumab Combination Treatment” of the
protocol body for a summary of preliminary safety and efficacy results. 
♦
Dose Escalation: Because this is a Phase 1/2 dose escalation study, the sample size at each dose cannot
be determined exactly, as it depends on the number of observed toxicities. Approximately between 3 and
12 subjects are expected to be treated during dose escalation in each Dose Level, and up to 15 subjects
may be dosed at selected Dose Levels.
♦
The Cohort Expansion: During cohort expansion, approximately 18 subjects are expected to be enrolled
in each of the 3 unknown or low historic response cohort expansions and 35 subjects in each of the 2
cohorts with higher historic ORR and treated at the previously determined MTD, MAD, or at an
alternative dose that is not to exceed the MAD.
♦
CRC, SCCHN, and HCC Cohorts: The sample size for each cohort will be guided by a 2-stage Gehan
design. In order to determine whether a target ORR is likely in a tumor cohort, approximately 9 subjects 
will be treated at Stage 1 in each tumor type, as outlined in Table 2. For a tumor type in which no
responses are observed, it will be concluded that the true ORR is unlikely to be greater than or equal to
the target ORR and no more subjects will be enrolled in these tumors. For tumor cohort(s) in which at
least 1 response among the first approximately 9 subjects is observed, up to an additional 9 subjects will
be enrolled as guided by Table 3. With approximately 9 subjects in Stage 1, there is no more than a 10%
chance of declaring that there is no therapeutic effect when actually there is an effect. A total of up to
approximately 18 subjects across the 2 stages per tumor will guarantee an estimate of the true ORR with
12% precision.
♦
NSCLC and MEL Cohorts: A total of approximately 35 subjects will be enrolled per tumor cohort based
on achieving a higher precision with a reasonable control on the type I error. In a cohort of approximately
35 subjects, if 12, 14, or 16 responses are observed, then the lower limit of the 1-sided 90% confidence
interval (CI) for the ORR is 24%, 29%, or 34%, respectively. In addition, 19 responses would need to
be observed in approximately 35 subjects so that the lower limit of the 1-sided 90% CI for the ORR is
42%. These calculations are based on the Clopper-Pearson method for exact CIs. If the true ORR in a
tumor type is 45%, then with approximately 35 subjects in a cohort there is 96% chance of observing at
least 10 responses, and 93% chance of observing at least 11 responses, and there is 7% chance of
observing 10 or fewer responses (false negative rate). If the true ORR for a tumor is only 30% rather
than 45%, then there is a 35% and 14% chance, respectively, that there will be at least 12 or at least
14 responses in approximately 35 subjects (false positive rate).
−
The SCCHN Cohort Expansion (Part 2; Completed): See Section 1 “Clinical Experience with Lirilumab 
and Nivolumab Combination Treatment” of the protocol body for a summary of preliminary safety and 
efficacy results. A total of approximately 35 subjects will be enrolled in the SCCHN Expansion Cohort 
(Part 2; completed). The null hypothesis that the true ORR is 25% will be tested against a 1-sided alternative: 
ORR = 40%. The null hypothesis will be rejected if 12 or more responses are observed in 35 subjects. This 
design gives a 1-sided type 1 error rate of 0.15 and a power of 0.81. 
−
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment): The SCCHN Randomized Cohorts
(Part 3) has a primary endpoint of ORR. Overall 2-sided alpha is set at 0.10. The final analysis of ORR will 
take place 6 months after last patient first treatment. A total of approximately 225 subjects will be enrolled 
if PD-L1 is expressed in ≥1% of tumor cells, and will be randomized in a 2:1 ratio to the 2 treatment arms, 
nivolumab combined with lirilumab (Arm A) and nivolumab monotherapy (Arm B), stratified by PD-L1+ ≥
50% expression (yes/no) and prior treatment with cetuximab (yes/no). The sample size considers the 
Revised Protocol No.: 12
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precision of the estimated ORR in Arm A. With 150 participants in Arm A, if 50 responses are observed, the 
estimated ORR will be 33% and the 90% CI will be [26%, 41%]. (Study CA209-041, 90% CI for nivolumab 
arm in PD-L1+ [9%, 25%].)
−
The Signal Detection Cohort Expansion (Part 4): Removed with Revised Protocol 12.
−
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 -
closed to enrollment): A total of 40 subjects will be enrolled in the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5). With this sample size, the average width of 
the 2-sided 80% Clopper-Pearson CI for the ORR will be approximately 16% to 21% (assuming that the 
expected ORR in subjects with platinum-refractory recurrent or metastatic SCCHN is between 13% and 
33%).
−
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6): Removed with Revised Protocol 12.
•
Statistical Analysis:
−
Safety: All recorded AEs will be listed and tabulated by system organ class, preferred term, and dose and
coded according to the most current version of MedDRA. Vital signs and clinical laboratory test results will
be listed and summarized by treatment. Any significant physical examination findings and results of clinical
laboratory tests will be listed. ECG results will be evaluated by the investigator and abnormalities, if present,
will be listed. Summary tables will be presented on safety parameters for each treatment arm and/or tumor 
types, if applicable.
−
PK: Summary statistics will be tabulated for the PK parameters of lirilumab, nivolumab, and ipilimumab by
dose and study day/week. For 
the Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), summary tables will also be presented by 
each randomized treatment arm. To describe the dependency on dose of anti-KIR, scatter plots of Cmax and 
AUC(TAU) vs dose will be provided for each day measured. Dose proportionality of lirilumab when co-
administered with nivolumab will be assessed based on a power model. Dose proportionality of lirilumab 
when co-administered with nivolumab, and of lirilumab when co-administered with nivolumab and 
ipilimumab will be assessed based on a power model.
−
Immunogenicity Analyses: A listing will be provided of all available immunogenicity data. Additionally, a 
listing of immunogenicity data from those subjects with at least 1 positive ADA at any timepoint will be 
provided by treatment for each analyte. The number (%) of subjects with the following anti-drug responses 
will be reported for each analyte if applicable, by dose, and overall: Baseline ADA Positive, ADA Positive 
(Persistent Positive, Only the Last Sample Positive), ADA Positive with Neutralizing Positive, and ADA 
Negative. To examine the potential relationship between immunogenicity and safety, the frequency and type 
of AEs of special interest may be examined by overall immunogenicity status. Associations between trough 
concentrations of lirilumab (or nivolumab or ipilimumab) and corresponding ADA assessments may be 
explored.
−
Efficacy Analyses:
♦
The SCCHN Randomized Cohorts (Part 3) Primary Endpoints Analysis: The primary endpoint of
ORR will be analyzed for the SCCHN Randomized Cohorts (Part 3). Subjects will be enrolled if PD-L1 
is expressed in ≥ 1% of tumor cells. CIs will be provided separately for each treatment arm using the 
Clopper-Pearson method.
−
Secondary Endpoints Analysis: Individual BOR, DOR, OS, and PFS will be listed using RECIST v1.1
criteria. Summary tables will be presented on efficacy endpoints for each treatment arm. The OS and PFS 
rates at specific timepoints and corresponding CI will be estimated by KM methodology depending on data 
availability. ORR, DOR and PFS analyses will include subjects in the cohort expansion phase and subjects 
in dose escalation matching those in cohort expansion by disease type and treatment. Individual changes in 
the tumor burden over time will be presented graphically within a disease type. The secondary endpoint of 
OS is defined as the time from randomization to the date of death. A subject who has not died will be censored 
at last known date alive. OS will be followed continuously while subjects are on the study drug and every 3 
months for up to 3 years following the first dose of study drug via in-person or phone contact after subjects 
discontinue the study drug.
 
Revised Protocol No.: 12
Date: 08-May-2018
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♦
The number and percentage of subjects in each category of BOR (CR, partial response [PR], stable 
disease [SD], PD, or unable to determine) will be presented by treatment arm and/or tumor types, if 
applicable. Finally, a waterfall plot showing the biggest reduction in the sum of target lesions will be 
produced for response-evaluable subjects.
−
Biomarker Analyses: The pharmacodynamic effect on TILs and expression of tumor markers including PD-
L1 
 will be assessed by summary statistics, and investigated graphically to explore patterns 
of change. In addition, the correlation of TIL changes and tumor marker expression with measures of
peripheral blood markers will be explored graphically and by appropriate statistics based on data availability.
−
Outcomes Research Analyses - Removed with Revised Protocol 12.
−
Interim Analysis:
♦
Data emerging from the unblinded parts of this study may be needed for timely decisions about 
adjustments to procedures in subsequent parts of the study. Therefore, data may be reviewed prior to the 
final lock of the study database. While the study is still ongoing, additional interim analyses may also be 
performed for administrative purposes or publications. In that case, analyses will only consist of listings, 
summaries, and graphs of the available data, and no formal inferences requiring any adjustment to 
statistical significance level will be performed. Efficacy analyses based on interim data may use 
response-evaluable or all-treated populations depending on the purpose of the analysis. 
♦
The Dose Escalation and Cohort Expansion (Part 1; completed) of the study is the dose-escalation study 
and includes expansion cohorts in specific tumor types. In the dose expansion portion of the Dose 
Escalation and Cohort Expansion (Part 1; completed), in order to assess if the target response rate is 
likely for tumor cohorts with unknown or low historic ORR, the tumor response will be initially based 
on the tumor measurements from the first approximately 9 subjects in each cohort to facilitate decisions 
on continuing enrollment in that tumor. If no responses are observed in approximately the first 
approximately 9 subjects with tumor measurements, enrollment in that tumor cohort will not continue. 
However, accrual to these tumor types may continue, while the Stage I response assessments are 
performed.
Revised Protocol No.: 12
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 12: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 12 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for the Dose Escalation and Cohort Expansion (Part 1; 
Completed) and the SCCHN Cohort Expansion (Part 2; Completed) ....... 
1.1.2 Rationale for the SCCHN Randomized Cohorts (Part 3) ........................ 
1.1.3 Rationale for the Signal Detection Cohort Expansion (Part 4) ............... 
1.1.4 Rationale for the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5 - closed to enrollment) and the Signal 
Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6 - removed) ............................................. 
1.1.4.1 Experience with Nivolumab and Ipilimumab Combination 
Treatment .............................................................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.2.1 The Dose Escalation and Cohort Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) ........................................ 
1.2.2 The SCCHN Randomized Cohorts (Part 3 - Closed to enrollment) ........ 
1.2.3 The Signal Detection Cohort Expansion (Part 4) .................................... 
1.2.4 The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - Closed to enrollment) .......................... 
1.2.5 The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.1.1 Primary Objective for the Dose Escalation and Cohort Expansion 
(Part 1; Completed) and the SCCHN Cohort Expansion (Part 2; 
Completed) ............................................................................................ 
1.3.1.2 Primary Objective for the SCCHN Randomized Cohorts (Part 3 - 
closed to enrollment) ............................................................................. 
1.3.1.3 Primary Objective for the Signal Detection Cohort Expansion (Part 
4) ........................................................................................................... 
1.3.1.4 Primary Objective for the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment) ............................................................................................ 
1.3.1.5 Primary Objective for the Signal Detection in Previously Untreated 
MEL with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 
6) ........................................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
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1.3.2.1 Secondary Objectives for the Dose Escalation and Cohort 
Expansion (Part 1; Completed) and the SCCHN Cohort Expansion 
(Part 2; Completed) .............................................................................. 
1.3.2.2 Secondary Objectives for the SCCHN Randomized Cohorts (Part 3 
- closed to enrollment) .......................................................................... 
1.3.2.3 Secondary Objectives for the Signal Detection Cohort Expansion 
(Part 4) .................................................................................................. 
1.3.2.4 Secondary Objectives for the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment) ............................................................................................ 
1.3.2.5 Secondary Objectives for the Signal Detection in Previously 
Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6) ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Lirilumab: Pharmacology ........................................................................ 
1.4.2 Lirilumab: Toxicity .................................................................................. 
1.4.3 Lirilumab: Pre-clinical Metabolism and Pharmacokinetics ................... 
1.4.4 Lirilumab: Clinical Pharmacology and Safety ........................................ 
1.4.4.1 Pharmacokinetics of Lirilumab....................................................... 
1.4.5 Nivolumab: Pharmacology ...................................................................... 
1.4.6 Nivolumab: Toxicity ................................................................................. 
1.4.7 Nivolumab: Pre-clinical Metabolism and Pharmacokinetics .................. 
1.4.8 Nivolumab: Clinical Pharmacology and Safety ...................................... 
1.4.8.1 Pharmacokinetics of Nivolumab ..................................................... 
1.4.9 Ipilimumab: Pharmacology ..................................................................... 
1.4.10 Ipilimumab: Toxicity .............................................................................. 
1.4.11 Ipilimumab: Pre-clinical Metabolism and Pharmacokinetics ............... 
1.4.12 Ipilimumab: Clinical Pharmacology and Safety .................................... 
1.4.12.1 Pharmacokinetics of Ipilimumab .................................................. 
1.4.13 Rationale for Selection of Schedule, Dose, and Tumor Types ............... 
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1.4.13.1 Rationale for Schedule, Dose, and Tumor Types for the Dose 
Escalation and Cohort Expansion (Part 1; Completed) and the SCCHN 
Cohort Expansion (Part 2; Completed): Lirilumab and Nivolumab 
Weight-based Dosing ............................................................................ 
1.4.13.2 Rationale for Schedule, Dose, and Tumor Types for the SCCHN 
Randomized Cohorts (Part 3 - closed to enrollment) and the Signal 
Detection Cohort Expansion (Part 4 - removed): Flat Doses .............. 
1.4.13.3 Rationale for Schedule and Dose for the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination 
(Part 5 - closed to enrollment) or the Signal Detection in Previously 
Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6 - removed): Lirilumab, Nivolumab, and 
Ipilimumab Weight-based Dosing......................................................... 
1.4.14 Rationale for Use of Immune-Related Response Criteria...................... 
1.4.15 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease .................................................................................... 
1.4.16 Rationale for Use of Blood and Tumor Tissue in Biomarker Studies .... 
1.4.17 Rationale for Shorter Infusion Durations in the SCCHN Randomized 
Cohorts (Part 3 - closed to enrollment), the Signal Detection Cohort 
Expansion (Part 4 - removed), the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment), and the Signal Detection in Previously Untreated MEL with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6 - removed) . 
1.4.17.1 Rationale for Shorter Infusion Times for Nivolumab Monotherapy
...............................................................................................................
1.4.17.2 Rationale for Shorter Infusion Times for Nivolumab in 
Combination with Ipilimumab .............................................................. 
1.4.18 Rationale for Patient-Reported Outcomes Evaluation in the SCCHN 
Randomized Cohorts (Part 3 - closed to enrollment) ................................. 
1.4.19 Rationale for Two Year Duration of Treatment ..................................... 
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 The Dose Escalation and Cohort Expansion (Part 1; Completed) .......... 
3.1.1.1 Dose Escalation (Completed) ......................................................... 
3.1.1.2 Cohort Expansion (Completed) ...................................................... 
3.1.2 The SCCHN Cohort Expansion (Part 2; Completed) .............................. 
3.1.3 The SCCHN Randomized Cohorts (Part 3 closed to enrollment) ............ 
3.1.4 The Signal Detection Cohort Expansion (Part 4) .................................... 
3.1.5 The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) .......................... 
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3.1.6 The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .................................... 
3.2 Post-study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Permitted Therapy ................................................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.5.1 Treatment Beyond Disease Progression .................................................. 
3.6 Treatment of Infusion Reactions ....................................................................... 
3.7 Post-treatment Study Follow-up ....................................................................... 
3.7.1 Withdrawal of Consent ............................................................................ 
3.7.2 Lost to Follow-Up .................................................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Noninvestigational Product ..................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.1.4 Preparation of Study Drug(s) .................................................................. 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
4.7 Retained Samples for Bioavailability / Bioequivalence ................................... 
4.8 Dose Limiting Toxicities .................................................................................. 
4.8.1 Definition ................................................................................................. 
4.8.2 Definition of Hepatic DLT ....................................................................... 
4.8.2.1 Definition of Hepatic DLT for Subjects with HCC ......................... 
4.8.3 Definition of Non-hematologic DLT ........................................................ 
4.8.4 Definition of Hematologic DLT ............................................................... 
4.9 Guidelines for Dose Modification .................................................................... 
4.9.1 Intra-subject Dose Escalation .................................................................. 
4.9.2 Dose Reductions....................................................................................... 
4.9.3 Dose Delays Due To Toxicity .................................................................. 
4.9.4 Criteria for Subsequent Dosing ............................................................... 
4.9.5 Guidelines for Permanent Discontinuation ............................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
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5.1.1 Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) ........................................ 
5.1.2 The SCCHN Randomized Cohorts (Part 3 - closed to enrollment) ......... 
5.1.3 The Signal Detection Cohort Expansion (Part 4) .................................... 
5.1.4 The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) and the Signal 
Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6 - removed with Revised Protocol 12) .... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Microsatellite Instability Testing ............................................................. 
5.4 Efficacy Assessments ........................................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics: Collection and Processing ........................................ 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 
 Biomarker Assessments ................................................................ 
5.7.3 Assessments for Subjects Undergoing Tumor Biopsies ........................... 
5.7.3.1 PD-L1 Testing on Screening Tumor Biopsies ................................. 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
5.9.1 Immunogenicity Assessments ................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Non-serious Adverse Events ............................................................................. 
6.2.1 Non-serious Adverse Event Collection and Reporting ............................ 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
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6.6 Potential Drug-induced Liver Injury ................................................................. 
6.6.1 Potential Drug-induced Liver Injury for Subjects with HCC .................. 
6.7 Other Safety Considerations ............................................................................. 
6.8 Treatment Algorithms for Drug-related Adverse Events .................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.1.1 Dose Escalation (Part 1; Completed) ...................................................... 
8.1.2 Cohort Expansion (Part 1; Completed) ................................................... 
8.1.3 The SCCHN Cohort Expansion (Part 2; Completed) .............................. 
8.1.4 The SCCHN Randomized Cohorts (Part 3 - closed to enrollment) ......... 
8.1.5 The Signal Detection Cohort Expansion (Part 4) .................................... 
8.1.7 The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .................................... 
8.2 Population for Analyses .................................................................................... 
8.3 Endpoint Definitions ......................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.1.1 Dose Escalation and Cohort Expansion (Part 1; Completed) and 
the SCCHN Cohort Expansion (Part 2; Completed) ............................ 
8.3.1.2 The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)  
8.3.1.3 The Signal Detection Cohort Expansion (Part 4) ........................... 
8.3.1.4 The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) .................... 
8.3.1.5 The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .............................. 
8.3.2 Secondary Endpoints ............................................................................... 
8.3.2.1 The Dose Escalation and Cohort Expansion (Part 1; Completed) 
and the SCCHN Cohort Expansion (Part 2; Completed) ..................... 
8.3.2.2 The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)  
8.3.2.3 The Signal Detection Cohort Expansion (Part 4) ........................... 
8.3.2.4 The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) .................... 
8.3.2.5 The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .............................. 
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8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 The SCCHN Randomized Cohorts (Part 3) Primary Endpoint 
Analysis ................................................................................................. 
8.4.2.2 Secondary Endpoints Analysis ........................................................ 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other 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 ............................................................................................... 
9.1.3 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 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 2 IRRECIST ............................................................................................. 
APPENDIX 3 RECIST V1.1 ........................................................................................ 
APPENDIX 4 HEAD AND NECK SQUAMOUS CELL CARCINOMAS 
CLASSIFICATIONS .............................................................................................. 
APPENDIX 5 CHILD-PUGH SCORE ........................................................................ 
APPENDIX 6 GUIDANCE ON CONTRACEPTION ................................................. 
APPENDIX 7 ECOG PERFORMANCE STATUS ..................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
Lirilumab (BMS-986015) is a fully human monoclonal antibody that is designed to act as a 
checkpoint inhibitor by blocking the interaction between killer cell immunoglobulin-like receptor 
(KIR)2DL-1,-2,-3 inhibitory receptors and their ligands facilitating activation of natural killer 
(NK) cells and, potentially some subsets of T cells, ultimately leading to anti-tumor activity.
The Dose Escalation and Cohort Expansion (Part 1) and the squamous cell carcinoma of the head 
and neck (SCCHN) Cohort Expansion (Part 2) have both completed enrollment and are not 
applicable starting with Amendment 13 and all subsequent amendments. For preliminary safety 
and efficacy results, see Section 1 “Clinical Experience with Lirilumab and Nivolumab 
Combination Treatment” of the protocol body.
At the time of Amendment 13, preliminary data from an initial cohort of subjects in 
Study CA223001 suggested a signal of potential efficacy in recurrent or metastatic SCCHN 
subjects with disease progression on or after platinum-based therapy. Specifically, preliminary 
data in 29 evaluable subjects treated with the combination of lirilumab plus nivolumab showed an 
objective response rate (ORR) of 24% (7/29) in the all-comer population and an ORR of 41% 
(7/17) in the programmed cell death ligand 1 positive (PD-L1+) population.1 Whereas, nivolumab 
monotherapy, in a similar population of patients with previously treated SCCHN, showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥1% 
programmed cell death ligand 1 (PD-L1) expression.2 Preliminary data also indicated the 
combination of lirilumab plus nivolumab is safe, with the addition of lirilumab to nivolumab 
adding little additional toxicity to that typically observed with nivolumab alone. Based on these 
results, the protocol was revised to add additional cohorts (Parts 3-6; see description in Section 
3.1).
Subsequent efficacy analysis of additional recurrent or metastatic SCCHN subjects with disease 
progression on or after platinum-based therapy treated with the combination of lirilumab and
nivolumab did not demonstrate a differential efficacy signal as compared to nivolumab 
monotherapy treatment in a similar population of SCCHN subjects. Based on the review of these 
data, Revised Protocol 12 will implement the following:
•
Enrollment permanently closed in Part 3, a single-blinded, placebo-controlled, randomized 
cohort expansion of lirilumab in combination with nivolumab vs nivolumab monotherapy 
in subjects with platinum-refractory recurrent or metastatic SCCHN who are PD-L1+.
•
Removal of Part 4, a signal detection cohort expansion of nivolumab and lirilumab at a flat 
dose in subjects with sqNSCLC, ESCC, BC, and other squamous histologies and in 
subjects with SCCHN who have received prior PD-1/PD-L1 directed therapy. No subjects 
were enrolled.
•
Enrollment permanently closed in Part 5, a safety and signal detection with a triplet 
regimen of lirilumab in combination with nivolumab and ipilimumab in subjects with 
platinum-refractory recurrent or metastatic SCCHN.
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•
Removal of Part 6, a safety and signal detection with a triplet regimen of lirilumab in 
combination with nivolumab and ipilimumab in subjects with previously untreated 
metastatic melanoma. No subjects were enrolled.
•
Removal of overall survival visits for all subjects, select sample collection and study visits, 
additional subjects entering treatment beyond progression and retreatment at the time of 
disease progression.
•
All subjects will be permitted a maximum of up to 2 years of treatment as specified in the 
individual study parts. 
Background of NK Cells and KIR in Inflamed Tumors
An analysis of the immune infiltration in a large cohort of head and neck tumors, integrating 
genetic data with RNA-seq–based deconvolution of immune cell populations and 
effector/regulatory molecules was done3 and found that SCCHN is one of the most highly immune-
infiltrated cancer types, and in fact, the most highly NK cell– and Treg-infiltrated cancer type. 
These tumors are poised to benefit from immunotherapy that includes Treg and NK checkpoint-
targeted approaches that may have unique applicability in head and neck cancer.
Analysis of the levels of NK-cell infiltration in SCCHN showed that the CD56bright subpopulation 
is predominantly found in lymph nodes and peripheral blood and believed to be the likely precursor 
to CD56dim cells, which are far more cytotoxic and play a critical role in antitumor immunity.4
Strikingly, SCCHN tumors had the numerically highest levels of infiltration with CD56dim NK 
cells, compared with other highly immune-infiltrated cancer types. CD56dim NK cells are inhibited 
by KIRs, which are absent on CD56bright NK cells. CD56dim NK-cell infiltration correlated 
strongly with overexpression of the KIR inhibitory receptor genes KIR2DL1 and KIR2DL3. These 
data suggest that SCCHN tumors are prime candidates for trials of anti-KIR antibodies.
It has been shown that there are high levels of immunoregulatory influence in SCCHNs, which 
harbor the highest levels of Treg infiltration and the highest Treg/CD8+ T-cell ratio across all 
cancers, suggesting that these tumors are poised to respond to immunotherapeutic modalities that 
relieve inhibitory pathways. Treg function and proliferation rely on a number of targetable 
pathways. CTLA-4 is highly constitutively expressed on Tregs. Its activation is necessary for Treg 
function and proliferation. CTLA-4 inhibitors have clearly been shown to promote antitumor 
immunity in MEL. Blockade of the CTLA-4 receptor on activated Tregs may therefore dampen 
the immunosuppressive function of these cells in head and neck tumors. A growing body of 
evidence suggests that CTLA-4 blockade does, in some contexts, repress Treg function and 
accumulation in the tumor microenvironment.
Analysis of immune-cell infiltration and levels of immune activation in other highly inflamed 
cancer types, namely MEL, prostate, kidney clear cell, cervical/endometrial, sqNSCLC, adeno 
NSCLC, breast, bladder, and thyroid5 showed that the levels of CD56bright NK-cell infiltration was 
predominantly found in lymph nodes and peripheral blood and is believed to be the likely precursor 
to CD56dim cells, which are far more cytotoxic and play a critical role in antitumor immunity.
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Taken together, these data reveal that inflamed tumors such as SCCHN and MEL are infiltrated 
with Tregs and KIR-overexpressing CD56dim NK cells, to a higher degree than other cancer types. 
These findings suggest these tumors possess an immune landscape that is poised to respond to 
immunotherapeutic approaches that block inhibitory signals to T cells and NK cells. 
Background of Anti-KIR Antibody Lirilumab (BMS-986015)
Lirilumab binds specifically and with high affinity to subsets of KIRs (ie, KIR2DL1, -2, and -3 
and KIR2DS1 and -2), thus preventing the interaction between KIR and HLA-C. Therefore 
NK-cell activation is determined by the balance of activating (positive) and inhibitory (negative) 
receptor stimulation. Tumor cells are able to evade innate immunity through the interaction of KIR 
with HLA-C. By blocking this interaction, lirilumab facilitates the activation of NK cells and 
subsequent killing of the tumor cell. Blockade of inhibitory KIR by lirilumab is, thus, a promising 
mechanism to promote killing of tumor cells by the innate immune system.
Lirilumab is being studied as a potential immunotherapy alone and in combination with other
agents in subjects with various hematologic malignancies and solid tumors. A total of 550 subjects 
have been treated with lirilumab across 5 studies as of 13-Jul-2017 assessing safety, 
pharmacokinetics (PK), biomarker modulation, and clinical activity. The first (Study CA223003, 
IPH2102-101) is a monotherapy, dose-escalation, Phase 1 trial to determine the safety and 
maximum tolerated dose (MTD) of BMS-986015 (IPH2102) and is completed. The second (Study 
CA223004, IPH2102-201) is a double-blind, placebo-controlled, Phase 2 trial of lirilumab
evaluating the relapse-free survival in subjects with AML in complete remission but ineligible for 
allogeneic transplant and is completed. One-third of subjects in this study received placebo. The 
third (Study CA223001), fourth (Study CA223002), and fifth (Study CA223028) are Phase 1 (or 
Phase 1/2) trials of lirilumab in combination with the anti-PD-1 antibody nivolumab (Study 
CA223001), the anti-CTLA-4 antibody ipilimumab (Study CA223002), and the Signaling 
Lymphocytic Activation Molecule Family Member 7 antibody elotuzumab (Study CA223028) 
were initiated to determine if coordinate modulation of the innate and adaptive immune systems 
results in greater clinical benefit. Study CA223002 was terminated early, Study CA223028 is 
completed and study CA223001 is ongoing.
The majority of adverse events (AEs) in these 5 trials were mild or moderate (Grade 1 or 2), 
self-limiting, and manageable. The most common related AEs in the monotherapy trials were 
asthenia, bronchitis, diarrhea, headache, fatigue, pruritus, and thrombocytopenia. The most 
common related AEs in the combination trials were fatigue, infusion-related reaction, pruritus, 
rash, nausea, chills, diarrhea, rash maculo-papular, and pyrexia. The data to date support a positive 
safety profile of lirilumab.
Background of Nivolumab: Mechanism of Action
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
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addition to antigen recognition by the T-cell receptor.6 Collectively, these signals govern the 
balance between T-cell activation and tolerance. 
PD-1 is a member of the cluster of differentiation (CD) 28 family of T-cell co-stimulatory 
receptors, which also include CD28, CTLA-4, inducible T-cell co-stimulator (ICOS), and B- and 
T-lymphocyte attenuator (BTLA).7 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of interleukin (IL)-2, IL-10, IL-13, interferon-gamma (IFN-γ), and B-cell lymphoma-
extra large. PD-1 expression has also been noted to inhibit T-cell activation and expansion of 
previously activated cells. Evidence for a negative regulatory role of PD-1 comes from studies of 
PD-1-deficient mice, which develop a variety of autoimmune phenotypes.8 These results suggest 
that PD-1 blockade has the potential to activate anti-self T-cell responses, but these responses are 
variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is 
not accompanied by a universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (concentration required for 
50% efficacy [EC50]: 0.39 to 2.62 nM) and inhibits the binding of PD-1 to its ligands PD-L1 and 
programmed cell death ligand 2 (PD-L2) (concentration required for 50% inhibition 
[IC50] ± 1 nM). Nivolumab binds specifically to PD-1 and not to related members of the CD28 
family such as CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 pathway by nivolumab 
results in a reproducible enhancement of both proliferation and IFN-γ release in the mixed 
lymphocyte reaction. Using a cytomegalovirus (CMV) re-stimulation assay with human peripheral 
blood mononuclear cell (PBMC), the effect of nivolumab on antigen-specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV-specific memory T cells in a 
dose-dependent manner vs isotype-matched control. In vivo blockade of PD-1 by a murine analog 
of nivolumab enhances the anti-tumor immune response and results in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).9
Pre-clinical Results Utilizing Murine Anti-PD-1 and Anti-KIR Antibodies
Pre-clinical studies tested the hypothesis that the combination of anti-KIR and anti-PD-1 would
potentiate anti-tumor efficacy in a murine solid tumor model. Both nivolumab (human anti-PD-1 
antibody) and lirilumab recognize only human sequences. Thus, a murine-specific PD-1 antibody
and anti-Ly49 antibody, an F(ab)2 that recognizes Ly49C/I, which is the KIR homologue in mice,
were used to test this hypothesis. Mice were injected with the syngeneic MC38 murine colon
carcinoma cell line and, following the formation of palpable tumors, they were randomized to 1 of
4 cohorts to receive control IgG, anti-Ly49 antibody, anti-PD-1 antibody, or both antibodies. Mice
treated with a control IgG antibody had rapid growth of tumors (upper left panel of Figure 1-1).
Mice treated with anti-Ly49 antibody (lower left panel of Figure 1-1) did not differ significantly
from control animals. Those treated with a murine anti-PD-1 antibody (upper right panel of
Figure 1-1) showed latency in tumor progression, and 30% of mice continued to be free of tumor.
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Those treated with both antibodies (lower right panel of Figure 1-1) also had latency in tumor
progression and 60% of mice continued to be free of tumor.
Figure 1-1:
Anti-PD-1 and Anti-Ly49C/I (5E6 F(ab’)2) in MC38 Murine Colon 
Carcinoma Model
Female C57BL/6 mice were injected subcutaneously with 2e6 (2 × 106) MC38 tumor cells. After randomization of 
animals, treatments began 7 days later. Mice were treated intraperitoneally on Days 7, 10, and 14 with control mAb, 
anti-PD-1, and/or anti-Ly49C/I (5E6 F[ab’]2). Animals receiving anti-Ly49C/I (5E6 F[ab’]2) were dosed 
additionally on Days 17, 21, and 24. Tumor measurements were taken twice weekly. Shown here are data from 
individual animals.
Fab = fragment antigen-binding; mAb = monoclonal antibody; mIgG = murine immunoglobulin; TF = tumor free.
These results provide pre-clinical evidence of the additive benefit of anti-KIR antibody to
potentiate the efficacy of an anti-PD-1 antibody in a murine solid tumor model.
Clinical Experience with Lirilumab and Nivolumab Combination Treatment 
As of 13-Jul-2017, a total of 322 subjects have been treated with the combination of lirilumab and 
nivolumab in the current study (Study CA223001). AEs evaluated as related to the combination of 
lirilumab and nivolumab were reported in 217 (67.4%) exposed subjects. The most common 
related AEs reported in > 10% subjects were fatigue, 62 (19.3%) subjects; and pruritus, 43 (13.4%) 
subjects; infusion-related reaction, 43 (13.4%) subjects each. Thirty-six (11.2%) subjects reported 
a related Grade 3 or 4 event. Lipase increased were reported in 5 (1.6%) subjects and amylase 
increased, aspartate aminotransferase increased, and infusion related reaction were reported in 4 
(1.2%) subjects each. There were no related Grade 5 events reported. Fourteen (4.3%) subjects 
reported related events leading to study discontinuation. With continued enrollment and follow-up 
of treated subjects, no new safety signals have been identified.
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At the time of Amendment 13, preliminary data from an initial cohort of subjects in 
Study CA223001 suggested a signal of potential efficacy in recurrent or metastatic SCCHN 
subjects with disease progression on or after platinum-based therapy. Specifically, preliminary 
data in 29 evaluable subjects treated with the combination of lirilumab plus nivolumab showed an 
ORR of 24% (7/29) in the all-comer population and an ORR of 41% (7/17) in the PD-L1+ 
population.1 No responses (0/12) were observed in the PD-L1 negative population. To put into 
context nivolumab monotherapy in a similar population of patients with previously treated 
SCCHN (recently approved by the US FDA for the treatment of patients with recurrent or
metastatic SCCHN with disease progression on or after platinum-based therapy) showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥1% 
PD-L1 expression.2 Also of note, in 5 out of the 7 lirilumab plus nivolumab responders, the 
reduction in tumor burden was substantial, exceeding greater than 80%.1 Responses appeared
durable, with the median DOR not reached. 
Subsequent efficacy analysis of additional SCCHN subjects treated with the combination of 
lirilumab and nivolumab did not demonstrate a differential efficacy signal as compared to 
nivolumab monotherapy treatment in a similar population of SCCHN subjects. Efficacy 
parameters analyzed included ORR regardless of tumor PD-L1 status, ORR in PD-L1+ population, 
median PFS and median duration of responses.
Background: Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 Ig 
superfamily that competes with CD28 for B7. CTLA-4-mediated signals are inhibitory and turn 
off T-cell-dependent immune responses.10 Ipilimumab is a fully human monoclonal IgG1κ that 
binds to the CTLA-4 antigen expressed on a subset of T cells from human and non-human 
primates. The proposed mechanism of action for ipilimumab is interference of the interaction of 
CTLA-4 with B7 molecules on antigen-presenting cells, with subsequent blockade of the 
inhibitory modulation of T-cell activation promoted by the CTLA-4/B7 interaction.
Background: Anti-KIR Antibody in Combination with Anti-CTLA-4 Antibodies
Pre-clinical studies tested the hypothesis that the combination of anti-KIR and anti-CTLA-4 
antibodies would potentiate anti-tumor efficacy in a murine AML model. Both lirilumab and 
ipilimumab (human anti-CTLA-4 antibody) recognize only human receptors. Thus, a 
murine-specific anti-CTLA-4 antibody and anti-Ly49C/I (5E6 F(ab’)2) were used to test this 
hypothesis. Mice were infused with the murine leukemia C1498 cell line and randomized to 
1 of 4 cohorts to receive control immunoglobulin (Ig)G antibody, anti-CTLA-4 monoclonal 
antibody, anti-Ly49C/I (5E6 F(ab’)2), or both anti-CTLA-4 monoclonal antibody and 
anti-Ly49C/I (5E6 F(ab’)2). Mice treated with control antibody had a median survival of 25.5 days. 
Mice treated with anti-CTLA-4 did not differ significantly from control animals (median 
26.0 days, P = 0.37). Those treated with anti-Ly49C/I (5E6 F(ab’)2) had prolonged survival 
(median 27.0 days, P = 0.016). Those treated with both antibodies had further prolonged survival 
(median 29.5 days, P < 0.001). It is possible that the combination of the 2 antibodies has a more 
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potent effect than either alone. However, the difference in survival between anti-Ly49C/I (5E6 
F(ab’)2) alone and both antibodies (27.0 days vs 29.5 days, respectively) did not reach statistical 
significance (P = 0.17). It is possible that a prolonged dosing schedule will yield more robust 
results, and that this combination of antibodies will be efficacious in other cancer models. These 
results provide pre-clinical evidence of the benefit of an anti-KIR antibody to potentiate the 
efficacy of an anti-CTLA-4 antibody in a murine AML model.11
Clinical Experience with Lirilumab and Ipilimumab Combination Treatment
CA223002 was primarily designed to evaluate the safety, tolerability, and MTD of lirilumab, an 
anti-KIR monoclonal antibody, when administered in combination with an approved dose of 
ipilimumab in subjects with select advanced tumors. The study was to be conducted in 2 parts, 
with a dose-escalation phase followed by a dose-expansion phase. During the dose-escalation 
phase, subjects received BMS-986015 (0.1, 0.3, 1, or 3 mg/kg) and ipilimumab (3 mg/kg) as 
Induction therapy (every 3 weeks [Q3W] for 4 doses) and then Maintenance therapy (every 
12 weeks [Q12W] for 4 doses) for a total of up to 1.4 years of therapy. 
During the conduct of the dose-escalation phase, the study was terminated for business reasons 
that were unrelated to any AEs associated with the use of lirilumab in this or any other ongoing 
clinical study. No further subjects were enrolled after termination of the study, but subjects already 
receiving treatment in the study were permitted to complete treatment and clinical follow-up as 
per protocol. This report presents results of the evaluation of safety and tolerability (the primary 
objective), as well as preliminary anti-tumor activity (a secondary objective). 
AEs were reported for all 22 (100%) of the subjects treated in this study. The most frequently 
reported AEs (> 25% of all treated subjects) were fatigue (45.5%), nausea (40.9%), malignant 
neoplasm progression (36.4%), back pain (27.3%), diarrhea (27.3%), pneumonia (27.3%), pyrexia 
(27.3%), and vomiting (27.3%). There were no apparent dose-related trends in the occurrence of 
any AEs. Of the 16 subjects for whom best overall response (BOR) was evaluable, 3 subjects had 
a partial response, 5 subjects had stable disease (SD), and 8 subjects had progressive disease (PD). 
In conclusion, lirilumab was generally well tolerated when administered at doses of 0.1 to 1 mg/kg 
in combination with an approved dose of ipilimumab (3 mg/kg) in subjects with advanced or 
metastatic solid tumors.12
To date, the cumulative safety data support a manageable safety profile for lirilumab that is 
consistent with the profile of other immunotherapies.
1.1
Study Rationale
1.1.1
Rationale for the Dose Escalation and Cohort Expansion (Part 1;
Completed) and the SCCHN Cohort Expansion (Part 2; Completed)
Anti-PD-1 monoclonal antibody (nivolumab) is an activator of T-cell responsiveness (ie, adaptive
immunity) and has demonstrated activity in clinical studies for subjects with refractory and
metastatic solid tumors, including NSCLC, renal cell carcinoma (RCC), MEL, and possibly other
tumor types. The safety profile of this agent is tolerable. KIR plays an important role in regulating
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NK-cell activation, and diminution of KIR function is likely to potentiate the innate immune
response. Lirilumab is a fully human anti-KIR monoclonal antibody that has shown minimal side
effects in a Phase 1 study. The aim of this study is to coordinately potentiate adaptive and innate
immunity to enhance the anti-tumor activity of anti-PD-1 antibody by the addition of an anti-KIR
antibody in subjects with advanced solid tumors who currently have poor prognosis and limited
treatment options. The Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort 
Expansion (Part 2) of this study will address the feasibility and safety and preliminary efficacy of
the combined administration of lirilumab and nivolumab. The Dose Escalation and Cohort 
Expansion (Part 1) has completed enrollment, and the SCCHN Cohort Expansion (Part 2) 
of this study will close to enrollment as the SCCHN Randomized Cohorts (Part 3) opens.
1.1.2
Rationale for the SCCHN Randomized Cohorts (Part 3)
With Revised Protocol 12, enrollment in Part 3 is closed.
This cohort will formally assess the efficacy and safety of lirilumab and nivolumab combination 
therapy and nivolumab monotherapy in subjects with advanced or metastatic SCCHN in a 
randomized expansion. 
Head and neck cancers are among the most common cancers worldwide, accounting for more than 
550,000 cases and around 300,000 deaths each year13 and these trends are increasing. In the US, 
~48,330 new cases of oral cavity and pharynx cancer were reported; and ~9,570 people were 
predicted to die of this disease in 2016.14 About ~90% of all head and neck cancers are squamous 
cell. Most SCCHNs arise from the epithelial lining of the oral cavity, oropharynx, larynx, and 
hypopharynx. The most important risk factors identified in SCCHNs include tobacco and alcohol 
use, and in a subgroup of SCCHNs (particularly oropharynx tumors), human papilloma virus 
(HPV) is a strong independent prognostic factor.15 Metastatic and recurrent SCCHN that is no 
longer amenable to local surgical/radiation therapy causes substantial morbidity and high 
mortality, with a median progression-free survival (PFS) of < 6 months and median overall 
survival (OS) of less than 12 months.
Ongoing trials with immune checkpoint inhibitors in SCCHN have shown promising preliminary 
results. A 17.7% ORR has been observed in the ongoing KEYNOTE 012 (NCT01848834) clinical 
trial of 192 subjects with the recurrent/metastatic SCCHN treated with the anti-PD-1 agent 
pembrolizumab.16 Recently, nivolumab was approved by the US FDA for the treatment of patients 
with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. 
The approval was based on results from the Phase 3, CheckMate-141 trial in which nivolumab 
demonstrated statistically significant and clinically meaningful superior OS vs the comparator arm 
(the investigator’s choice of methotrexate, docetaxel, or cetuximab), with a 30% reduction in the 
risk of death (HR = 0.70 [95% CI: 0.53 to 0.92; P = 0.0101]).17 The median OS was 7.5 months 
(95% CI: 5.5 to 9.1) for nivolumab compared to 5.1 months (95% CI: 4.0 to 6.0) for the 
investigator’s choice.2,17 Despite this recent data, patients with recurrent or metastatic SCCHN are 
a population with unmet medical need and combination immunotherapy agents remains an area of 
active clinical evaluation.
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BMS-986015
lirilumab
At the time of Amendment 13, preliminary data from an initial cohort of subjects in 
Study CA223001 suggested a signal of potential efficacy in recurrent or metastatic SCCHN 
subjects with disease progression on or after platinum-based therapy. Specifically, preliminary 
data in 29 evaluable subjects treated with the combination of lirilumab plus nivolumab showed an 
ORR of 24% (7/29) in the all-comer population and an ORR of 41% (7/17) in the PD-L1+ 
population.1 No responses (0/12) were observed in the PD-L1 negative population. To put into 
context nivolumab monotherapy in a similar population of patients with previously treated 
SCCHN (recently approved by the US FDA for the treatment of patients with recurrent or 
metastatic SCCHN with disease progression on or after platinum-based therapy) showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥1% 
PD-L1 expression.2 Also of note, in 5 out of the 7 lirilumab plus nivolumab responders, the 
reduction in tumor burden was substantial, exceeding greater than 80%. Responses appeared
durable, with the median DOR not reached. These results indicate lirilumab plus nivolumab may 
have clinically meaningful greater clinical activity than nivolumab alone, particularly in inflamed 
(PD-L1+) tumors and with little added toxicity.
Furthermore, lirilumab in combination with nivolumab has an acceptable safety profile in subjects 
with advanced refractory solid tumors. The safety profile associated with lirilumab in combination 
with nivolumab was generally consistent with that observed with nivolumab monotherapy. Overall 
treatment-related adverse events (TRAEs) was reported in 114 (72%) subjects, and Grade 3 to 4 
TRAEs were reported in 24 (15%) subjects. Discontinuations due to TRAEs occurred in 12 (8%)
subjects.12
Evaluating lirilumab in combination with nivolumab in subjects with tumor PD-L1+, 
platinum-refractory SCCHN will potentially provide further treatment options for patients with a 
high unmet medical need.
1.1.3
Rationale for the Signal Detection Cohort Expansion (Part 4)
With Revised Protocol 12, Part 4 is removed.
1.1.4
Rationale for the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5 - closed to enrollment) and the 
Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6 - removed)
With Revised Protocol 12, Part 5 is closed to enrollment and Part 6 is removed.
The combination of nivolumab and ipilimumab has a well-established regimen and safety profile.
Nivolumab and ipilimumab clinical activity is well established in multiple tumor types including 
MEL and NSCLC and are described in Section 1.1.4.1. This combination continues to be evaluated 
in a range of tumor types including RCC, BC, SCCHN. 
The safety profile of nivolumab and ipilimumab is well characterized from a large safety database 
at different dose and schedules as monotherapy or in combination. Consistent with the mechanism 
of action of nivolumab and ipilimumab, the most frequently reported drug-related AEs observed 
in clinical trials are those associated with activation of the immune system. The most common 
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lirilumab
types of immune-mediated AEs include endocrinopathies, diarrhea/colitis, hepatitis, pneumonitis, 
nephritis, and rash. In the combination regimen, the frequency and intensity of these events may 
vary and will depend on the specific dose and schedule used. Study CA209012 evaluating multiple 
dose regimens of nivolumab in combination with ipilimumab showed numerically higher response 
rates in cohorts evaluating the approved dose of nivolumab 3 mg/kg and the safety of combination 
improved with the lower dose of ipilimumab, 1 mg/kg was given less frequently (Q6W or Q12W) 
(See Section 1.1.4.1). Therefore the combination dosing schedule selected for this study 
(nivolumab 3 mg/kg every 2 weeks [Q2W] plus ipilimumab 1 mg/kg every 6 weeks [Q6W]) 
utilizes the approved nivolumab dose and provides the highest dose and frequency of ipilimumab 
feasible in a combination regimen where the immune-mediated AEs were mostly low grade and 
manageable with prompt use of corticosteroids (see Section 1.1.4.1).
Safety Profile of Lirilumab in Combination with Nivolumab and with Ipilimumab
Safety and preliminary efficacy of lirilumab in combination with nivolumab and ipilimumab have 
been described in Section 1 “Clinical Experience with Lirilumab and Ipilimumab Combination 
Treatment” and “Clinical Experience with Lirilumab and Nivolumab Combination Treatment.” To 
date, the cumulative safety data support a manageable safety profile for lirilumab in combination 
with nivolumab and ipilimumab that is consistent with the profile of other immunotherapies. 
Therefore, it is not expected that the addition of lirilumab will add additional toxicities to the 
known safety profile of nivolumab and ipilimumab.
As an additional safety measure, initially approximately 10 subjects will be enrolled and followed 
for at least 4 weeks of safety assessment from the start of study drug administration before 
additional subjects are enrolled in the study to ensure there is no major safety signal with the 
combination. Any findings will be discussed between the BMS Medical Monitor and investigators 
and an agreement will be reached as to whether a lower dose or an alternate dose schedule should 
be examined or whether any additional treatment guidelines should be implemented prior to 
enrollment of additional subjects on study.
Biological Rationale for the Combination of Lirilumab with Nivolumab and Ipilimumab
As described in Section 1 “Background of NK cells and KIR in Inflamed Tumors,” immune 
infiltrate analysis in the inflamed tumors such as SCCHN and MEL, show infiltration with Tregs 
and KIR-overexpressing CD56dim NK cells, to a higher degree than other cancer types. These 
findings suggest that head and neck tumors possess an immune landscape that is poised to respond 
to immunotherapeutic approaches that block inhibitory signals to T cells and NK cells, such as 
immune checkpoint inhibitors (nivolumab and ipilimumab), including antibodies blocking KIR 
signaling (lirilumab).
Therefore, the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5) will evaluate if the addition of ipilimumab, a Treg-targeted agent will 
enhance the efficacy seen with the combination of lirilumab and nivolumab in SCCHN. 
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BMS-986015
lirilumab
1.1.4.1
Experience with Nivolumab and Ipilimumab Combination Treatment
Pre-clinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may
improve anti-tumor 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 
anti-tumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer 
models. In a murine MEL 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 
Tregs, as compared to either agent alone.18
Clinical activity of nivolumab and ipilimumab combination was evaluated in subjects with 
stage IV non-squamous cell lung cancer (NSCLC) as first line treatment in CA209012 study.19
This was a large phase 1, multi-arm safety study of nivolumab monotherapy and nivolumab in 
combination with various systemic anticancer therapies like ipilimumab, platinum based 
chemotherapies and EGFR tyrosine kinase inhibitor.
The regimens for these cohorts were:
•
Arm N (n=31): nivolumab 1 mg/kg + ipilimumab 1 mg/kg Q3W for 4 cycles, followed by 
nivolumab 3 mg/kg Q2W
•
Arm O (n=40): nivolumab 1 mg/kg Q2W + ipilimumab 1 mg/kg Q6W
•
Arm P (n=38): nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q12W
•
Arm Q (n=39): nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W
The most frequently reported drug-related AEs in the newer nivolumab plus ipilimumab cohorts 
were fatigue (29.0%), diarrhea (25.0%), pruritus (23.7%), and fatigue (23.1%) in arms N, O, P, 
and Q, respectively. Drug-related SAEs reported in more than 2 subjects/cohort treated in the 
newer nivolumab plus ipilimumab cohorts were adrenal insufficiency, hypophysitis, pneumonitis, 
autoimmune hepatitis, diarrhea, colitis, and acute kidney injury. Drug-related Grade 3 to 4 AEs 
were reported in 9 (29.0%) subjects in Arm N, 16 (40.0%) subjects in Arm O, 14 (36.8%) subjects 
in Arm P, and 13 (33.3%) subjects in Arm Q. Drug-related AEs leading to discontinuation 
reported in more than 1 subject treated in the new nivolumab plus ipilimumab arms included 
alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, colitis, 
myalgia, pneumonitis, rash, autoimmune hepatitis, infusion-related reaction, facial nerve disorder, 
esophagitis, and transaminases increased. Most deaths in CA209012 were due to disease 
progression. The only deaths reported due to study drug toxicity were in the nivolumab + 
ipilimumab original treatment groups (respiratory failure following Grade 3 colitis, pulmonary 
hemorrhage, and toxic epidermal necrolysis in a subject with a history of ulcerative colitis). 
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lirilumab
Clinical activity was observed in all combination cohorts but numerically higher response rates 
were observed in cohorts evaluating the approved dose of nivolumab 3 mg/kg, with confirmed 
response rates ≥ 39% (cohorts P and Q).19 With comparable efficacy and safety data from cohorts 
P and Q, the nivolumab plus ipilimumab every 6 week (Q6W) dosing schedule (cohort Q) was the 
selected regimen moving forward.20 Aside from utilizing the approved nivolumab dose in NSCLC, 
it would also provide the highest dose and frequency of ipilimumab feasible in a combination 
regimen.
To date, there are no data on the combination of nivolumab and ipilimumab in SCCHN. CA209714 
and CA209651 are studies evaluating this combination of nivolumab 3 mg/kg Q2W and 
ipilimumab 1 mg/kg Q6W in SCCHN and are ongoing.
Given the similarity in patient profiles of NSCLC and SCCHN, and that nivolumab 3 mg/kg Q2W
and ipilimumab 1 mg/kg Q6W have shown adequate safety and increased efficacy compared to 
single agent nivolumab in CA209012, our hypothesis is that we will see a similar effect in SCCHN.
Given that the safety profile of lirilumab in combination with nivolumab (see Section 1: “Clinical 
Experience with Lirilumab and Nivolumab Combination Treatment”) and ipilimumab is not 
different as compared to nivolumab or ipilimumab monotherapy, respectively, with the exception 
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BMS-986015
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of infusion reactions, which were only Grade 1 and 2, easily manageable, and did not lead to 
discontinuations, it is not anticipated that the addition of lirilumab at 3 mg/kg every 4 weeks 
(Q4W) to the combination of nivolumab 3 mg/kg Q2W and ipilimumab 1 mg/kg Q6W will 
increase the toxicity of the regimen.
Similarly, clinical activity of lirilumab when added to nivolumab plus ipilimumab has the potential 
to enhance the activity seen with nivolumab and ipilimumab in MEL. Nivolumab and ipilimumab 
in combination in subjects with previously untreated, unresectable or metastatic MEL evaluated in 
CA209067, a randomized Phase 3 study, demonstrated improved PFS; the median PFS was 
11.5 months (95% CI, 8.9 to 16.7) in the nivolumab-plus-ipilimumab group, 6.9 months (95% 
confidence interval [CI], 4.3 to 9.5) in the nivolumab group, and 2.9 months (95% CI, 2.8 to 3.4) 
in the ipilimumab group. 
1.2
Research Hypothesis
1.2.1
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed)
It is anticipated that the combination of anti-KIR antibody (lirilumab) and anti-PD-1 antibody
(nivolumab) will demonstrate adequate safety and tolerability at pharmacologically relevant doses
and suggest preliminary signs of clinical activity so as to permit further clinical testing.
1.2.2
The SCCHN Randomized Cohorts (Part 3 - Closed to enrollment)
It is anticipated that treatment with nivolumab alone or in combination with lirilumab will lead to 
clinically meaningful tumor reductions, as measured by ORR, in subjects with platinum-refractory 
recurrent or metastatic SCCHN who are PD-L1+.
1.2.3
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
1.2.4
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - Closed to enrollment)
It is anticipated that the triplet regimen of anti-KIR antibody (lirilumab), anti-PD-1 antibody 
(nivolumab), and anti-CTLA-4 antibody (ipilimumab) to treat subjects with platinum-refractory 
recurrent or metastatic SCCHN will demonstrate adequate safety and tolerability at 
pharmacologically relevant doses for further clinical testing. 
1.2.5
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
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BMS-986015
lirilumab
1.3
Objectives
1.3.1
Primary Objective
1.3.1.1
Primary Objective for the Dose Escalation and Cohort Expansion 
(Part 1; Completed) and the SCCHN Cohort Expansion (Part 2; 
Completed)
The Dose Escalation and Cohort Expansion (Part 1): To assess the safety and tolerability of
lirilumab given in combination with nivolumab and to identify DLTs and the MTD of the
combination in subjects with advanced (metastatic and/or unresectable) solid tumors.
The SCCHN Cohort Expansion (Part 2): To assess the safety and preliminary anti-tumor activity
of the combination of lirilumab and nivolumab in subjects with advanced solid tumors.
1.3.1.2
Primary Objective for the SCCHN Randomized Cohorts (Part 3 - closed 
to enrollment)
To estimate the ORR of lirilumab given in combination with nivolumab in subjects with recurrent
or metastatic SCCHN that has relapsed or progressed within 6 months of the last dose of a
platinum-containing therapy and whose tumors express PD-L1.
1.3.1.3
Primary Objective for the Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
1.3.1.4
Primary Objective for the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5 - closed to enrollment)
To assess the safety and preliminary anti-tumor activity of the combination of lirilumab with 
nivolumab and ipilimumab in subjects with platinum-refractory recurrent or metastatic SCCHN.
1.3.1.5
Primary Objective for the Signal Detection in Previously Untreated MEL 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
1.3.2
Secondary Objectives
1.3.2.1
Secondary Objectives for the Dose Escalation and Cohort Expansion 
(Part 1; Completed) and the SCCHN Cohort Expansion (Part 2;
Completed)
The secondary objectives are as follows:
•
To characterize the PK of lirilumab and nivolumab when co-administered.
•
To monitor immunogenicity of lirilumab and nivolumab when administered as combination 
therapy.
•
To assess the pharmacodynamic effect in tumor tissue on TIL subsets from MEL and SCCHN 
subjects treated with lirilumab given in combination with nivolumab.
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BMS-986015
lirilumab
1.3.2.2
Secondary Objectives for the SCCHN Randomized Cohorts (Part 3 -
closed to enrollment)
The secondary objectives are as follows:
•
To estimate disease control rate (DCR), DOR, and time to response of lirilumab given in 
combination with nivolumab.
•
To assess depth of response of lirilumab given in combination with nivolumab and of 
nivolumab monotherapy.
•
To assess the OS of lirilumab given in combination with nivolumab and nivolumab 
monotherapy.
•
To assess the PFS of lirilumab given in combination with nivolumab and nivolumab 
monotherapy.
•
To estimate the ORR by investigator assessment of lirilumab given in combination with 
nivolumab and nivolumab monotherapy.
•
To assess the safety of lirilumab given in combination with nivolumab in subjects with 
SCCHN.
1.3.2.3
Secondary Objectives for the Signal Detection Cohort Expansion 
(Part 4)
Removed with Revised Protocol 12.
1.3.2.4
Secondary Objectives for the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment)
The secondary objective is as follows:
•
To estimate DOR of lirilumab given in combination with nivolumab and ipilimumab.
•
To assess depth of response of lirilumab given in combination with nivolumab and ipilimumab.
•
To characterize the PK and immunogenicity of lirilumab in combination with nivolumab and 
ipilimumab.
•
To investigate the immunomodulatory properties of lirilumab in combination with nivolumab 
and ipilimumab, and to evaluate potential baseline and on-treatment biomarkers in peripheral 
blood and tumor for association with efficacy in subjects with platinum-refractory recurrent or 
metastatic SCCHN.
•
To explore biomarkers of lirilumab in combination with nivolumab and ipilimumab as therapy 
in all subjects with platinum-refractory recurrent or metastatic SCCHN.
1.3.2.5
Secondary Objectives for the Signal Detection in Previously Untreated 
MEL with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
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BMS-986015
lirilumab
Revised Protocol No.: 12
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BMS-986015
lirilumab
1.4
Product Development Background
Additional information for lirilumab (anti-KIR antibody), nivolumab (anti-PD-1 antibody), and 
ipilimumab (anti-CTLA-4 antibody) follows and is also available in the respective Investigator
Brochures (IBs).19,21,22
1.4.1
Lirilumab: Pharmacology
Lirilumab is a fully human IgG4 monoclonal antibody that binds specifically and with high affinity 
to a subset of KIRs, namely KIR2DL-1, -2 and -3 and KIR2DS-1 and -2, thus preventing 
interaction between KIR and HLA-C. Surface plasmon resonance analysis demonstrated that the 
mean monovalent affinity of lirilumab for recombinant soluble KIR2DL-1 was 2.04 × 10-8 M 
(standard deviation 0.31 × 10-8) and that for KIR2DL-3 was 3.01 × 10-10 M (standard deviation 
0.41 × 10-10).
1.4.2
Lirilumab: Toxicity
Neither lirilumab nor IPH-2101 binds to NK cells from non-human primate or other species 
traditionally used for safety testing. Safety testing was performed in mice because Ly49C/I, the 
murine inhibitory receptor, is functionally homologous to human KIR. There were no adverse 
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BMS-986015
lirilumab
findings in mice treated with lirilumab at 10 mg/kg once weekly for 4 weeks or with the surrogate 
anti-Ly49 antibody 5E6 F(ab’)2 10 mg/kg twice weekly for 13 weeks.
1.4.3
Lirilumab: Pre-clinical Metabolism and Pharmacokinetics
Please see the most recent IB for lirilumab for current data.21
1.4.4
Lirilumab: Clinical Pharmacology and Safety
As of the data cut-off for the current lirilumab IB (13-Jul-2017)21, 550 subjects have been treated 
with lirilumab or placebo in 2 completed, 2 ongoing, and 1 terminated trials: 1 monotherapy Phase 
1 trial, 1 monotherapy placebo-controlled Phase 2 trial, 1 combination therapy Phase 1/2 trial, and 
2 combination therapy Phase 1 trials. Of those subjects, 37 subjects received lirilumab 
monotherapy (Study CA223003, Study IPH2102-101), 152 subjects received either lirilumab 
monotherapy or placebo in a 2:1 ratio (Study CA223004, Study IPH2102-201), 322 subjects 
received lirilumab in combination with nivolumab (Study CA223001), 22 subjects received 
lirilumab in combination with ipilimumab (Study CA223002), and 17 subjects received 
elotuzumab in combination with lirilumab (Study CA223028). In total, approximately 
499 subjects received lirilumab. The majority of AEs in these 5 trials were mild or moderate 
(Grade 1 or 2), self-limiting, and manageable. The most common related AEs in the monotherapy 
trials were asthenia, bronchitis, diarrhea, headache, fatigue, pruritus, and thrombocytopenia. The 
most common related AEs in the combination trials were fatigue, infusion-related reaction, 
pruritus, rash, nausea, chills, diarrhea, rash maculo-papular, and pyrexia. The data to date support 
a positive safety profile of lirilumab. 
1.4.4.1
Pharmacokinetics of Lirilumab
Final PK data from 1 Phase 1 and preliminary PK data from 2 Phase 1 studies that investigated 
escalating doses of lirilumab monotherapy (Study CA223003, Study IPH2102-101) or 
combination therapy with nivolumab (Study CA223001) or ipilimumab (Study CA223002) are 
presented below. Validated ligand binding assay methods were used to detect lirilumab, 
nivolumab, and ipilimumab in human serum.
A PK model suggests that the PK profile of lirilumab is likely to be comparable to IPH-2101. In 
previous IPH-2101 Phase 1 clinical studies in subjects with AML and multiple myeloma, a 
2-compartment model with first order elimination was found to adequately describe the data with 
dose-dependent clearance (CL), such that CL decreased with increasing doses. The terminal 
half-life (T-HALF) at the highest dose (3 mg/kg) was determined to be within 15 to 21 days, which 
is consistent with reported values in the literature.
In Study CA223001, PK of lirilumab at a Dose Level of 0.1 to 3 mg/kg in combination with 
nivolumab 3 mg/kg was characterized after the first and fourth doses of lirilumab, based on the 
availability of the preliminary data. The accumulation ratio based on the area under the plasma 
concentration-time curve (AUC) following the fourth dose compared to the first dose ranged from 
1.4 to 1.5, resulting in a mean effective T-HALF of BMS-986015 of 16 to 17 days. For the 
nivolumab 3-mg/kg Dose Level, across different Dose Levels of lirilumab, the geometric mean of 
maximum observed concentration (Cmax) and trough observed concentration (Cmin) after the first 
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dose were 59.8 μg/mL and 17.9 μg/mL, respectively, and after the seventh dose were 111.5 μg/mL 
and 61.7 μg/mL, respectively, which are consistent with PK parameters obtained after 
administration of nivolumab monotherapy.
In Study CA223002, PK of lirilumab at Dose Levels of 0.1 to 1 mg/kg in combination with 
ipilimumab (BMS-734016) 3 mg/kg was characterized after the first and fourth doses of lirilumab, 
based on the availability of the preliminary data. The geometric mean accumulation index was 1.4. 
For the ipilimumab 3-mg/kg Dose Level, across different Dose Levels of lirilumab, the geometric 
mean of Cmax and Cmin after the first dose was 66.5 μg/mL and 8.9 μg/mL, respectively, and the 
geometric mean of Cmax and Cmin after the fourth dose was 74.9 μg/mL and 13.0 μg/mL, 
respectively. These values are consistent with PK parameters obtained after administration of 
ipilimumab monotherapy.
1.4.5
Nivolumab: Pharmacology
Nivolumab is a fully human IgG4 monoclonal antibody that binds to PD-1 with nanomolar affinity
(KD = 3.06 nM) and a high degree of specificity, thus precluding binding to its ligands PD-L1 and
PD-L2. Nivolumab does not bind to other related family members, such as BTLA, CTLA-4, ICOS,
or CD28. Pre-clinical testing of nivolumab demonstrated that binding to PD-1 results in enhanced
T-cell proliferation and release of IFN-γ in vitro.
1.4.6
Nivolumab: Toxicity
Toxicology studies in cynomolgus monkeys revealed that nivolumab was well tolerated at doses
up to 50 mg/kg given twice weekly for 27 doses. Serum chemistry changes were limited to a
reversible 28% decrease in triiodothyronine in females without concomitant abnormalities in other
markers of thyroid function.
Preliminary new non-clinical safety findings of adverse pregnancy outcomes and infant losses in
the absence of overt maternal toxicity have been reported.23 The findings of increased late-stage
pregnancy loss and early infant deaths/euthanasia in nivolumab-exposed pregnant monkeys
suggest a potential risk to human pregnancy if there is continued treatment with nivolumab during
pregnancy.
Additional non-clinical information on nivolumab toxicity can be found in the IB for nivolumab.19
1.4.7
Nivolumab: Pre-clinical Metabolism and Pharmacokinetics
Please see the most recent IB for nivolumab for current data.19
1.4.8
Nivolumab: Clinical Pharmacology and Safety
Extensive details on the safety profile of nivolumab are available in the IB and will not be repeated 
herein.19
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical studies 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, 
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severity, or causality of AEs with respect to nivolumab Dose Level. The safety profile of 
nivolumab combination therapy varies with the agent combined with nivolumab but is generally 
consistent with the safety profiles observed with either agent alone, and in some cases, both 
frequency and severity of AEs were greater than those observed with either agent alone.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 1. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (HRT; endocrinopathies) as instructed in 
these algorithms. Nivolumab should not be used in subjects with active autoimmune disease, given 
the mechanism of action of the antibody.
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.19
1.4.8.1
Pharmacokinetics of Nivolumab
The PK of nivolumab were studied in subjects over a dose range of 0.1 to 20 mg/kg administered 
as a single dose or as multiple doses of nivolumab Q2W or Q3W. Based on a population 
pharmacokinetics (PPK) analysis using data from patients with various tumor types, including 
MEL, NSCLC, and RCC and a time varying CL model, nivolumab CL was shown to decrease 
over time, with a median maximal reduction from baseline values of approximately 25% resulting 
in a geometric mean steady state clearance (CLss) (percent coefficient of variation [% CV]) of 8.2
mL/h (53.9%). The decrease in CLss is not considered to be clinically relevant. The geometric 
mean [% CV] apparent volume of distribution at steady state (Vss) is 6.8 L (27.3%), and geometric 
mean elimination T-HALF is 25 days (77.5%). Steady-state concentrations of nivolumab were 
reached by 12 weeks when administered at 3 mg/kg Q2W, and systemic accumulation was 
approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over the dose 
range of 0.1 to 10 mg/kg administered Q2W. The CL of nivolumab increased with increasing body 
weight. The PPK analysis suggested that the following factors had no clinically important effect 
on the CL of nivolumab: age (29 to 87 years), gender, race, baseline lactate dehydrogenase, PD-
L1, solid tumor type, baseline tumor size, and hepatic impairment. 
Although Eastern Cooperative Oncology Group (ECOG) status, baseline glomerular filtration rate, 
albumin, body weight, had an effect on nivolumab CL, the effect was not clinically meaningful. 
PPK analysis suggested that nivolumab CL in subjects with cHL was approximately 32% lower 
relative to subjects with NSCLC; however, the lower CL in cHL subjects was not considered to be 
clinically relevant as nivolumab exposure was not a significant predictor for safety risks for these 
patients.
Full details on the clinical pharmacology aspects of nivolumab can be found in the IB.19
1.4.9
Ipilimumab: Pharmacology
Ipilimumab is a fully human IgG1κ monoclonal antibody that has specificity and a high affinity
for human CTLA-4. The calculated dissociation constant value from an average of several studies 
was 5.25 nM. Binding of ipilimumab to purified, recombinant human CTLA-4 antigen was also 
demonstrated by enzyme-linked immunosorbent assay with half-maximal binding at 15 ng/mL, 
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whereas saturation was observed at approximately 0.1 μg/mL. No cross-reactivity was observed 
against human CD28. Ipilimumab completely blocked binding of B7.1 and B7.2 to human CTLA-
4 at concentrations higher than 6 and 1 μg/mL, respectively. 
1.4.10
Ipilimumab: Toxicity
In IV repeat-dose toxicology studies in monkeys, ipilimumab was tolerated without adverse effects 
at doses up to 30 mg/kg/day administered every 3 days for 3 doses,24,25,26 at 10 mg/kg (equivalent 
to human dose on body-weight basis) administered weekly for 1 month,27 at 1 mg/kg administered 
weekly for 10 weeks,28 and at doses up to 10 mg/kg/day administered approximately monthly for 
up to 6 months.27,28,29,30 In the pivotal 6-month toxicity study (10 mg/kg administered on Days 0, 
28, 56, 84, and 140), treatment-related findings were limited to decreases in absolute and relative 
thyroid (44% to 50%) and testicular (27% to 50%) weights. However, there were no corresponding 
microscopic changes in these organs, and thus, 10 mg/kg was considered to be the no observable 
adverse effect level.30
In addition, increased incidences of third-trimester abortion, stillbirth, premature delivery, low 
birth weight, and infant mortality occurred following IV administration of ipilimumab to pregnant 
cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses 
of 2.6 or 7.2 times higher than the clinical exposure at a dose of 3 mg/kg or 0.9 to 2.1 times higher 
than the clinical exposure at a dose of 10 mg/kg every 21 days of ipilimumab. Based on the results 
of the monkey reproductive study, ipilimumab is not recommended for use during pregnancy 
unless the potential benefit justifies the potential risk to the fetus.
1.4.11
Ipilimumab: Pre-clinical Metabolism and Pharmacokinetics
Please see the most recent IB for ipilimumab for current data.22
1.4.12
Ipilimumab: Clinical Pharmacology and Safety
More than 19,500 subjects have been enrolled in ipilimumab studies in several cancer types in 
completed and ongoing studies, as well as a compassionate use program. The focus of the clinical 
program is in MEL, prostate cancer, and lung cancer, with advanced MEL being the most 
comprehensively studied indication. Ipilimumab is being investigated both as monotherapy and in 
combination with other modalities such as chemotherapy, radiation therapy, and other 
immunotherapies. 
Phase 3 programs are ongoing in MEL, prostate cancer, and lung cancer. In MEL, 2 completed 
Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically meaningful and 
statistically significant survival benefit in pre-treated advanced MEL and previously untreated 
advanced MEL, respectively. The safety profile of ipilimumab is generally consistent across these 
trials with a) the majority AEs being inflammatory in nature, which is consistent with the proposed 
mechanism of action of ipilimumab; b) the same types of such immune-mediated events in the 
gastrointestinal tract, skin, liver, and endocrine system being reported; and c) most of these events 
being manageable with immune suppressive therapies.
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Additional details on the safety profile of ipilimumab, including results from clinical studies, are 
available in the ipilimumab IB.22
1.4.12.1
Pharmacokinetics of Ipilimumab
The PK of ipilimumab has been extensively studied in subjects with MEL at the 3- and 10-mg/kg 
doses administered as a 1.5-hour IV infusion. The PK of ipilimumab was characterized by 
population PK (PPK) analysis and determined to be linear and time invariant in the dose range of 
0.3 to 10 mg/kg. The mean CL (± standard deviation) value after IV administration of 10 mg/kg 
was 18.3 ± 5.88 mL/h, and the mean Vss (± standard deviation) value was 5.75 ± 1.69 L. 
The PPK of ipilimumab was studied in 785 subjects (3200 serum concentrations) with advanced 
MEL in 4 Phase 2 studies (CA184004, CA184007, CA184008, and CA184022),31 1 Phase 3 study 
(CA184024), and 1 Phase 1 study (CA184078). The PPK analysis demonstrated that the PK of 
ipilimumab is linear, the exposures are dose proportional across the tested dose range of 0.3 to 
10 mg/kg, and the model parameters are time invariant, similar to that determined by 
non-compartmental analyses. Volume of central compartment (Vc) and peripheral compartment 
were found to be 4.35 and 3.28 L, respectively, suggesting that ipilimumab first distributes into 
plasma volume and, subsequently, into extracellular fluid space. CL of ipilimumab and Vc were 
found to increase with increase in body weight. However, there was no significant increase in 
exposure with increase in body weight when dosed on a milligram per kilogram basis, supporting 
dosing of ipilimumab based on a weight-normalized regimen. The PK of ipilimumab is not affected 
by age, gender, race, and immunogenicity (anti-drug antibody [ADA] status); concomitant use of 
chemotherapy; prior therapy; body weight; performance status; or tumor type. Other covariates 
had effects that were either not statistically significant or were of minimal clinical relevance.
1.4.13
Rationale for Selection of Schedule, Dose, and Tumor Types
1.4.13.1
Rationale for Schedule, Dose, and Tumor Types for the Dose Escalation
and Cohort Expansion (Part 1; Completed) and the SCCHN Cohort 
Expansion (Part 2; Completed): Lirilumab and Nivolumab Weight-based
Dosing
The nivolumab dose of 3 mg/kg is an active dose that is well tolerated. Doses of lirilumab given
as a single agent have ranged from 0.1 to 10 mg/kg, resulted in pharmacodynamic modulation of
the target, and been well tolerated. This is the first study evaluating the combination of these
2 antibodies. Therefore, the nivolumab dose will remain constant at 3 mg/kg and the lirilumab
antibody will be tested in dose escalation at 0.1, 0.3, 1, and 3 mg/kg. Based on further data that
may emerge, evaluating higher Dose Levels will be considered as appropriate. This is a Phase 1/2
study to determine the safety of the antibodies given in combination, so all subjects with solid
tumors (with the exception of primary central nervous system [CNS] tumors) are eligible to
participate during dose escalation. Nivolumab has shown clinical benefit in subjects with various
solid tumors. Thus, following dose escalation, subjects with select tumor types will be eligible to
participate in the cohort expansion part of the study in order to gather additional safety, tolerability,
preliminary efficacy, and pharmacodynamic information regarding the combination of lirilumab
and nivolumab.
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1.4.13.2
Rationale for Schedule, Dose, and Tumor Types for the SCCHN 
Randomized Cohorts (Part 3 - closed to enrollment) and the Signal 
Detection Cohort Expansion (Part 4 - removed): Flat Doses
A flat dose of nivolumab 240 mg Q2W (Study Days 1, 15, 29, and 43 in an 8-week cycle) will be
used in combination with a flat dose of lirilumab 240 mg Q4W (Study Days 1 and 29) in the
SCCHN Randomized Cohorts (Part 3) either in combination with lirilumab or as monotherapy in 
combination with placebo for lirilumab.
Nivolumab monotherapy has been extensively studied in the NSCLC patient population in Studies 
CA209003, CA209063, CA209017, and CA209057 with body-weight-normalized dosing 
(milligram per kilogram). Nivolumab PK and exposures of subjects in these studies have been 
characterized by PPK analysis of data collected from these studies, together with PK data from 
several Phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. Nivolumab 
PK was determined to be linear, with dose-proportional exposures over a dose range of 0.1 to 
10 mg/kg. Nivolumab CL and volume of distribution were found to increase with increasing body 
weight, but the increase was less than proportional, indicating that a milligram per kilogram dose 
represents an over-adjustment for the effect of body weight on nivolumab PK. Conversely, given 
the relationship between nivolumab PK and body weight, a flat dose is expected to lead to lower 
exposures in heavier subjects, relative to the exposures in lighter subjects.
Table 1.4.13.2-1 presents summary statistics of the estimated nivolumab steady-state trough, peak,
and time-averaged concentration (steady-state trough concentration [Cminss], steady-state peak 
concentration [Cmaxss], and time-averaged concentration at dosing interval [Cavgss], 
respectively) in NSCLC subjects receiving 3 mg/kg, together with corresponding statistics of 
exposures predicted for a flat dose of nivolumab 240 mg. It should be noted that a dose of 
nivolumab 240 mg is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is the 
approximate median body weight of NSCLC subjects in the 3 Phase 2 and 3 clinical studies of 
nivolumab monotherapy in NSCLC subjects (CA209017, CA209057, and CA209063). As evident 
from the data presented in Table 1.4.13.2-1, the geometric mean values of Cminss, Cmaxss, and 
Cavgss with flat dosing are slightly (< 15%) higher than that produced by a 3-mg/kg dose, and the 
%CV in these measures of exposure is only slightly (< 10%) greater than that of the 3-mg/kg 
dosing.
Table 1.4.13.2-1:
Summary Statistics of Nivolumab Steady-state Exposure
Nivolumab Dose
Cminss Geo. Mean
[μg/mL] (%CV)
Cmaxss Geo. Mean
[μg/mL] (%CV)
Cavgss Geo. Mean
[μg/mL] (%CV)
240 mg
61.5 (44.6)
133.7 (35.0)
82.4 (38.2)
3 mg/kg
54.7 (41.9)
118.9 (31.8)
73.3 (35.6)
Geo = geometric.
Nivolumab has been shown to be safe and well tolerated up to a Dose Level of 10 mg/kg, and the 
relationship between nivolumab exposure produced by 3 mg/kg and efficacy has been found to be 
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relatively flat. Taken together, the PK, safety, and efficacy data indicate that the safety and efficacy 
profile of nivolumab 240 mg will be similar to that of nivolumab 3 mg/kg and will be used in 
Part 3. 
The PK and safety of nivolumab have been evaluated in the Asian population. The comparison of 
PK parameters in global and Japanese subjects suggests that the PK of nivolumab is similar in 
these populations. Nivolumab is shown to be safe and well tolerated in Japanese subjects. The 
similar PK and safety profile of nivolumab between global and Japanese subjects supports the use 
of similar dosing in the Asian population as is being used in global clinical studies.
Based on these data, a flat dose of nivolumab 240 mg Q2W is appropriate for further investigation.
Lirilumab is being studied as a potential immunotherapy alone and in combination with other 
agents in subjects with various hematologic malignancies and solid tumors with body weight 
normalized dosing (milligram per kilogram). A preliminary PPK analysis of data collected from 3 
studies (CA223001, CA223002, and CA223003) suggests that lirilumab PK is linear, with dose 
proportional exposures over a dose range of 0.1 to 10 mg/kg. Lirilumab CL and volume of 
distribution was found to increase with increasing body weight, but the increase was less than 
proportional, indicating that a milligram per kilogram dose represents an over-adjustment for the 
effect of body weight on lirilumab PK. Conversely, given the relationship between lirilumab PK 
and body weight, a flat dose is expected to lead to lower exposures in heavier subjects, relative to 
the exposures in lighter subjects. 
Table 1.4.13.2-2 presents summary statistics of the estimated lirilumab peak and trough 
concentrations after the 1st dose and steady state (Cmin1, Cmax1, Cminss and Cmaxss) in subjects 
receiving 3 mg/kg, together with corresponding statistics of exposures predicted for a flat lirilumab 
dose of 240 mg. It should be noted that a dose of lirilumab 240 mg is identical to a dose of 3 mg/kg 
for subjects weighing 80 kg. As evident from the data presented in Table 1.4.13.2-2, the geometric 
mean values of Cmin1, Cmax1, Cminss and Cmaxss with flat dosing are slightly higher (< 10% 
difference) than that produced by a 3 mg/kg dose.
Table 1.4.13.2-2:
Summary Statistics of Predicted Lirilumab Exposure
Lirilumab Dose
Cmin1 Geo. Mean
[μg/mL] (cv %)
Cmax1 Geo. Mean
[μg/mL] (cv %)
Cminss Geo. Mean
[μg/mL] (cv %)
Cmaxss Geo. Mean
[μg/mL] (cv %)
240 mg
8.897 (61.06)
66.113 (40.06)
14.262 (85.26)
83.209 (41.25) 
3 mg/kg
8.261 (58.61)
61.513 (37.54)
13.263 (81.98)
77.678 (38.49)
Lirilumab has been shown to be well tolerated up to a dose level of 10 mg/kg. Similar observations 
have been made for nivolumab, which was converted from a weight-based dose to a flat dose. 
Taken together, the PK, safety, and efficacy profile of lirilumab 240 mg is expected to be similar 
to that of lirilumab 3 mg/kg and will be used in combination with nivolumab 240 mg Q2W in the 
SCCHN Randomized Cohorts (Part 3) to maintain continuity in order to pursue and confirm an 
ongoing signal (from the SCCHN Cohort Expansion [Part 2]). Doses of lirilumab given as a single 
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agent have ranged from 0.1 to 10 mg/kg, resulted in pharmacodynamic modulation of the target, 
and have been well tolerated.
For the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination 
(Part 5), utilizing the triple combination of lirilumab, nivolumab, and ipilimumab for the first time, 
the study drugs will be administered using the milligram per kilogram dosing regimen to assess 
safety of this combination before other dosing regimens (including flat dosing) will be considered.
1.4.13.3
Rationale for Schedule and Dose for the Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed 
to enrollment) or the Signal Detection in Previously Untreated MEL with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6 - removed): 
Lirilumab, Nivolumab, and Ipilimumab Weight-based Dosing
As of 30-Aug-2016, 159 subjects were treated with the lirilumab plus nivolumab combination in 
Study CA223001. Nivolumab was administered at 3 mg/kg Q2W and lirilumab was administered 
Q4W at doses ranging from 0.1 mg/kg to 3 mg/kg. Most of the 159 treated subjects were treated 
at the nivolumab 3 mg/kg + lirilumab 3 mg/kg Dose Level. TRAEs and Grade 3 to 4 TRAEs were 
reported in 72% (114/159) and 15% (24/159) of subjects, respectively. Discontinuations due to 
TRAEs occurred in 8% (12/159) of subjects. The rates of AEs of the combination of lirilumab and 
nivolumab are consistent to what has been reported with nivolumab monotherapy with the 
exception of infusion related reactions which were higher in the combination. These infusion 
reactions were Grade 1 and 2 events only, which occurred mainly with the first infusion and did 
not lead to discontinuation.
As of 15-Jul-2016, 22 subjects were treated with the lirilumab plus ipilimumab combination in 
Study CA223002. Ipilimumab was administered at 3 mg/kg and lirilumab was administered at 
doses ranging from 0.1 to 3 mg/kg. Subjects received lirilumab in combination with ipilimumab 
Q3W for a total of 4 doses (induction), and then Q12W for an additional 4 doses starting at Week 
24 (maintenance). Three subjects were administered lirilumab 0.1 mg/kg + ipilimumab 3 mg/kg, 
8 with lirilumab 0.3 mg/kg + ipilimumab 3 mg/kg, 6 with lirilumab 1 mg/kg + ipilimumab 3 
mg/kg, and 5 with lirilumab 3 mg/kg + ipilimumab 3 mg/kg. At the second dose level (lirilumab 
0.3 mg/kg + ipilimumab 3 mg/kg), 1 subject reported iridocyclitis during the DLT period. This 
was a Grade 2 event that did not improve to Grade 1 within 2 weeks despite treatment with topical 
and intraocular injection of steroids, resulting in a DLT. The second cohort (lirilumab 0.3 mg/kg 
+ ipilimumab 3 mg/kg) was thus expanded to 6 evaluable subjects. In the third cohort (lirilumab 1 
mg/kg + ipilimumab 3 mg/kg), 1 subject reported a DLT of Grade 3 rash. This cohort was thus 
expanded to 6 evaluable subjects, and no further DLT occurred in these subjects. In the fourth 
cohort (lirilumab 3 mg/kg + ipilimumab 3 mg/kg), 5 subjects were enrolled; 2 subjects completed 
DLT evaluation period while 3 subjects progressed during DLT period and withdrew from the 
study. The study was terminated on 08-Dec-2014, and last patient last visit was occurred on 
21-Apr-2015. This termination was due to strategic reasons and not due to any safety concerns.
TRAEs were reported by 15 of 22 (68.2%) exposed subjects. Two subjects reported at least 
1 Grade 3 event related to the combination of lirilumab and ipilimumab (erythematous rash and 
pruritus in 1 subject and hypopituitarism in the other subject). There were no related Grade 4 or 
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5 events reported. Discontinuations due to TRAEs occurred in 1 subject (iridocyclitis Grade 2). 
Two (9.1%) SAEs (iridocyclitis and hypopituitarism) were considered to be related to study 
therapy by the investigator. There were no treatment-related deaths.
Refer to Section 1.1.4.1 for data from CA209012 regarding nivolumab and ipilimumab 
combination treatment.
Preliminary assessment of the combination of 3 immunotherapy agents (lirilumab, nivolumab, and 
ipilimumab) will start with evaluating previously evaluated treatment schedules with a focus on 
understanding the safety and tolerability of these agents when combined. Initial dosing will test 
nivolumab 3 mg/kg Q2W combined with ipilimumab 1 mg/kg Q6W, and lirilumab 3 mg/kg Q4W.
Since lirilumab has been well tolerated as single agent (up to 10 mg/kg) and in combination with 
nivolumab (Study CA223001) and ipilimumab (Study CA223002) at 3 mg/kg,21 lirilumab at 
3mg/kg will be used in this combination. Additional refinement of the dose/schedule of 
administering this combination may be pursued via a future protocol amendment.
1.4.14
Rationale for Use of Immune-Related Response Criteria
NOTE: This section will only be applicable for the Dose Escalation and Cohort Expansion (Part 1; 
completed) and the SCCHN Cohort Expansion (Part 2; completed) of this study.
Clinical evidence suggests that some subjects treated with immune-modulating agents may have
PD before demonstrating clinical response.32 The mechanism behind this finding is unknown but
may include an early inflammatory and immune cell trafficking phase that can be misinterpreted
as tumor growth or as the kinetics of fast tumor growth vs initial slow anti-tumor activity. What is
clear is that the use of standard response criteria has the potential of removing subjects from study
too early. In the ipilimumab study, approximately 10% of subjects who were deriving clinical
benefit had evidence of disease progression as determined by modified World Health Organization
criteria.22 Therefore, exploratory response criteria modified from Response Evaluation Criteria in
Solid Tumors (RECIST) have been developed to take into account an immune-mediated pattern
of objective response (irRECIST).9
Appendix 2 lists irRECIST criteria. The 2 main modifications are that disease progression will
require confirmation at least 4 weeks following the restaging scan and that the appearance of new
lesions may not be considered disease progression. In this protocol, irRECIST will be used for
study conduct. Statistical analyses will be primarily based on RECIST version 1.1 (v1.1) criteria
(see Appendix 3).
With Amendment 13 (Revised Protocol 10), additional study parts will use RECIST v1.1 instead
of irRECIST. 
1.4.15
Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease
No longer applicable with Revised Protocol 12.
Accumulating clinical evidence indicates that some subjects treated with immune system 
stimulating agents may develop progression of disease (by conventional response criteria) before 
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demonstrating clinical objective responses and/or SD. This phenomenon was observed in 
approximately 10% of subjects in the Phase 1 study of nivolumab and also with ipilimumab 
monotherapy.32 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 in this study will be allowed to continue study 
therapy after initial investigator-assessed RECIST v1.1 defined progression if they are assessed to 
be deriving clinical benefit and tolerating study drug (Section 3.5.1). Such subjects must 
discontinue study therapy upon further evidence of progression.
1.4.16
Rationale for Use of Blood and Tumor Tissue in Biomarker Studies
The sample collection and biomarker assessment strategy is designed to address key questions
regarding the actions of lirilumab in combination with nivolumab and ipilimumab and the
simultaneous modulation of innate and adaptive immune systems. Specifically, the measurements
obtained from the various biomarker assessments will help answer the following questions:
 
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The tumor-based biomarker analysis will be mandatory for 10 subjects in the MEL cohort
expansion and the SCCHN cohort of the Dose Escalation and Cohort Expansion (Part 1; 
completed).
For all subjects in 
the Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), biopsies will be mandatory at 
baseline if a subject has accessible lesions and if the risks associated with obtaining biopsies are 
deemed clinically acceptable as judged by the investigator. In addition
 
the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5), all subjects will have a fresh biopsy collected on treatment if biopsy risk is 
acceptable. All subjects will be offered the opportunity to undergo biopsies at any time during the
study. In addition, any tumor that remains following clinically indicated procedures should be
saved as fresh frozen tumor or formalin-fixed, paraffin-embedded (FFPE) tumor or both and
submitted for biomarker testing. Tumor biopsies are required in these cohorts in order to 
characterize status 
and expression of tumor specific proteins such as PD-L1
 
 
A previous amendment has changed the timing
of the on-treatment biopsy to approximately 4 weeks ± 3 days on therapy to increase the likelihood
of obtaining tumor tissue in subjects. In 
 the Signal 
Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) the on-
treatment biopsy will be collected at Day 15 ± 3 to ensure that tumor tissue is available from all 
subjects.
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1.4.17
Rationale for Shorter Infusion Durations in the SCCHN Randomized 
Cohorts (Part 3 - closed to enrollment), the Signal Detection Cohort 
Expansion (Part 4 - removed), the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment), and the Signal Detection in Previously Untreated MEL with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6 - removed)
1.4.17.1
Rationale for Shorter Infusion Times for Nivolumab Monotherapy
The impact of infusion time on nivolumab safety has been assessed in an ongoing 
community-based trial (CA209153) in subjects with previously treated advanced or metastatic 
NSCLC.33 As of an interim data lock on 26-Oct-2015, 322 subjects received nivolumab 3 mg/kg 
Q2W via a 30-minute infusion and 355 subjects were administered the same regimen with a 
60-minute infusion time. 
Overall, the safety profiles of the 30- and 60-minute infusion groups were similar with regard to 
the incidence of any-grade treatment-related AEs (53% and 51%, respectively). The incidence of 
Grade 3 to 4 select AEs occurring in ≥2% of subjects was comparable in the pulmonary (3% and 
2%), hepatic (2% and 3%), and gastrointestinal (2% and 2%) categories between the 30- and 
60-minute infusion groups. Any-grade infusion reactions occurred in 3% and 2% of subjects given 
30- or 60-minute infusions, respectively. The incidence of Grade 3 to 4 infusion reactions was 
< 1% for both infusion groups. Table 1.4.17.1-1 shows the individual AEs reported within the 
hypersensitivity/infusion reaction category.
Table 1.4.17.1-1:
Hypersensitivity/Infusion Reaction AEs by Infusion Time
Nivolumab 3 mg/kg Q2W
30-minute Infusion
n = 322
60-minute Infusion
n = 355
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Infusion reaction, n (%)
9 (3)
2 (< 1)
6 (2)
3 (< 1)
     Hypersensitivity
5 (2)
0
1 (< 1)
0
     Infusion-related reaction
2 (< 1)
0
5 (< 1)
3 (< 1)
     Anaphylaxis
1 (< 1)
1 (< 1)
0
0
     Bronchospasm
1 (< 1)
1 (< 1)
0
0
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Hypersensitivity/infusion reactions were generally manageable using dosing interruptions 
(8 subjects in the 30-minute infusion and 3 subjects in the 60-minute infusion), with only a limited 
impact on the dose received. Systemic corticosteroids were administered in a limited number of 
cases (3 subjects in the 30-minute infusion and 1 subject in the 60-minute infusion), and treatment 
was discontinued as a result of hypersensitivity/infusion reactions in even fewer cases (1 subject
in the 30-minute infusion and 2 subjects in the 60-minute infusion).
In addition, the PPK modeling demonstrated similar exposures in both infusion groups 
(Figure 1.4.17.1-1), suggesting that the 30-minute infusion does not pose an increased risk to 
subjects.
Figure 1.4.17.1-1:
Model-predicted Cmax After the First Dose and at Steady State by 
Infusion Time
In conclusion, nivolumab can be safely infused over 30 minutes, and the safety profile is 
comparable to the 60-minute infusion, with a low incidence of infusion-related reactions. As a 
result, the 30-minute infusion time has been implemented across the entire nivolumab program.
1.4.17.2
Rationale for Shorter Infusion Times for Nivolumab in Combination with 
Ipilimumab
Long infusion times, especially when multiple agents are administered sequentially to an 
individual, place a burden on patients and treatment centers. Establishing that nivolumab and 
ipilimumab can be safely administered using shorter infusion times of 30-minute duration for 
nivolumab and ipilimumab in combination with 60-minute infusion of lirilumab in subjects will 
diminish the burden provided there is no change in safety profile.
Previous clinical studies of nivolumab monotherapy and ipilimumab monotherapy and the 
combination of nivolumab and ipilimumab have used a 60-minute infusion duration for nivolumab 
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and 90-minute infusion duration for ipilimumab (1- to 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 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 to 2 and were 
manageable. An infusion duration of 30 minutes for 3 mg/kg, or 240 mg, or 360 mg is not 
expected to present any safety concerns compared to the prior experience with the nivolumab 
10-mg/kg dose infused over a 60-minute duration.
•
Similarly, ipilimumab 10 mg/kg has been safely administered over 90 minutes. In 
Study CA184022, where ipilimumab was administered up to a dose of 10 mg/kg, on-study 
drug-related hypersensitivity events (Grade 1 to 2) were reported in 1 subject (1.4%) in the 
0.3 mg/kg group and in 2 subjects (2.8%) 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 to 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 a 90-minute 
infusion in large Phase 3 studies in prostate cancer (Study CA184043) and as adjuvant therapy 
for stage 3 MEL (Study CA184029), with infusion reactions occurring in subjects. 
Administering ipilimumab 1 mg/kg represents one-tenth of the 10-mg/kg dose.
Of note, Study CA209153, a Phase 3b/4 safety study of nivolumab in subjects with advanced or
metastatic NSCLC who have progressed during or after at least 1 prior systemic regimen, has used 
a 30-minute infusion in a cohort of 332 subjects with no safety issues.19
Lirilumab infusion for all parts of the study will remain at 60 minutes. In this study, the rate of 
infusion reactions seen with nivolumab and lirilumab combination is 18%. These reactions were 
Grades 1 and 2, occurred mostly with the first infusion, were manageable, and did not lead to 
discontinuation.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon
across nivolumab or ipilimumab clinical studies or the nivolumab and ipilimumab combination
and the lirilumab and nivolumab combination. Furthermore, a 30-minute break after the infusion 
of each drug of the combination will ensure the appropriate safety monitoring before the start of 
the subsequent infusion. Overall, a change in safety profile is not anticipated with a 30-minute 
infusion of nivolumab, ipilimumab, with 60-minute infusion of lirilumab.
1.4.18
Rationale for Patient-Reported Outcomes Evaluation in the SCCHN 
Randomized Cohorts (Part 3 - closed to enrollment)
No longer applicable with Revised Protocol 12.
1.4.19
Rationale for Two Year Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated.
In Study 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 
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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 (ie., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.34
Moreover, accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be 
sufficient for long term benefit. In study 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.35 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).36
Taken together, the data suggest 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. Also, 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.
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 
study CA223001 treatment with lirilumab and nivolumab as well as lirilumab, nivolumab and 
ipilimumab will be extended for up to 2 years in this study. 
1.5
Overall Risk/Benefit Assessment
Subjects with recurrent, unresectable or metastatic tumors represent an important unmet need. 
Lirilumab is an NK cell-directed anti-KIR antibody and has the potential to improve clinical
outcomes in tumors where NK cell biology plays an important role. There is clinical data available 
to suggest the potential to improve clinical outcomes in tumors included in this study.
•
Clinical activity of nivolumab monotherapy in subjects with recurrent or metastatic SCCHN 
who progressed from a platinum-containing therapy evaluated in CA209141 randomized Phase 
3 study, demonstrated prolonged survival benefit with nivolumab as compared to investigator’s 
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choice (IC) of chemotherapy. In these populations, the safety profile of nivolumab was shown 
to be favorable as compared to standard of care chemotherapy. 
•
At the time of Amendment 13, preliminary data in 29 evaluable recurrent and metastatic 
SCCHN subjects whose disease progressed on or after platinum-based therapy treated with the 
combination of lirilumab plus nivolumab showed an ORR of 24% (7/29) in the all-comer 
population and an ORR of 41% (7/17) in the PD-L1+ population.1 No responses (0/12) were 
observed in the PD-L1 negative population. Also of note, in 5 out of 7 lirilumab plus 
nivolumab responders, the reduction in tumor burden was substantial, exceeding greater than 
80%. Responses appeared durable, with the median DOR not reached. Subsequent efficacy 
analysis of additional SCCHN subjects treated with the combination of lirilumab and 
nivolumab did not demonstrate a differential efficacy signal as compared to nivolumab 
monotherapy treatment in a similar population of SCCHN subjects. Therefore, with Revised 
Protocol 12, enrollment in Parts 3 and 5 is closing and Parts 4 and 6 are removed from the 
protocol. Individual subjects who continue to have clinical benefit with the combination of 
lirilumab and nivolumab without an increase in adverse events will be permitted to remain on 
study treatment until protocol-specified discontinuation criteria are met. 
•
Transcriptome data from 280 tumors profiled by TCGA showed that SCCHN, NSCLC, and 
bladder tumors have high infiltration of NK cells and KIR gene expression suggesting that KIR 
blockade with lirilumab may enhance antitumor activity of nivolumab in patients with 
SCCHN. In addition analysis of tumor tissues from patients with NSCLC showed that the 
expression of NK cells in squamous cell carcinoma was significantly higher than in 
adenocarcinoma and large cell carcinoma and the survival time of lung cancer patients was 
positively related to NK-cell infiltration degree in lung cancer37 supporting the evaluation of 
lirilumab in combination with nivolumab in tumors with squamous histology
•
Clinical activity of ipilimumab when added to lirilumab plus nivolumab has the potential to 
enhance the activity seen with lirilumab and nivolumab in SCCHN. Analysis of the immune 
infiltration in a large cohort of head and neck tumors, integrating genetic data with RNA-seq–
based deconvolution of immune cell populations and effector/regulatory molecules was done3
and found that SCCHN tumors, are infiltrated with Tregs and KIR-overexpressing CD56dim
NK cells, to a higher degree than other cancer types. These findings suggest that head and neck 
tumors possess an immune landscape that is poised to respond to immunotherapeutic 
approaches that block inhibitory signals to T cells and NK cells, such as immune checkpoint 
inhibitors (nivolumab and ipilimumab), including antibodies blocking KIR signaling 
(lirilumab). In addition, clinical activity of nivolumab plus ipilimumab combination in subjects 
with stage IIB-IV NSCLC as first-line treatment in CA209012 study, a large Phase 1, multi-
arm safety study of nivolumab monotherapy and nivolumab in combination with various 
systemic anticancer therapies including ipilimumab. Clinical activity was observed in all 
combination cohorts with numerically higher response rates observed in cohorts evaluating 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, with confirmed response rates ≥30% and 
median PFS ~8 months. Given the similarity in patient profiles of NSCLC and SCCHN, 
nivolumab 3 mg/kg Q2W and ipilimumab 1 mg/kg Q6W will be the treatment regimen used 
in the reference arm and the backbone regimen for the experimental arm to which lirilumab 
3 mg/kg Q4W will be added. 
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Furthermore, lirilumab in combination with nivolumab or with ipilimumab has an acceptable 
safety profile in subjects with advanced refractory solid tumors. The safety profile associated with 
lirilumab in combination with nivolumab was generally consistent with that observed with 
nivolumab monotherapy. TRAEs were reported in 217 of 322 (67.4%) patients and Grade 3 to 4 
TRAEs were reported in 36 (11.2%) patients. Discontinuations due to TRAEs occurred in 
14 (4.3%) patients.12 The safety profile associated with lirilumab in combination with ipilimumab
was generally consistent with that observed with ipilimumab monotherapy. AEs were reported for 
all 22 (100%) of the subjects treated in this study. The most frequently reported AEs (> 25% of all 
treated subjects) were fatigue (45.5%), nausea (40.9%), malignant neoplasm progression (36.4%), 
back pain (27.3%), diarrhea (27.3%), pneumonia (27.3%), pyrexia (27.3%), and vomiting (27.3%). 
Lastly, the safety profile of nivolumab and ipilimumab is well characterized from a large safety 
database at different doses and schedules as monotherapy or in combination. Consistent with the 
mechanism of action of nivolumab and ipilimumab, the most frequently reported drug-related AEs 
observed in clinical trials are those associated with activation of the immune system. The most 
common types of immune-mediated AEs include endocrinopathies, diarrhea/colitis, hepatitis, 
pneumonitis, nephritis and rash. In the combination regimen, the frequency and intensity of these 
events may vary and depend on the specific dose and schedule used. In the combination dosing 
schedule selected for this study (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W), 
immune-mediated AEs were mostly low grade and manageable with prompt use of corticosteroids. 
Lirilumab in combination with nivolumab and ipilimumab will be evaluated for the first time.
To assure an ongoing favorable risk/benefit assessment for subjects enrolled onto CA223001, the 
following safety measures will be employed throughout the conduct of the study:
•
Rigorous safety monitoring by BMS to ensure subjects’ safety including regular and systematic 
review of safety data, close follow-up of reported safety events, intensive site and study 
investigator training/education on the implementation of the immune-related toxicity 
management algorithms as well as regular safety conference calls with study investigators.
•
Safety lead-in: Initially approximately 10 subjects will be enrolled each in the Signal 
Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) and 
followed for at least 4 weeks of safety assessment from the start of study drug administration
before additional subjects are enrolled in the study to ensure there is no major safety signal 
with the combination. Any findings will be discussed between the BMS Medical Monitor and 
investigators and an agreement will be reached as to whether a lower dose or an alternate dose 
schedule should be examined or whether any additional treatment guidelines should be 
implemented prior to enrollment of additional subjects on study. As of 06-Apr-2018, 
preliminary analysis of 10 subjects treated during the safety lead-in have not identified any 
new safety signals of the lirilumab, nivolumab and ipilimumab triplet combination relative to 
monotherapy or doublet combinations of these study treatments. Individual subjects who 
continue to have clinical benefit with the combination of lirilumab and nivolumab without an 
increase in adverse events will be permitted to remain on study treatment until protocol-
specified discontinuation criteria are met.
•
There is some risk associated with tumor biopsies, including bleeding, infection, and pain. 
While there is no direct benefit to subjects who undergo these procedures, there is the distinct 
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possibility that the 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.
The potential direct benefit to subjects who participate in this study is that therapy with these 
agents may result in SD, PR, or even complete response (CR).
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 US 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.
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 or 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 IB(s) 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.
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed
consent form(s) that 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(s) 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(s) and any other information to be provided to the subjects, prior to the beginning of the
study and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal
guardian and the subject subsequently becomes capable of making and communicating his or
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is
relevant to the subject’s consent. The investigator or a person designated by the investigator
should fully inform the subject or the subject’s legally acceptable representative or legal
guardian of all pertinent aspects of the study and of any new information relevant to the
subject’s willingness to continue participation in the study. This communication should be
documented.
The confidentiality of records that could identify subjects must be protected, respecting the privacy
and confidentiality rules applicable to regulatory requirements, the subjects’ signed informed 
consent form and, in the US, the subjects’ signed Health Insurance Portability and Accountability 
Act Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct
access to subject records.
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may
only be enrolled in the study with the consent of a legally acceptable representative. The subject
must also be informed about the nature of the study to the extent compatible with his or her
understanding, and, should this subject become capable, he or she should personally sign and date
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or
her written consent but who is capable of forming an opinion and assessing information to refuse
participation in, or to be withdrawn from, the clinical study at any time should be considered by
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and
should prevail over interests of science and society.
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3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1/2 study that will be conducted in 6 parts. A brief overview of the study parts 
follows below.
Please note that the Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort 
Expansion (Part 2) have both completed enrollment and are not applicable starting with
Amendment 13 and all subsequent amendments. For preliminary safety results, see Section 1
“Clinical Experience with Lirilumab and Nivolumab Combination Treatment.”
•
Part 1 (Completed): The Dose Escalation and Cohort Expansion of the study will consist of a
dose escalation assessment of the safety and tolerability of lirilumab administered in 
combination with nivolumab in subjects with advanced solid tumors and 5 cohort expansions
at either the MTD, maximum administered dose (MAD), or at an alternative dose as
determined by the investigators and the Sponsor.
•
Part 2 (Completed): The SCCHN Cohort Expansion will be an additional cohort expansion at
Dose Level 4 in subjects with platinum-refractory recurrent or metastatic SCCHN.
•
Part 3 (Closed to enrollment): The SCCHN Randomized Cohorts will involve a single-blinded,
placebo-controlled, randomized cohort expansion of lirilumab in combination with nivolumab
vs nivolumab monotherapy in subjects with platinum-refractory recurrent or metastatic
SCCHN who are PD-L1+.
•
Part 4 (Removed): The Signal Detection Cohort Expansion will be an additional cohort 
expansion of nivolumab and lirilumab at a flat dose in subjects with sqNSCLC, ESCC, BC,
and other squamous histologies (including squamous cell cancers of the skin, cervix, vulva, 
vagina, penis, anorectal and of unknown primary site) and in subjects with SCCHN who have 
received prior PD-1/PD-L1 directed therapy.
•
Part 5 (Closed to enrollment): The Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination will be an open-label safety and signal detection cohort with a 
triplet regimen of lirilumab in combination with nivolumab and ipilimumab in subjects with 
platinum-refractory recurrent or metastatic SCCHN.
•
Part 6 (Removed): The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination will be a safety and signal detection cohort with a 
first-line triplet regimen of lirilumab in combination with nivolumab and ipilimumab in 
subjects with previously untreated metastatic MEL.
Subjects will not be allowed to crossover between any parts or allowed to crossover to other BMS
studies, including CA209714 and CA209651 for SCCHN. 
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Figure 3.1-1:
Overall Study Design for All Study Arms (Study CA223001)
a
Treatment period is until PD, treatment discontinuation, or a maximum of up to 2 years of treatment as specified in the individual study parts, whichever occurs 
earlier.
b
Subjects must have PD-L1+ tumors. PD-L1+, defined as PD-L1 expressed in > 1% of tumor cells.
c
150 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 150 days after last dose
d
No longer required with Revised Protocol 12.
CRC=colorectal cancer; HCC=hepatocellular carcinoma; R=randomization.
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lirilumab
3.1.1
The Dose Escalation and Cohort Expansion (Part 1; Completed)
Subjects in the dose escalation and cohort expansion periods of the Dose Escalation and Cohort 
Expansion (Part 1) will complete up to 4 study periods: screening, treatment, clinical follow-up, 
and survival follow-up. Screening (up to 28 days). Treatment (up to maximum of 2 years). 
Clinical follow-up (150 days). Survival follow-up (up to 3 years following the first dose of study 
drug). Survival follow-up is no longer applicable with Revised Protocol 12 and no further visits 
should be conducted. With revised protocol 12, the total time on study for any individual subject 
will not exceed approximately 2.5 years.
The treatment period will last up to twelve 8-week treatment cycles. For subjects receiving 
lirilumab and nivolumab combination therapy in the Dose Escalation and Cohort Expansion 
(Part 1), each treatment cycle is composed of 4 doses of nivolumab and 2 doses of lirilumab. 
Nivolumab will be administered on Days 1, 15, 29, and 43 of each treatment cycle, and lirilumab 
will be administered on Days 1 and 29 of each treatment cycle.
Following each treatment cycle (for all assigned treatments), the decision to treat a subject with 
additional cycles of study therapy will be based on tumor assessment (evaluation performed 
between Days 49 and 56 and completed before the first dose in the next cycle). Treatment decisions 
related to subject management will be based exclusively on irRECIST for the Dose Escalation and 
Cohort Expansion (Part 1) (see Section 1.4.14 for the rationale and Appendix 2 for definitions).
For the Dose Escalation and Cohort Expansion (Part 1), subjects with an overall response of irPD-
unconfirmed, irSD, irPR, or irCR-unconfirmed at the end of a given cycle will continue to the next 
treatment cycle. Subjects will generally be allowed to continue study therapy until the first 
occurrence of any of the following: 1) achievement of irCR-confirmed; 2) completion of 
12 cycles; 3) confirmation of irPD; 4) clinical deterioration suggesting that no further benefit from 
treatment is likely; 5) intolerability to therapy; or 6) meeting criteria for discontinuation of study 
therapy as outlined in Sections 3.5 and 4.9.5. 
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30, 
60, 100, and 150 to monitor for AEs.
A study schematic is presented below in Figure 3.1.1-1.
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Figure 3.1.1-1:
Study Period Schematic for the Dose Escalation and Cohort 
Expansion (Part 1; Completed)
a Survival follow-up no longer applicable with Revised Protocol 12
3.1.1.1
Dose Escalation (Completed)
A 3 + 3 + 3 design will be used to assess the safety of lirilumab given in combination with
nivolumab. The dosages during dose escalation are provided in Table 3.1.1.1-1. The DLT
observation period will last for 8 weeks or until the completion of Cycle 1, whichever is longer.
Three subjects will be treated initially at each Dose Level. If 0 DLTs occur in a cohort of 3 subjects,
a new cohort of 3 subjects will be treated at the next higher Dose Level. If 1 of 3 subjects
experiences a DLT, that cohort will be expanded to 6 subjects. If 1 of 6 subjects experiences a
DLT, a new cohort of 3 subjects will be treated at the next higher Dose Level. If 2 of 6 DLT
subjects experience a DLT, that cohort will be expanded to 9 subjects. If 2 of 3, 3 of 6, or 3 of 9
subjects experience DLTs within a cohort, then that Dose Level will be determined to have
exceeded the MTD. If no MTD is reached through Cohort 4, then additional cohorts at lirilumab 
6 mg/kg and lirilumab 10 mg/kg, given in combination with nivolumab 3 mg/kg, may be
considered based on the aggregate safety experience during dose escalation and in consultation
and agreement between investigators and Sponsor via a protocol amendment.
After determining the MTD, MAD, or completion of dose escalation without identifying the MTD
and to further explore pharmacodynamic/biomarker objectives, 3 to 12 additional subjects may be
enrolled in each Dose Level for a total of up to 15 subjects at any Dose Level (original 3 to 
12 subjects from dose escalation plus additional subjects required to have a total cohort size of 15).
Screen-
ing
period
Clinical
follow-up
Survival
follow-up a
- irCR unconfirmed
- irPR
- irSD
- irPD-unconfirmed
Visits
Days 30, 60, 100, 
150
to monitor for
adverse events
Day -28 
1
15
29 43 49-56
Scans
Clinic visits or 
telephone contact
every 3 months
for up to 3 years 
following the first 
dose of study 
drug
Treatment period: up to twelve 8-week cycles
Includes assessment between Days 49 to 56
= Nivolumab administration
= Lirilumab administration
- irCR confirmed
- completion of 12 cycles
- irPD confirmed
- PD and clinical
   deterioration
- toxicity
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No intra-subject dose escalation or reduction is allowed. Subjects who withdraw from the study
during the DLT period for reasons other than a DLT may be replaced within the same Dose Level.
For the purpose of making decisions on dose escalation from a safety perspective, subjects will be
considered evaluable if they have received 3 out of the 4 scheduled nivolumab doses through the
8-week observation period only if the 1 missed dose was secondary to non-medical reasons. In
addition, subjects with dosing delays of ≥ 3 weeks in Cycle 1 for non-DLT events will be
considered not evaluable for making decisions on dose escalation and should be replaced.
Dose escalation will be based on the number of DLTs experienced during Cycle 1.
The initial 6 subjects at each Dose Level will have peripheral blood evaluations for
pharmacodynamic markers.
Table 3.1.1.1-1:
Dosages During Dose Escalation
Dose Level
Number
Total Subjects a
Lirilumab 
(IV; mg/kg)
Nivolumab
(IV; mg/kg)
1
n = approximately 3 to 15
0.1
3
2
n = approximately 3 to 15
0.3
3
3
n = approximately 3 to 15
1
3
4
n = approximately 3 to 15
3
3
Total
n = approximately 12 to 60
a 3 to 12 subjects will be enrolled during dose escalation. Additional subjects may be added to each Dose Level after 
completion of the dose escalation period of the study for a total of up to 15 subjects per Dose Level.
All available clinical and laboratory data and the nature, time of onset, and time to resolution of
DLTs observed during dose escalation will be reviewed to determine whether an alternative dose
schedule should be examined after consultation between the investigators and the Sponsor, if
needed. If agreed upon, the alternative schedule will be identified by a protocol amendment.
3.1.1.2
Cohort Expansion (Completed)
The purpose of the cohort expansions is to gather additional safety, tolerability, preliminary
efficacy, and pharmacodynamic information regarding the combination of lirilumab and
nivolumab. Once the safety profile of all doses tested has been characterized and the MTD of
combined administration of lirilumab and nivolumab has been defined, the cohort expansion will
be initiated at the MTD, the MAD, or an alternate dose, if recommended by the investigators and
the Sponsor. Treatment doses in the cohort expansion groups will not exceed the MAD. Five cohort
expansions will be restricted to the tumor types listed in Table 3.1.1.2-1. The NSCLC and MEL
cohorts, which have demonstrated activity with nivolumab monotherapy, will be used to assess
increased activity of the combination therapy. The colorectal cancer (CRC), SCCHN, and
hepatocellular carcinoma (HCC) cohorts will explore activity of the combination therapy in tumors
with unknown or historically low responses to nivolumab monotherapy. Continuous evaluation of
toxicity events in the cohort expansions will be performed throughout enrollment in the cohort
Revised Protocol No.: 12
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expansions. If the rate of DLTs exceeds 33%, then the findings will be discussed and further
enrollment may be interrupted. If a cohort expansion is discontinued due to toxicity, a new cohort
may be initiated at a previously tested lower Dose Level.
In each of the NSCLC and MEL cohorts, approximately 35 subjects will be enrolled to allow for
a more precise estimate of the ORR in these tumors following combination treatment. The sample
size for the other 3 cohorts will be guided by Gehan38 design. In order to determine if a target
response rate (eg, 25 to 30%) is likely, an initial number of subjects (eg, 9) will be treated at first
(Stage I) in a cohort, as outlined in Table 3.1.1.2-1. In the tumor cohort in which no responses are
observed, it will be concluded that the true response rate is unlikely to be greater than or equal to
the target rate and no more subjects will be enrolled in that cohort. Otherwise, in the cohorts in
which at least 1 response among the Stage I subjects is observed, up to 9 additional subjects will
be treated for a total of 18 subjects per tumor type, as guided by Table 3.1.1.2-2. In Stage I,
approximately 9 subjects will be enrolled per tumor type. The number of subjects enrolled in Stage
II per tumor cohort will be guided by the number of responders observed in Stage I and the required
precision of the ORR estimate. This is summarized in Table 3.1.1.2-2 below, using a precision of
12% around the ORR point estimate.
Table 3.1.1.2-1:
Tumor Types Eligible for Cohort Expansion
Tumor Type
Stage I Subjects
Stage II Subjects
Total Subjects
NSCLC
N/A
N/A
Approx. 35
MEL
N/A
N/A
Approx. 35
CRC
9
4 to 9
Approx. 9 to 18
SCCHN
9
4 to 9
Approx. 9 to 18
HCC
9
4 to 9
Approx. 9 to 19
Totals
Approx. 97 to 124
Approx. = approximately; N/A = not applicable.
The actual sample size per cohort in Stage II to achieve desired precision (standard error) of 12%
for the ORR estimate, as guided by the Gehan design, depends on the number of responses 
observed in Stage I (see Table 3.1.1.2-2), assuming a target ORR of 25% to 30%.
Table 3.1.1.2-2:
Cohort Expansion Sample Sizes by n of Responses in Stage I for 
CRC, SCCHN, and HCC Tumors
Stage I Number of Responses
in the First 9 Subjects
Stage II n a
Total n/Cohort 
0
0
9
1
4
13
2
8
17
3
9
18
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Table 3.1.1.2-2:
Cohort Expansion Sample Sizes by n of Responses in Stage I for 
CRC, SCCHN, and HCC Tumors
Stage I Number of Responses
in the First 9 Subjects
Stage II n a
Total n/Cohort 
4
8
17
5
5
14
6
0
9
a Based on 12% precision for the ORR estimates and a target ORR of 25% to 30%.
3.1.2
The SCCHN Cohort Expansion (Part 2; Completed)
To further explore emerging efficacy and safety data in subjects with SCCHN; an additional cohort
of approximately 35 subjects will be treated at Dose Level 4 (see Table 4.1-1). The null hypothesis 
that the true ORR is 25% will be tested against a one-sided alternative: ORR = 40%. The null 
hypothesis will be rejected if 12 or more responses are observed in 35 subjects. This design gives
a 1-sided type I error rate of 0.15 and a power of 0.81.
Subjects will complete up to 4 study periods: screening, treatment, clinical follow-up, and survival 
follow-up. Screening (up to 28 days). Treatment (up to maximum of 2 years). Clinical follow-
up (150 days). Survival follow-up (up to 3 years following the first dose of study drug). Survival 
follow-up is no longer applicable with Revised Protocol 12 and no further visits should be 
conducted. With revised protocol 12, the total time on study for any individual subject will not 
exceed approximately 2.5 years.
The treatment period will last up to twelve 8-week treatment cycles for the SCCHN Cohort 
Expansion (Part 2). For subjects receiving lirilumab and nivolumab combination therapy in the 
SCCHN Cohort Expansion (Part 2), each treatment cycle is composed of 4 doses of nivolumab 
and 2 doses of lirilumab. Nivolumab will be administered on Days 1, 15, 29, and 43 of each 
treatment cycle, and lirilumab will be administered on Days 1 and 29 of each treatment cycle. 
Following each treatment cycle (for all assigned treatments), the decision to treat a subject with 
additional cycles of study therapy will be based on tumor assessment (evaluation performed 
between Days 49 and 56 and completed before the first dose in the next cycle). Treatment decisions 
related to subject management will be based exclusively on irRECIST for the SCCHN Cohort 
Expansion (Part 2) (see Section 1.4.14 for the rationale and Appendix 2 for definitions). For the 
SCCHN Cohort Expansion (Part 2), subjects with an overall response of irPD-unconfirmed, irSD, 
irPR, or irCR-unconfirmed at the end of a given cycle will continue to the next treatment cycle. 
Subjects will generally be allowed to continue study therapy until the first occurrence of any of 
the following: 1) achievement of irCR-confirmed; 2) completion of 12 cycles; 3) confirmation of 
irPD; 4) clinical deterioration suggesting that no further benefit from treatment is likely; 
5) intolerability to therapy; or 6) meeting criteria for discontinuation of study therapy as outlined 
in Sections 3.5 and 4.9.5. 
Revised Protocol No.: 12
Date: 08-May-2018
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The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30, 
60, 100, and 150 to monitor for AEs.
A study schematic is presented below in Figure 3.1.2-1.
The SCCHN Cohort Expansion (Part 2) of this study closed to enrollment when the SCCHN 
Randomized Cohorts (Part 3) opened.
Figure 3.1.2-1:
Study Period Schematic for Part 2 (Completed)
a Survival follow-up no longer applicable with Revised Protocol 12
3.1.3
The SCCHN Randomized Cohorts (Part 3 closed to enrollment)
To further explore emerging efficacy and safety data in subjects with SCCHN, lirilumab in
combination with nivolumab and nivolumab monotherapy will be evaluated in a single-blind, 
placebo-controlled, randomized, expansion study. All subjects will submit fresh tumor biopsies 
that will be tested for PD-L1 status, and subjects will be enrolled if they have PD-L1+ tumors.
(Refer to Section 5.7.3.1 for the definition of PD-L1+.)
Subjects will be treated with 1 of the following:
•
Arm A: flat dose of lirilumab 240 mg Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg
Q2W (Days 1, 15, 29, 43) until PD
•
Arm B: placebo for lirilumab Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg Q2W 
monotherapy (Days 1, 15, 29, 43) until PD
Screen-
ing
period
Clinical
follow-up
Survival
follow-up a
- irCR unconfirmed
- irPR
- irSD
- irPD-unconfirmed
Visits
Days 30, 60, 100, 
150
to monitor for
adverse events
Day -28 
1
15
29 43 49-56
Scans
Clinic visits or 
telephone 
contact
every 3 months
for up to 3 years 
following the 
first dose of 
study drug
Treatment period: up to twelve 8-week cycles
Includes assessment between Days 49 to 56
= Nivolumab administration
= Lirilumab administration
- irCR confirmed
- completion of 12 cycles
- irPD confirmed
- PD and clinical
   deterioration
- toxicity
Revised Protocol No.: 12
Date: 08-May-2018
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Approximately 225 subjects will be randomized to the 2 treatment arms in a 2:1 ratio (150 subjects
to Arm A and 75 subjects to Arm B) and stratified by the following factors: PD-L1 ≥ 50% 
expression and prior treatment with cetuximab.
Subjects will complete up to 4 study periods: screening, treatment, clinical follow-up, and survival
follow-up. Screening (up to 35 days). Treatment (until PD, treatment discontinuation, or a 
maximum of up to 12 cycles of treatment, whichever occurs earliest). Clinical follow-up
(150 days). Survival follow-up (up to 3 years following the first dose of study drug). With revised 
protocol 12, the total time on study for any individual subject will not exceed approximately 2.5 
years. Survival follow-up is no longer applicable with Revised Protocol 12.
The treatment begins with the contact to the Interactive Voice Response System (IVRS) to 
randomize the subject. Randomization should take place within approximately 35 days of 
enrollment. The treatment period will last up until PD for the SCCHN Randomized Cohorts
(Part 3). For subjects receiving lirilumab and nivolumab combination therapy in Arm A of the 
SCCHN Randomized Cohorts (Part 3), each 8-week treatment cycle is composed of 4 doses of 
nivolumab and 2 doses of lirilumab. Nivolumab will be administered on Days 1, 15, 29, and 43 of 
each treatment cycle, and lirilumab will be administered on Days 1 and 29 of each treatment cycle. 
For subjects in Arm B receiving nivolumab monotherapy, each treatment cycle is composed of 
4 doses of nivolumab and 2 doses of placebo for lirilumab. Nivolumab will be administered on 
Days 1, 15, 29, and 43 of each treatment cycle, and placebo for lirilumab will be administered on 
Days 1 and 29 of each treatment cycle. 
Following each 8-week treatment cycle (for all assigned treatments), the decision to treat a subject 
with additional cycles of study therapy will be based on tumor assessment (evaluation performed 
between Days 49 and 56 and completed before the first dose in the next cycle). Treatment decisions 
related to subject management will be based on RECIST v1.1 (see Appendix 3). Subjects will 
generally be allowed to continue study therapy until the first occurrence of any of the following: 
1) PD (confirmed or unconfirmed); 2) clinical deterioration suggesting that no further benefit from 
treatment is likely; 3) intolerability to therapy; 4) meeting criteria for discontinuation of study 
therapy as outlined in Sections 3.5 and 4.9.5 or 5) maximum treatment duration of 12 treatment 
cycles. 
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30, 
60, 100, and 150 to monitor for AEs.
A study schematic of the study period is presented below in Figure 3.1.3-1.
Tumor progression or response endpoints will be assessed using a centralized imaging review 
(independent radiologic review committee) and the RECIST v1.1 criteria. With Revised Protocol 
12, submission of scans to centralized imaging review is no longer required. For the purposes of
subject management, clinical decision making will be based on investigator-assessed radiographic 
assessment using RECIST v1.1. Therefore timepoint tumor response evaluations will be recorded
on the case report form (CRF) based on investigators’ assessments using RECIST v1.1 criteria.
Dose reductions will be not be allowed for lirilumab or nivolumab. Crossover will not be 
permitted.
Revised Protocol No.: 12
Date: 08-May-2018
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The primary endpoint is ORR based on IRC assessment.
The study design schematic is presented in Figure 3.1.3-2. See Section 3.1 for a description of the
study phases for this cohort.
Figure 3.1.3-1:
Study Design Schematic for the SCCHN Randomized Cohorts
(Part 3)
Figure 3.1.3-2:
Study Period Schematic for the SCCHN Randomized Cohorts (Part 3)
a Biopsy will be taken at screening and at Day 15 (± 3days).
b Survival follow-up no longer applicable with Revised Protocol 12
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Date: 08-May-2018
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3.1.4
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
3.1.5
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment)
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 
5) is an open-label, Phase 2 cohort expansion study in subjects ≥18 years old with 
platinum-refractory recurrent or metastatic SCCHN that is not amenable to curative therapy 
evaluating lirilumab in combination with nivolumab and ipilimumab as a treatment. There will be 
continuous monitoring of safety via a safety lead-in, described in detail later in this section. 
Subjects must have tumor progression or recurrence after prior platinum-containing systemic 
therapy for recurrent or metastatic disease. In addition, subjects who have progressed within 
6 months of platinum-based therapy used as part of concurrent chemoradiation (definitive or 
adjuvant therapy) are also eligible.
All subjects in this cohort with be tested for PD-L1 status. All testing for PD-L1 status will be 
performed on a fresh biopsy obtained during screening, and results must be available prior to 
randomization. In the event that the biopsy sample collected during screening is not evaluable for 
PD-L1, the site will be notified and an archival specimen may be submitted for PD-L1 testing.
Additional subjects may be enrolled, if necessary, to ensure an adequate representation of the 
patient population (ie, non-, lower-, and higher-PD-L1 expressers).
 
 
 
(see Sections 5.7.3.1
 
). Subjects will undergo PD-L1 
 screening evaluations to determine eligibility 
within 35 days prior to enrollment.
Subjects will be treated with lirilumab, nivolumab, and ipilimumab combination (see Table 5.1.4-
2 for dosing schedule) as follows:
−
Nivolumab 3 mg/kg IV Q2W (± 3 days)
−
Ipilimumab 1 mg/kg IV Q6W (± 3 days) following the administration of nivolumab
−
Lirilumab 3 mg/kg IV Q4W (± 3 days) will be the final drug administered on any specific 
treatment day
Approximately 40 subjects will be enrolled.
The total duration of the study from enrollment to primary endpoint ORR analysis is expected to 
be approximately 21 months, assuming 12 to 15 months accrual duration. 
Subjects will complete up to 4 study periods: screening, treatment, clinical follow-up, and survival
follow-up. Screening (up to 35 days). Treatment (until PD, treatment discontinuation, or a 
maximum of 8 cycles of treatment, whichever occurs earlier). Clinical follow-up (150 days). 
Survival follow-up (up to 3 years following the first dose of study drug). With revised protocol 
12, the total time on study for any individual subject will not exceed approximately 2.5 years.
Survival follow-up is no longer applicable with Revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
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The treatment begins with the contact to the IVRS to assign the subject’s treatment. The first dose
of study drug should take place within approximately 35 days of enrollment. The treatment period 
will last up until PD for the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5). Nivolumab will be administered Q2W, ipilimumab will be 
administered Q6W, and lirilumab will be administered Q4W in all subjects.
Safety lead-in: There will be continuous monitoring of safety. Initially approximately 10 subjects 
will be enrolled and followed for at least 4 weeks of safety assessment from the start of study drug
administration before additional subjects are enrolled in the study to ensure there is no major safety 
signal with the combination. Any findings will be discussed between the BMS Medical Monitor 
and investigators and an agreement will be reached as to whether a lower dose or an alternate dose 
schedule should be examined or whether any additional treatment guidelines should be 
implemented prior to enrollment of additional subjects on study.
Following each treatment cycle (12 weeks of study therapy consisting of 6 doses of nivolumab 
given Q2W, 2 doses of ipilimumab given Q6W, and 3 doses of lirilumab given Q4W), the decision 
to treat a subject with additional study therapy will be based on tumor assessment done Q8W
(evaluation performed Q8W and completed before study therapy is continued). Treatment 
decisions related to subject management will be based on investigator-assessed radiographic 
assessment using RECIST v1.1 (see Appendix 3). Subjects with an overall response of SD, PR, or 
CR-unconfirmed at the time of each assessment may continue study drug. Subjects will generally 
be allowed to continue study drug until the first occurrence of any of the following: 1) achievement 
of CR-confirmed; 2) PD (confirmed or unconfirmed); 3) clinical deterioration suggesting that no 
further benefit from treatment is likely; 4) intolerability to therapy; 5) meeting criteria for 
discontinuation of study therapy as outlined in Sections 3.5 and 4.9.5 or 6) maximum treatment 
duration of 8 treatment cycles.(See section 3.5.1).
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30, 
60, 100, and 150 to monitor for AEs.
A study period schematic is presented below in Figure 3.1.5-1 and Figure 3.1.5-2.
For the purposes of subject management, clinical decision-making will be based on RECIST v1.1. 
Therefore, timepoint tumor response evaluations will be recorded on the CRF based on 
investigators’ assessments using RECIST v1.1 criteria.
Revised Protocol No.: 12
Date: 08-May-2018
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Figure 3.1.5-1:
Study Schematic for the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5)
a Biopsy will be taken at screening. Initially approximately 10 subjects will be enrolled and followed for at least 4 weeks of safety assessment from the start of 
study drug administration before additional subjects are enrolled in the study to ensure there is no major safety signal with the combination.
Revised Protocol No.: 12
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Figure 3.1.5-2:
Study Period Schematic for the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5)
a Biopsy will be taken at screening and Day 15 (± 3 days). Initially approximately 10 subjects will be enrolled and followed for at least 4 weeks of safety assessment 
from the start of study drug administration before additional subjects are enrolled in the study to ensure there is no major safety signal with the combination.
b Until PD, treatment discontinuation, or a maximum of 8 cycles of treatment, whichever occurs earliest.
c Survival follow-up no longer applicable with Revised Protocol 12
Revised Protocol No.: 12
Date: 08-May-2018
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3.1.6
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
3.2
Post-study Access to Therapy
At the end of the treatment phase of the study, BMS will not continue to supply study drug to
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that
the subject receives appropriate standard of care to treat the condition under study. No exceptions
to these criteria will be granted by the Sponsor.
3.3
Study Population
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. No
exceptions will be granted.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The subject must sign the informed consent form prior to the performance of any study
related procedures that are not considered part of standard of care.
2) Target Population
a) Subjects must have histologic or cytologic confirmation of a solid malignancy that is
advanced (metastatic and/or unresectable):
i.
Dose Escalation (Part 1) Not applicable starting with Protocol Amendment 13
and all subsequent amendments.
i. All solid tumor histologies will be permitted during dose escalation,
except for subjects with primary CNS tumors or with CNS metastases
as the only site of active disease.
ii. Subjects must have received, and then progressed or been intolerant to,
at least 1 standard treatment regimen in the advanced or metastatic
setting, if such a therapy exists (except for subjects with MEL).
ii.
Cohort Expansion (Part 1) Not applicable starting with Protocol Amendment 13
and all subsequent amendments.
i. The following 5 tumor types will be permitted during cohort expansion.
1. NSCLC
a) Must have recurrent or PD during or after platinum
doublet-based chemotherapy for advanced or metastatic
disease or must have recurrent or PD within 6 months
after completing platinum-based chemotherapy for local
disease.
b) Subjects must have known epidermal growth factor 
receptor (EGFR) and anaplastic lymphoma kinase 
(ALK) status.
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c) Subjects with an activating EGFR mutation must have
received an EGFR tyrosine kinase inhibitor.
d) Subjects with an ALK translocation must have received
an ALK inhibitor.
2. MEL
a) Must have received prior therapy with ipilimumab.
b) BRAF mutation status must be known, and if a BRAF
mutation (V600E or V600K) is present, the subject must
have received a RAF or a MEK inhibitor.
3. CRC
a) Subjects must have phenotypes:
i.
Microsatellite
instability
(MSI)
stable
(no
alterations) or MSI low (only 1 alteration) with
MSI expression
detected
by an accredited
laboratory per local process. See Section 5.3.1 or
ii. Deoxyribonucleic acid (DNA) mismatch repair
gene proficient on tumor immunohistochemistry
(IHC).
b) Known Kirsten Ras (KRAS) mutation status.
c) Prior therapy requirement:
i. Must have received at least 1 standard systemic
therapy, such as fluoropyrimidine, oxaliplatin or
irinotecan,
bevacizumab,
cetuximab
or
panitumumab
(if
KRAS
wild
type),
or
regorafenib.
or
ii. Subject
refused
standard
therapy
for
the
treatment of metastatic (Stage 4) or locally
advanced disease. The subject’s refusal must be
documented.
4. SCCHN (oral cavity, pharynx, larynx)
a) Must document HPV status and subtype, particularly
HPV16 and HPV18.
b) Must have evidence of progression or recurrence within
6 months of last dose of platinum therapy.
c) Radiation therapy must have been completed at least
4 weeks prior to study drug administration.
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5. HCC that is not amenable to surgical resection
a) Subjects must have PD, or been intolerant to, at least
1 line of therapy or refuse treatment with sorafenib.
b) Child-Pugh score of B (7 points or less and must not have
encephalopathy) (see Appendix 5).
c) Subjects must have testing for hepatitis B surface antigen
(HBsAg), hepatitis B surface antibody, hepatitis B core
antibody, hepatitis B DNA polymerase chain reaction 
(PCR), hepatitis C antibody, hepatitis C ribonucleic acid 
(RNA) PCR.
d) Subjects with hepatitis B infection must have hepatitis B
DNA viral load < 100 IU/mL and must be on anti-viral
therapy per institutional guidelines.
e) Subjects with hepatitis B infection must not have
co-infection with hepatitis C or hepatitis D (must obtain
hepatitis D antibody testing).
f)
Subjects must not have clinically significant ascites or
clinically significant variceal bleeding.
6. The SCCHN Cohort Expansion (Part 2; completed) in squamous 
cell carcinoma of the head and neck (oral cavity, pharynx,
larynx) Not applicable starting with Protocol Amendment 13
and all subsequent amendments.
a) Histologically confirmed, incurable, locally advanced,
recurrent or metastatic SCCHN (oral cavity, pharynx,
larynx), Stage 3/4 and not amenable to local therapy with
curative intent (surgery or radiation therapy with or
without chemotherapy).
b) Confirmation of tumor HPV status: Prior testing results
are acceptable if known. If tumor HPV status is
unknown, subjects must consent to allow their submitted
archived tumor tissue sample in the form of block or
unstained slides to be tested for confirmation of tumor
HPV status.
c) Tumor progression or recurrence within 6 months of last
dose of platinum therapy in the adjuvant (ie, with
radiation after surgery), primary (ie, with radiation),
recurrent, or metastatic setting. Clinical progression after
platinum therapy is an allowable event for entry and is
defined as progression of a lesion at least 10 mm in size
that is amenable to caliper measurement (eg, superficial
skin lesion as per RECIST v1.1) or a lesion that has been
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visualized,
photographically
recorded
with
measurements, and shown to have progressed.
d) Prior
curative
radiation
therapy
must
have
been
completed at least 4 weeks prior to study drug
administration. Prior focal palliative radiotherapy must
have been completed at least 2 weeks before study drug
administration.
e) Subjects must consent to allow the acquisition of existing
FFPE material for performance of correlative studies
including (but not limited to) the analysis of PD-L1
expression by IHC (additional subjects may be enrolled 
if necessary to ensure an adequate number of higher PD-
L1 expressers):
i. FFPE tissue may be in the form of either a block
or unstained slides, but a fresh biopsy may be
performed when a subject’s prior archived tumor
tissue has been exhausted;
ii. Tumor tissue must be confirmed as shipped to the
central laboratory prior to subjects receiving
study drug.
ii. Subjects must have ≤5 prior treatment regimens. The following are not 
considered separate lines of treatment: addition of a compound to an 
ongoing regimen, restarting the same regimen after a drug holiday, or 
switching from IV to oral therapy.
iii. The SCCHN Randomized Cohorts (Part 3 - enrollment closed)
1. Histologically confirmed recurrent or metastatic SCCHN (oral
cavity, pharynx, larynx), Stage 3/4 and not amenable to local
therapy with curative intent (surgery or radiation therapy with or
without chemotherapy).
2. Documentation of p16-positive or p16-negative disease to
determine HPV status of tumor for SCCHN of the oropharynx.39
Note: If results are not available, then a sample (tissue on
microscopic slides, tissue block or a fresh tissue biopsy in
formalin) should be sent to the central laboratory for analysis
and confirmed as shipped.
3. Tumor progression or recurrence within 6 months of last dose of
platinum therapy in the adjuvant (ie, with radiation after
surgery), primary (ie, with radiation), recurrent, or metastatic
setting. Clinical progression after platinum therapy is an
allowable event for entry and is defined as progression of a
lesion at least 10 mm in size that is amenable to caliper
measurement (eg, superficial skin lesion as per RECIST v1.1) or
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a lesion that has been visualized and photographically recorded
with measurements and shown to have progressed.
4. Prior curative radiation therapy must have been completed at
least 4 weeks prior to study drug administration. Prior focal
palliative radiotherapy must have been completed at least
2 weeks before study drug administration.
5. Subjects must be PD-L1+ on fresh biopsies by IHC testing 
performed by the central laboratory during the screening period. 
Refer to Section 5.7.3.1 for the definition of PD-L1+.
iv. The Signal Detection Cohort Expansion (Part 4 - removed with Revised 
Protocol 12)
1. Squamous non-small cell lung cancer:
a) Subjects with histologically or cytologically documented 
squamous cell NSCLC who present with Stage 
IIIB/Stage IV disease (according to version 7 of the 
International Association for the Study of Lung Cancer 
Staging Manual in Thoracic Oncology), or with recurrent 
or PD following multimodal therapy (radiation therapy, 
surgical resection, or definitive chemoradiation therapy 
for locally advanced disease).
b) Subjects must have experienced disease recurrence or 
progression 
during 
or 
after 
1 
prior 
platinum 
doublet-based chemotherapy regimen for advanced or 
metastatic disease.
i. Maintenance 
therapy 
following 
platinum 
doublet-based chemotherapy is not considered as 
a separate regimen of therapy. 
ii. Subjects who received platinum-containing 
adjuvant,
neoadjuvant,
or 
definitive 
chemoradiation 
therapy 
given 
for 
locally 
advanced disease, and developed recurrent (local 
or metastatic) disease within 6 months of 
completing therapy are eligible.
iii. Subjects with recurrent disease > 6 months after 
platinum-containing adjuvant, neoadjuvant, or 
definitive chemoradiation therapy given for 
locally advanced disease, who also subsequently 
progressed 
during 
or 
after 
a 
platinum 
doublet-based regimen given to treat the 
recurrence, are eligible.
c)
Subjects must be PD-L1+ on fresh biopsies by IHC 
testing performed by the central laboratory during the 
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screening period. Refer to Section 5.7.3.1 for the 
definition of PD-L1+.
2. Squamous cell esophageal cancer:
a)
Subjects with histologically confirmed ESCC who must 
meet all of the following:
i. Subjects must have progression or refractory 
disease. Subjects must have had at least 
1 chemotherapy regimen for the treatment of 
metastatic (Stage IV) or locally advanced 
disease. 
or
ii. Subject actively refuses chemotherapy or 
biological therapy for the treatment of metastatic 
(Stage 
IV) 
or 
locally 
advanced 
disease 
considered as standard treatment for this disease 
stage, despite being informed by the investigator 
about the treatment options. Subjects actively 
refusing 
chemotherapy 
must 
have 
had 
progression or refractory disease prior to starting 
study drug. The subject’s refusal must be 
thoroughly documented. The investigator will 
discuss 
each 
individual 
subject 
refusing 
chemotherapy with the Sponsor’s Medical 
Monitor to confirm eligibility.
3. Bladder cancer:
a) Histological or cytological evidence of metastatic or 
surgically unresectable transitional cell carcinoma of the 
urothelium involving the bladder, urethra, ureter, or renal 
pelvis. Minor histologic variants (< 50% overall) are 
acceptable.
i. Subjects must have metastatic or surgically 
unresectable (cT4b, or any N+ [N1-3], or any M-
1) disease.
b) Subjects must have received, and then progressed or 
been intolerant to, at least 1 standard treatment regimen 
in the advanced or metastatic setting, if such a therapy 
exists.
4. Other Squamous Histologies: 
a) Histologic or cytological confirmation of squamous cell
carcinoma (excluding SCCHN, sqNSCLC, and ESCC) 
that 
is 
advanced 
(metastatic, 
recurrent 
and/or 
unresectable) such as, but not limited to, SCC of the skin, 
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cervix, vulva, vagina, penis, anorectal and of unknown 
primary site.
b) Participants must have received, and then progressed or 
been intolerant to, at least 1 standard treatment regimen 
in the advanced or metastatic setting, if such a therapy 
exists.
c) HPV status (except for SCC of the skin) must be 
documented if known.
5. Subjects with SCCHN who have received prior PD-1/PD-L1 
directed therapy:
a) Histologically confirmed, incurable, locally advanced, 
recurrent or metastatic SCCHN (oral cavity, pharynx, 
and larynx), Stage 3/4, and not amenable to local therapy 
with curative intent (surgery or radiation therapy with or 
without chemotherapy). 
b) Documentation of p16-positive or p16-negative disease 
to determine HPV status of tumor for SCCHN of the 
oropharynx.39 Note: If results are not available, then a 
sample (tissue on microscopic slides, tissue block, or a 
fresh tissue biopsy in formalin) should be sent to the 
central laboratory for analysis and confirmed as shipped. 
c) Subjects must have received prior immunotherapy with 
an anti-PD-1 or anti-PD-L1 containing regimen and must 
have progressive or recurrent disease after prior PD-
1/PD-L1 directed therapy.
d) The last dose of prior anti-PD-1/anti-PD-L1 must be 
≥28 days from initiation of study therapy.
e) Prior curative radiation therapy must have been 
completed at least 4 weeks prior to study drug 
administration. Prior focal palliative radiotherapy must 
have been completed ≥ 2 weeks before study drug 
administration.
f)
Subjects must be PD-L1+ on fresh biopsies by IHC 
testing performed by the central laboratory during the 
screening period. Refer to Section 5.7.3.1 for the 
definition of PD-L1+.
v. The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - enrollment closed)
1. Histologically confirmed SCCHN, from any of the following 
primary sites only: oral cavity, oropharynx, hypopharynx, and 
larynx
 
.
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2. Subjects must have metastatic or recurrent SCCHN that is not 
amenable to therapy with curative intent (surgery or radiation 
therapy with or without chemotherapy). Subjects who refuse 
potentially curative salvage surgery for recurrent disease are 
ineligible. Subjects must have tumor progression or recurrence 
after prior platinum-containing systemic therapy for recurrent or 
metastatic disease. In addition, subjects who have progressed 
within 6 months of platinum-based therapy used as part of 
concurrent chemoradiation (definitive or adjuvant therapy) are 
also eligible.
 
 
 
 
4. Submission of tumor tissue specimen to the central laboratory
for documentation of PD-L1 status by IHC at screening. Subject 
must have documentation of PD-L1 status by IHC performed by 
the central lab at randomization. Sample must be from a tumor 
biopsy collected during screening. Biopsy should be excisional, 
incisional or core needle. Fine needle aspiration is insufficient.
5. Prior palliative radiotherapy must have been completed at least 
4 weeks prior to first dose of study drug if radiotherapy was to 
the head and neck region and 2 weeks prior to first dose of study 
drug if radiotherapy was to other regions.
vi. The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6 - removed with 
Revised Protocol 12)
1. Histologically confirmed unresectable Stage 3 or 4 MEL as per 
American Joint Committee on Cancer staging system.
2. Subjects must have known BRAF V600 mutation status or 
consent to BRAF V600 mutation testing per local institutional 
standards during the Screening Period.
3. Treatment-naïve subjects (ie, no prior systemic anticancer 
therapy for unresectable or metastatic MEL).
a) Note: Prior adjuvant or neoadjuvant MEL therapy is 
permitted if it was completed at least 6 weeks prior to 
randomization and all related AEs have either returned 
to baseline or stabilized.
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4. Submission of tumor tissue specimen to the central laboratory 
for documentation of PD-L1 status by IHC at screening. Subject 
must have documentation of PD-L1 status by IHC performed by 
the central lab at randomization. Sample must be from a tumor 
biopsy collected during screening biopsy should be excisional, 
incisional or core needle. Fine needle aspiration is insufficient.
b) Presence of at least 1 lesion with measurable disease as defined by RECIST v1.1
criteria for response assessment. Subjects with lesions in a previously irradiated field
as the sole site of measurable disease will be permitted to enroll provided the lesion(s)
have demonstrated clear progression and can be measured accurately. As of Protocol 
Amendment 13, subjects undergoing biopsy do not need to have a biopsy lesion that is 
distinct from an index lesion.
c) Subjects must consent to allow the acquisition of existing FFPE material tissue block 
or tumor tissue sections for performance of correlative studies. In the Dose Escalation 
and Cohort Expansion (Part 1; completed) and the SCCHN Cohort Expansion (Part 2; 
completed), for NSCLC, tissue must have been collected within 6 months of study 
entry. For MEL, tissue must have been collected after prior systemic therapy, if any
(these criteria related to the Dose Escalation and Cohort Expansion [Part 1; completed] 
and the SCCHN Cohort Expansion [Part 2; completed] are not applicable starting with
Protocol Amendment 13 and all subsequent amendments). 
i.
In the SCCHN Randomized Cohorts (Part 3) and the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5): 
Subjects must consent to allow the acquisition of existing FFPE material tissue 
block or tumor tissue sections for performance of correlative studies. All 
subjects will be required to provide fresh biopsies at baseline if a subject 
has accessible lesions and if the risks associated with obtaining biopsies are 
deemed acceptable. In addition, all subjects in the SCCHN Randomized 
Cohorts (Part 3) and the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5) will be required to provide 
a fresh on-treatment biopsy if risk is acceptable. Fresh biopsy samples 
obtained during screening must be submitted to the central laboratory for PD-
L1 testing prior to subjects receiving study drug. In the event that the biopsy 
sample collected during screening is not evaluable for PD-L1, the site will be
notified and an archival specimen may be submitted for PD-L1 testing. 
d) A minimum of 10 subjects each in the MEL cohort and the SCCHN cohort (the Dose 
Escalation and Cohort Expansion [Part 1; completed]) will be required to undergo
mandatory pre-treatment and on-treatment biopsies in the cohort expansion phase at
acceptable clinical risk as judged by the investigator. All other subjects will have the
option of undergoing pre-treatment, on-treatment, and post-treatment biopsies. The
biopsy lesion must be distinct from an index lesion. In the SCCHN Cohort Expansion 
(Part 2; completed); a minimum of 15 subjects will be required to undergo mandatory 
pre-treatment and on-treatment biopsies at acceptable clinical risk as judged by the 
investigator. The biopsy lesion cannot be the sole lesion of measureable disease. 
Additional subjects may be enrolled in order to satisfy this requirement. These criteria 
related to the Dose Escalation and Cohort Expansion (Part 1; completed) and the 
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SCCHN Cohort Expansion (Part 2; completed) are not applicable starting with Protocol 
Amendment 13 and all subsequent amendments.
e) The first dose of study drug must be at least 28 days from the last dose of prior therapy.
f)
ECOG status of 0 or 1.
g) Life expectancy of ≥12 weeks.
h) Adequate organ function for all subjects except those with HCC as defined by the
following:
i.
White blood cell (WBC) ≥2000/μL
ii.
Neutrophils ≥1500/μL
iii.
Platelets ≥100 × 103/μL
iv.
Hemoglobin ≥9.0 g/dL
v.
Creatinine < 1.5 × upper limit of normal (ULN) or calculated creatinine 
clearance < 40 mL/min (using the Cockcroft-Gault formula)
vi.
ALT and AST ≤3 × ULN
vii.
Total bilirubin ≤1.5 × ULN (except subjects with Gilbert’s Syndrome who must
have a total bilirubin level of < 3.0 × ULN)
viii.
Normal thyroid function, or have controlled thyroid disorder
i)
Adequate organ function for all HCC subjects as defined by the following. Not 
applicable starting with Protocol Amendment 13 and all subsequent amendments.
i.
WBC ≥2000/μL (stable off any growth factor within 4 weeks of first study
drug administration)
ii.
Neutrophils ≥1000/μL (stable off any growth factor within 4 weeks of first
study drug administration)
iii.
Platelets ≥40 × 103/μL (transfusion to achieve this level is not permitted within
2 weeks of first study drug administration)
iv.
Hemoglobin ≥8.5 g/dL (transfusion to achieve this level is not permitted within
2 weeks of first study drug administration)
v.
Creatinine < 1.5 × ULN
vi.
ALT and AST ≤5 × ULN
vii.
Total bilirubin ≤3 mg/dL
viii.
International normalized ratio ≤2.3 or prothrombin time ≤6 sec above control
ix.
Albumin ≥2.8 g/dL
x.
Normal thyroid function, or have controlled thyroid disorder
j)
Ability to comply with treatment, PK and pharmacodynamics sample collection and
required study follow-up.
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k) Subject re-enrollment: this study permits the re-enrollment of a subject who has 
discontinued the study as a pre-treatment failure (ie, subject has not been 
randomized/has not been treated). If re-enrolled, the subject must be re-consented.
l)
Subjects with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity 
m) Subjects must have resting baseline oxygen saturation measured by pulse oximetry of 
≥ 92% at rest on room air.
3) Age, Sex, and Reproductive Status
a) Men and women, ages ≥18 years.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of study treatment with nivolumab and 5 months after the last dose of study 
drug (ie, 30 days [duration of ovulatory cycle] plus the time required for the study drug 
to undergo approximately 5 half-lives.)
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 
7 months after the last dose of study drug (ie, 90 days [duration of sperm turnover] plus 
the time required for the study drug to undergo approximately 5 half-lives.)
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 (see Appendix 6).
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) Subjects with untreated CNS metastases. Subjects are eligible if CNS metastases have been 
adequately treated and have neurologically returned to baseline (except for residual signs 
or symptoms related to the CNS treatment) for at least 2 weeks. In addition, subjects must 
be either off corticosteroids or on a stable or decreasing dose of prednisone 10 mg daily (or 
equivalent) for at least 2 weeks. Please note: For SCCHN subjects only, cases including 
base of skull lesions without definitive evidence of dural or brain parenchymal 
involvement, should be discussed with the Medical Monitor.
b) Participation in any prior clinical study with ipilimumab or with nivolumab, including
subjects in comparator arms (including CA209651 and CA209714), in which OS is listed
as the primary or co-primary endpoint and which has not completed analysis based on the
primary endpoint.
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c) SCCHN subjects only: Histologically confirmed recurrent or metastatic carcinoma of the
nasopharynx, and the skin and salivary gland or non-squamous histologies are not allowed.
d) Subjects with carcinomatous meningitis. 
2) Medical History and Concurrent Diseases
a) Subjects with previous malignancies (except non-MEL skin cancers, and the following in 
situ cancers: bladder, gastric, colon, esophageal endometrial, cervical/dysplasia, MEL, or 
breast) unless a complete remission was achieved at least 2 years prior to study entry AND 
no additional therapy is required during the study period.
b) Subjects with an active, known, or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
c) A known or underlying medical condition that, in the opinion of the investigator or
Sponsor, could make the administration of study drug hazardous to the subjects (such as 
ongoing interstitial pneumonitis), or could adversely affect the ability of the subject to
comply with or tolerate study. Not applicable starting with Protocol Amendment 13 and all 
subsequent amendments.
d) Uncontrolled or significant cardiovascular disease including, but not limited to any of the
following:
i)
Myocardial infarction or stroke/transient ischemic attack within the past 6 months
ii) Uncontrolled angina within the past 3 months
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 heart disease (ie, cardiomyopathy, congestive
heart failure with New York Heart Association functional classification 3 to 4,
pericarditis, significant pericardial effusion)
vi) Requirement of daily supplemental oxygen therapy
vii)History of myocarditis
e) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome. No HIV testing is required during screening. 
NOTE: Testing for HIV must be performed at study sites where mandated locally.
i)
Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by 
PCR are eligible. Not applicable starting with Protocol Amendment 13 and all 
subsequent amendments.
ii) Subjects with a history of resolved hepatitis A virus infection are eligible. Not 
applicable starting with Protocol Amendment 13 and all subsequent amendments.
f)
Evidence of active infection ≤7 days prior to initiation of study drug therapy (does not
apply to viral infections that are presumed to be associated with the underlying tumor type
required for study entry). Not applicable starting with Protocol Amendment 13 and all 
subsequent amendments.
g) Any serious or uncontrolled medical disorders.
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h) Any major surgery within 4 weeks of study drug administration.
i)
Subjects who are unable to undergo venipuncture and/or to tolerate venous access. Not 
applicable starting with Protocol Amendment 13 and all subsequent amendments.
j)
Any other sound medical, psychiatric and/or social reason as determined by the
investigator. Not applicable starting with Protocol Amendment 13 and all subsequent 
amendments.
k) All toxicities attributed to systemic prior anti-cancer therapy other than alopecia and
fatigue must have resolved to Grade 1 (National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE] version 4.03 [v4.03]) or baseline
before administration of study drug. Subjects with toxicities attributed to systemic prior
anti-cancer therapy, that are not expected to resolve, and that result in long lasting sequelae,
such as neuropathy after platinum-based therapy, are permitted to enroll.
l)
Subjects with a condition requiring systemic treatment with either corticosteroids 
(prednisone > 10 mg daily or equivalent) or other immunosuppressive medications within 
14 days of start of study drug (or randomization, for the SCCHN Randomized Cohorts
[Part 3] and the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination [Part 5]). Inhaled or topical steroids, and adrenal replacement steroid doses 
prednisone > 10 mg daily or equivalent, are permitted in the absence of active autoimmune 
disease.
3) Prohibited Prior Treatments and/or Therapies
a) Prior treatment with an anti-KIR antibody or an anti-PD-1, anti-PD-L1, anti-PD-L2, or 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways except as noted below.
b) Prior treatment regimens with any immune cell modulating antibody such as anti-CD137 
and anti-OX40. However, prior anti-CTLA-4 therapy is allowed if the last dose is 101 days 
or more from the first dose of study drug. Not applicable starting with Amendment 13 and 
all subsequent amendments.
c) Exposure to any other investigational drug within 4 weeks prior to the first dose of study
drug.
d) Treatment with any anti-cancer therapy, chemotherapy, radiation therapy, biologics for 
cancer, or investigational therapy within 28 days of first administration of study drug
(subjects with prior radiation, 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 v4.03]).
e) Prior focal palliative radiotherapy within 2 weeks prior to the first dose of study
administration.
f)
Use of non-oncology vaccines containing live virus for prevention of infectious diseases
within 4 weeks prior to study drug. The use of the inactivated seasonal influenza vaccine
(Fluzone®) is allowed. Not applicable starting with Protocol Amendment 13 and all 
subsequent amendments.
g) Use of growth factors, including, but not limited to, granulocyte-colony stimulating factor,
granulocyte macrophage-colony stimulating factor, or erythropoietin within 4 weeks prior
to the first dose of study drug. Not applicable starting with Protocol Amendment 13 and 
all subsequent amendments.
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K Use of packed red blood cells or platelet transfusion within 2 weeks prior to the first dose
of study drug Not applicable starting with Protocol Amendment 13 and all subsequent 
amendments.
i)
Inhaled or topical steroids and adrenal replacement doses prednisone > 10 mg/day or 
equivalent are permitted in the absence of active autoimmune disease.
j)
Use of receptor activator of nuclear factor kappa-B ligand inhibitors within 10 weeks prior
to the first dose of study drug. Not applicable starting with Protocol Amendment 13 and 
all subsequent amendments.
k) Use of bisphosphonates within 4 weeks prior to the first dose of study drug. Not applicable 
starting with Protocol Amendment 13 and all subsequent amendments.
l)
Use of any medicinal herbal preparations within 2 weeks prior to the first dose of study
drug. Not applicable starting with Protocol Amendment 13 and all subsequent 
amendments.
4) Physical and Laboratory Test Findings
a) Positive tests for HIV antibody (may obtain additional testing or substitute testing per
institutional guidelines to rule out infection) or known acquired immunodeficiency
syndrome.
b) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of the 
virus, eg, HBsAg (Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive 
(except if HCV-RNA negative).
i)
Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by 
PCR are eligible. Not applicable starting with Protocol Amendment 13 and all 
subsequent amendments.
ii) Subjects with a history resolved hepatitis A virus infection are eligible. Not applicable 
starting with Protocol Amendment 13 and all subsequent amendments.
c) Any Grade 4 laboratory abnormalities.
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components (eg, history of severe
hypersensitivity reactions to drugs formulated with polysorbate 80).
6) Sex and Reproductive Status
a) Women who are pregnant or are breastfeeding.
7) 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 to ensure 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 WOCBP is defined as any female who has experienced menarche and who has not undergone
surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal.
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Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the
absence of other biological or physiological causes. In addition, women under the age of 55 must
have a documented serum follicle-stimulating hormone (FSH) level > 40 mIU/mL to confirm
menopause.
Females treated with HRT are likely to have artificially suppressed FSH levels and may require a
washout period in order to obtain a physiologic FSH level. The duration of the washout period is
a function of the type of HRT used. The durations of the washout periods below are suggested
guidelines and the investigators should use their judgement in checking serum FSH levels. If the
serum FSH level is > 40 mIU/mL at any time during the washout period, the woman can be
considered postmenopausal.
•
1 week minimum for vaginal hormonal products (ie, rings, creams, and gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents (except as stated in Section 3.4.3).
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Sections 3.4.2 and 
3.4.3)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents).
3.4.2
Other Restrictions and Precautions
Subjects with a condition requiring systemic treatment with either corticosteroids (prednisone > 10 
mg daily or equivalent) or other immunosuppressive medications within 14 days of study drug
assignment or randomization are excluded. Inhaled or topical steroids, and adrenal replacement 
steroid doses prednisone > 10 mg daily or equivalent, are permitted in the absence of active 
autoimmune disease.
3.4.3
Permitted Therapy
Subjects are permitted the use of topical, ocular, intra-articular, intra-nasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses prednisone 
> 10 mg daily are permitted. A brief (< 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.
Subjects may continue to receive HRT.
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Regular concomitant use of bisphosphonates and receptor activator of nuclear factor kappa B 
ligand (RANK-L) inhibitors for prevention or reduction of skeletal-related events in subjects with 
bone metastases is allowed if initiated prior to first dose of study drug. Prior palliative radiotherapy 
must have been completed at least 2 weeks prior to randomization
Prior palliative radiotherapy must have been completed at least 4 weeks prior to randomization for 
cases of radiotherapy to the head and neck, and completed within 2 weeks prior to randomization 
for radiotherapy to other sites. On-study palliative radiotherapy is only allowed for treatment of 
painful bone lesions. Palliative surgical resection of tumor sites is not permitted. Subjects requiring 
palliative radiotherapy should be evaluated for objective evidence of disease progression prior to 
the initiation of such therapy, particularly if the most recent tumor assessment was more than 
4 weeks prior to the start of local therapy. If progression per RECIST v1.1 is identified on any 
tumor assessments prior to the initiation of palliative local therapy, then subjects must discontinue 
study drug. 
The potential for overlapping toxicities with radiotherapy and nivolumab/lirilumab; 
nivolumab/ipilimumab/lirilumab and nivolumab/ipilimumab currently is not known; however, 
anecdotal data suggest these combinations may be tolerable. As concurrent radiotherapy and the 
IO combination therapy have not been formally evaluated, in cases where palliative radiotherapy 
is required for a tumor lesion, 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 should resolve to Grade ≤1 prior to resuming nivolumab 
or nivolumab plus ipilimumab.
Palliative and supportive care for disease related symptoms may be offered to all subjects on the
study; for subjects in the Dose Escalation and Cohort Expansion (Part 1; completed), this must be 
after the DLT evaluation period. Limited radiation therapy or surgery to control isolated lesions is
permitted for subjects who have investigator-assessed clinical benefit (eg, irSD or irPR) following
consultation with the BMS Medical Monitor. Subjects should not receive study drug during
radiation or surgery.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the
discretion of the investigator) for any of the following reasons:
•
Withdrawal of informed consent (subject’s decision to withdraw for any reason)
•
Any clinical AE, laboratory abnormality, clinical deterioration, or concurrent illness that in the
opinion of the investigator indicates that continued participation in the study is not in the best
interest of the subject
•
Pregnancy
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for
treatment of either a psychiatric or physical (eg, infectious disease) illness
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•
Documented and confirmed irPD as defined by irRECIST for the Dose Escalation and Cohort 
Expansion (Part 1; completed) and the SCCHN Cohort Expansion (Part 2; completed) (see
Appendix 2). 
•
Documented PD for the SCCHN Randomized Cohorts (Part 3), and the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) as defined by 
RECIST v1.1 (see Appendix 3).
•
Documented and confirmed irCR as defined by irRECIST for the Dose Escalation and Cohort 
Expansion (Part 1; completed) and the SCCHN Cohort Expansion (Part 2; completed) (see 
Appendix 2)
•
Documented and confirmed CR for the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5) as defined by RECIST v1.1 (see 
Appendix 3).
•
Discretion of the investigator
•
Inability to comply with the protocol requirements
•
Protocol defined reasons for discontinuation (see Section 4.9.5)
•
Maximum treatment duration of up to a maximum of 2 years; 12 cycles in Parts 1, 2, and 3 or 
8 cycles in Part 5.
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the Sponsor or designee must occur.
All subjects who discontinue should comply with protocol specified follow-up procedures as
outlined in Section 5.1. The only exception to this requirement is when a subject withdraws consent
for all study procedures 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 CRF page.
3.5.1
Treatment Beyond Disease Progression
With Revised Protocol 12, no additional subjects are permitted to enter Treatment Beyond Disease 
progression. At the time of initial progressive disease, subjects will be required to discontinue 
study treatment and enter clinical follow-up.
As defined in Section 5.4; treatment related decisions will be governed by irRECIST based
response assessments. The proposed irRECIST criteria allows for continued study therapy beyond
initial RECIST v1.1 defined PD and will only be permitted provided the following criteria are met:
•
Clinical benefit as assessed by the investigator
•
Disease progression is not rapid
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•
Continues to meet all other study protocol eligibility criteria
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious
complications of disease progression (eg, CNS metastases)
•
Subjects have provided written informed consent prior to receiving additional treatment with
their assigned treatment.
In the combination setting, subjects who meet criteria may continue on lirilumab and nivolumab 
in combination but may not continue on 1 treatment or the other alone.
For the SCCHN Randomized Cohorts (Part 3), and the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), decisions related to treatment 
beyond progression will be made with RECIST v1.1. 
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 measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at 
least15 mm). Any new lesion considered nonmeasureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm).
3.6
Treatment of Infusion Reactions
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 (v4.03) guidelines.
Of note, since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypo-
or hypertension, bronchospasm, or other symptoms. 
Treatment recommendations applicable for all study drugs 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 
nivolumab administrations.
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For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤ 24 
hours).
Stop the nivolumab 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 nivolumab 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; presser or ventilatory support 
indicated).
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat
the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution 
for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued. Investigators should
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and
monitor 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).
If any vital sign is abnormal at the final check, the subject must be observed further for a period 
of time, as clinically indicated.
The start and stop time of the study drug infusion should be documented. If there are any new or 
worsening clinically significant changes since the last examination, report changes on the 
appropriate non-serious or SAE page.
When slowing or restarting an infusion due to an infusion reaction, vital signs should be monitored 
every 15 minutes (± 5 minutes) or as directed by the investigator until the infusion is completed 
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and/or the subject is stabilized. If a subject has an infusion reaction with nivolumab, the lirilumab, 
ipilimumab, or placebo for lirilumab infusion can be given (without prophylactic medications) if 
the infusion reaction resolves within 3 hours. For scheduling purposes after a nivolumab infusion 
reaction, the lirilumab, ipilimumab, or placebo for lirilumab infusion may be given the next day. 
Prophylactic pre-infusion medications should be given prior to all subsequent nivolumab 
infusions.
3.7
Post-treatment Study Follow-up
Overall survival data will no longer be collected with Revised Protocol 12.
In this study, OS is a secondary endpoint for the SCCHN Randomized Cohorts (Part 3)
. 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 4.9.5 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 (see 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.
3.7.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be
followed for protocol-specified follow-up procedures. The only exception to this is when a subject
specifically withdraws consent for any further contact with him/her or persons previously
authorized by subject to provide this information. Subjects should notify the investigator of the
decision to withdraw consent from future follow-up in writing 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; the information should be entered on the appropriate CRF page.
In the event that vital status (whether the subject is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directed in
accordance with local law.
3.7.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status.
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up
is defined by the inability to reach the subject after a minimum of 3 documented phone calls, faxes,
or emails as well as lack of response by subject to 1 registered mail letter. All attempts should be
documented in the subject’s medical records. If it is determined that the subject has died, the study
site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of a 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 BMS-retained
third-party representative to assist study site staff with obtaining subject’s contact information or
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other public vital status data necessary to complete the follow-up portion of the study. 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
TREATMENTS
All protocol-specified investigational and non-investigational products are considered study drug.
4.1
Study Treatments
The study drugs include lirilumab (BMS-986015), nivolumab (BMS-936558), and ipilimumab 
(BMS-734016). Table 4.1-1 below indicates the Dose Level to be used for each panel in the Dose 
Escalation and Cohort Expansion (Part 1; Completed). The placebo for lirilumab injection is 
normal saline injection, which is administered in a similar fashion as described for the lirilumab 
injection. The normal saline to use as placebo will not be provided by the Sponsor.
Table 4.1-1:
Treatment Administration (Dose Escalation and Cohort Expansion
[Part 1; Completed])
Dose Level
Lirilumab
Nivolumab
1
0.1 mg/kg
3 mg/kg
2
0.3 mg/kg
3 mg/kg
3
1 mg/kg
3 mg/kg
4
3 mg/kg
3 mg/kg
Product description and storage information is described in Table 4.1-2.
Cohort expansions will be treated at the highest tested dose or a different Dose Level as selected
by the Sponsor.
The Dose Escalation and Cohort Expansion (Part 1; completed), and the SCCHN Cohort 
Expansion (Part 2; completed): For treatment visits where both lirilumab and nivolumab are
administered, nivolumab will be administered first followed by lirilumab. Nivolumab will be 
administered as a 60-minute infusion; 30 minutes after completion of the nivolumab infusion, 
lirilumab will be administered as a 60-minute infusion.
The SCCHN Randomized Cohorts (Part 3) (Arm A): For treatment visits where both lirilumab and 
nivolumab are administered, nivolumab will be administered first followed by lirilumab. 
Nivolumab will be administered as a 30-minute infusion; 30 minutes after completion of the 
nivolumab infusion, lirilumab will be administered as a 60-minute infusion.
The SCCHN Randomized Cohorts (Part 3) (Arm B): For treatment visits where both placebo for 
lirilumab and nivolumab are administered, nivolumab will be administered first followed by 
placebo for lirilumab. Nivolumab will be administered as a 30-minute infusion; 30 minutes after 
completion of the nivolumab infusion, placebo for lirilumab will be administered as a 60-minute 
infusion.
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The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination 
(Part 5): On days when all 3 study drugs are given, nivolumab will be given first followed by 
ipilimumab followed by lirilumab. Nivolumab will be administered as a 30-minute infusion; 
30 minutes after completion of the nivolumab infusion, ipilimumab will be administered as a 
30-minute infusion; and 30 minutes after completion of the ipilimumab infusion, lirilumab will be 
administered as a 60-minute infusion. On days when nivolumab and lirilumab are given, 
nivolumab will be given first followed by lirilumab. Nivolumab will be administered as a 
30-minute infusion; 30 minutes after completion of the nivolumab infusion, lirilumab will be 
administered as a 60-minute infusion.
Detailed administration instructions will be provided separately via study site training materials
and Dosing Procedure Manual.
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Table 4.1-2:
Product Description and Dosage Form
Product Description and
Dosage Form
Potency
Primary Packaging
(Volume)/Label Type
Secondary Packaging
(Qty)/Label Type
Appearance
Storage Conditions
(Per Label)
BMS-986015-01 Solution 
for Injection, 50 mg/vial
(10 mg/mL) a
10 mg/mL
5-mL vial/open
Box/open
Clear to opalescent,
colorless liquid.
Essentially free of
particles.
Store at 2°C to 8°C
(36°F to 46°F) protect 
from light, protect from 
freezing
BMS-986015-01 Solution 
for Injection, 100 mg/vial
(10 mg/mL) a
10 mg/mL
10-mL vial/open
Box/open
Clear to opalescent,
colorless liquid.
Essentially free of
visible particles.
Store at 2°C to 8°C
(36°F to 46°F), protect 
from light, protect from 
freezing
BMS-936558-01 Solution 
for Injection, 40 mg/vial 
(10 mg/mL) b
10 mg/mL
10-mL vial/open
Box/open 
(as kit containing 
2×100 mg vials
BMS-936558-01 with 
1× 40 mg vial) 
Clear to opalescent, 
colorless to pale yellow 
liquid, light (few) 
particulates may be 
present.
Store at 2°C to 8°C 
(36°F to 46°F), Do not 
freeze. Protect from 
light.
BMS-936558-01 Solution 
for Injection, 10 mg/mL, 
10 mL
(100 mg/vial) b
10 mg/mL
10-mL vial/open
Box/open
OR 
Box/open 
(as kit containing 
2×100 mg vials with 
1× 40 mg vial 
BMS-936558-01)
Clear to opalescent,
colorless to pale yellow
liquid, light (few) 
particulates may be 
present
Store 2°C to 8°C (36°F 
to 46°F); protect from
light; protect from
freezing.
Ipilimumab Solution for 
Injection, 5 mg/mL, 40mL 
(200 mg/vial) c
5 mg/mL
50-mL vial/open
Box/open
Clear to slightly 
opalescent, colorless to 
pale yellow liquid. 
Light (few) particulates 
may be present
Store 2°C to 8°C. Store 
in original package. Do 
not freeze. Protect from 
light.
a BMS-986015-01 is also referred to as lirilumab.
b BMS-936558-01 is also referred to as nivolumab.
c BMS-734016 is also referred to as ipilimumab.
Solutions used as placebo (Normal Saline, ie, 0.9% Sodium Chloride Injection) should be sourced by investigative sites if available and permitted by local 
regulations. Storage should be in accordance with the product label.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is
defined as follows:
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, investigational product(s) is/are: lirilumab, nivolumab, ipilimumab, and placebo.
4.1.2
Noninvestigational 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
noninvestigational products.
In this protocol, noninvestigational product(s) is/are medications used to treat adverse events.
4.1.3
Handling 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, do not dispense the study drug and
contact BMS immediately.
4.1.4
Preparation of Study Drug(s)
The study drugs will be administered by IV infusion. Details with regard to IV admixing, infusion
rates, and stability will be provided separately in study site training materials and the Dosing 
Procedure Manual.
4.2
Method of Assigning Subject Identification
CA223001 is an open-label study with the exception of the SCCHN Randomized Cohorts (Part 3), 
which is site- and subject-blind. Subjects will undergo screening evaluations to determine
eligibility within 28 days prior to dosing for the Dose Escalation and Cohort Expansion (Part 1) 
and the SCCHN Cohort Expansion (Part 2) and 35 days for all other study parts. Enrolled subjects
will be assigned a subject number,
increasing sequentially with each
additional enrolled subject. The subject number will be assigned by the Sponsor via IVRS once
the subject signs the informed consent form. Each subject will then be identified by a distinct
patient identification number (PID) which is composed of the study site number and the subject
number. For example, the first subject screened (ie, enrolled) at study site number 1, will have a
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PID
. The investigator or designee will register the subject following the enrollment
procedures established by BMS. The following information is required for registration:
•
Date of birth
•
Gender
•
Diagnosis
•
Tumor Type
•
Date of Informed Consent
•
Planned date of 1st dose
Enrolled subjects meeting all eligibility criteria will be assigned to a dose cohort. Specific
instructions regarding enrollment and dose cohort assignment will be provided to the study sites
in their training materials.
The SCCHN Randomized Cohorts (Part 3)
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS for the SCCHN Randomized Cohorts (Part 3). Once enrolled in
IVRS, enrolled subjects who have met all eligibility criteria and have been assigned to the SCCHN 
Randomized Cohorts (Part 3) will be ready to be randomized through the IVRS in a 2:1 ratio of 
Arm A to Arm B:
•
Arm A: flat dose of lirilumab 240 mg Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg
Q2W (Days 1, 15, 29, and 43) until PD
•
Arm B: placebo for lirilumab Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg
monotherapy Q2W (Days 1, 15, 29, and 43) until PD
The following information is required for subject randomization:
•
Subject number
•
Date of birth
•
Prior cetuximab treatment (yes/no)
•
PD-L1 status
The stratification factor includes:
•
PD-L1 ≥ 50% expression (yes/no)
•
Prior cetuximab treatment (yes/no)
The first dose of study drug is to be administered within 3 days following randomization.
Specific instructions for using IVRS will be provided to the study sites in a separate document.
4.3
Selection and Timing of Dose for Each Subject
Each subject will be assigned to a specific Dose Level as listed in Table 3.1.1.1-1 in sequential
order during dose escalation. Subjects in cohort expansion will be treated at the MTD, the MAD,
or at an alternate dose, if recommended by the investigators and the Sponsor.
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Subjects in the SCCHN Randomized Cohorts (Part 3) will be treated with a flat dose of nivolumab 
240 mg Q2W in combination with a flat dose of lirilumab 240 mg Q4W or placebo for lirilumab 
Q4W.
Subjects in the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5) will be treated with a triplet combination of lirilumab 3 mg/kg Q4W, 
nivolumab 3 mg/kg Q2W, and ipilimumab 1 mg/kg Q6W. If conditions in Section 3.1.5 are met, 
a lower dose or an alternate dose schedule should be examined.
4.4
Blinding/Unblinding
Applicable for the single-blinded SCCHN Randomized Cohorts (Part 3).
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject's management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject's immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is the Interactive Response 
Technology (IRT).
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the IRT and is capable of breaking the blind through the IRT system without prior approval 
from the Sponsor. Following the unblinding, the investigator shall notify the Medical Monitor
and/or study director.
For information on how to unblind for emergency, please consult the IRT manual.
The subjects, investigator, and site staff will be blinded to the study drug administered (lirilumab
in combination with nivolumab or nivolumab monotherapy). For all subjects in the SCCHN 
Randomized Cohorts (Part 3), and the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5), each investigative site must assign an unblinded 
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pharmacist/designee and an unblinded site monitor will be assigned by sponsor to provide 
oversight of drug supply and other unblinded study documentation.
4.5
Treatment Compliance
Study drug will be administered in the clinical facility. The investigator or their designated study
personnel will maintain a log (Drug Accountability Log) of all study drugs received, dispensed
and destroyed. The investigator and the study personnel will ensure that each subject receives the
calculated dose of the study drug based on body weight.
Drug supplies will be inventoried and accounted for throughout the study. The Drug
Accountability Log will be reviewed by the study monitor during study site visits and at the
completion of the study. Any discrepancy should be brought to the attention of the Sponsor. For 
the SCCHN Randomized Cohorts (Part 3), treatment compliance will be monitored by drug 
accountability as well as the subject’s medical record and CRF.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
If study drugs (those supplied by BMS or sourced by the investigator) are to be destroyed on site,
it is the investigator’s responsibility to ensure that arrangements have been made for the disposal,
procedures for proper disposal have been established according to applicable regulations,
guidelines and institutional procedures, and appropriate records of the disposal have been
documented. The unused study drugs can only be destroyed after being inspected and reconciled
by the responsible BMS Study Monitor.
4.6.2
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 BMS 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.
4.7
Retained Samples for Bioavailability / Bioequivalence
Not applicable
4.8
Dose Limiting Toxicities
This section only applies to the Dose Escalation and Cohort Expansion (Part 1) and the SCCHN 
Cohort Expansion (Part 2), which have both completed enrollment and therefore this section and 
its subsections are not applicable starting with Amendment 13 and all subsequent amendments or 
revised protocols. 
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4.8.1
Definition
DLT will be determined based on the incidence, intensity, and duration of AEs as defined below 
that are related to study drug and that occur within 56 days (8 weeks, through the completion of
Cycle 1) of initiation of study drug in the Dose Escalation and Cohort Expansion (Part 1; 
completed). The severity of AEs will be graded according to the NCI CTCAE v4.03. Hepatic, non-
hematologic, and hematologic DLT will be defined separately as outlined below.
4.8.2
Definition of Hepatic DLT
Any of the following events will be considered a hepatic DLT except for subjects with HCC:
•
ALT or AST > 8 × ULN, regardless of duration
•
ALT or AST > 5 × and ≤8 × ULN, that fails to return to Grade 1 or less within 5 days despite
medical intervention
•
Grade 3 total bilirubin
•
ALT or AST > 3 × ULN and concurrent total bilirubin > 2 × ULN
4.8.2.1
Definition of Hepatic DLT for Subjects with HCC
In August 2011, an advisory board panel was convened to discuss treatment of subjects with
hepatitis B infection with or without HCC. The potential for hepatic flare with anti-viral therapy
such as entecavir, lamuvidine, or tenofovir was discussed. It was the consensus of the panel
members that the risk for this toxicity was low in subjects with low viral DNA loads who were on
anti-viral therapy for several months. In subjects with hepatitis C infection, transient Grade 4
transaminase levels can be observed. Protocol Section 4.8.2 describes the hepatic toxicity DLT
parameters used for subjects without HCC for this protocol. Due to the potential for hepatic
inflammation that could be greater due to viral infection the panel recommended that parameters
be adjusted to permit a higher level of hepatic toxicity with AST or ALT > 10 × ULN for
> 2 weeks, AST or ALT > 15 × ULN irrespective of duration, total bilirubin > 8 × ULN
irrespective of duration for subjects with elevated bilirubin at study entry or > 5 × ULN for those
with normal total bilirubin at study entry, concurrent AST or ALT > 3 × ULN and total bilirubin
> 5 × ULN for subjects entering treatment with a normal bilirubin and up to 8 × ULN for subjects
with
elevated
bilirubin,
or
clinical
deterioration
manifested
by
drug-related
hepatic
decompensation not identified above.
Therefore, for subjects with HCC, hepatic DLT criteria will differ due to intrinsic involvement of
the liver. In addition, for subjects with hepatitis B or hepatitis C, it is possible that virological
breakthrough may occur, leading to temporary hepatic damage that is greater than the parameters
detailed above. In these cases, subjects who regain virologic control may be allowed to resume
study therapy after agreement between the PI and the Medical Monitor.
Any of the following events will be considered a hepatic DLT for subjects with HCC:
•
ALT or AST > 15 × ULN, regardless of duration
•
ALT or AST > 10 × ULN for greater than 2 weeks
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•
total bilirubin > 8 × ULN regardless of duration for subjects with elevated bilirubin at study
entry or > 5 × ULN for subjects with normal bilirubin at study entry
•
ALT or AST > 3 × ULN and concurrent total bilirubin > 2 × ULN
4.8.3
Definition of Non-hematologic DLT
Any of the following events will be considered a non-hematologic DLT:
•
Grade 2 eye pain or reduction in visual acuity that requires systemic treatment
•
Grade 2 eye pain or reduction in visual acuity that does not respond to topical therapy and that
does not improve to Grade 1 within 2 weeks of initiation of topical therapy
•
Grade 3 non-hepatic or non-hematologic toxicity, with the following exceptions:
The following Grade 3 non-hematologic events will not be considered DLTs:
•
Grade 3 electrolyte abnormality that lasts less than 72 hours, is not clinically complicated, and
resolves spontaneously or responds to conventional medical intervention
•
Grade 3 increase in amylase or lipase that is not associated with clinical or radiographic
evidence of pancreatitis
•
Grade 3 nausea or vomiting that lasts less than 48 hours, and resolves to Grade 1 or less, either
spontaneously or with conventional medical intervention
•
Grade 3 fever that lasts less than 72 hours, and is not associated with hemodynamic
compromise (including hypotension, or clinical or laboratory evidence of end organ perfusion
impairment)
•
Grade 3 endocrinopathy that is well controlled by hormone replacement
•
Grade 3 tumor flare (defined as pain, irritation or rash that localizes to sites of known or
suspected tumor)
•
Grade 3 fatigue
•
Grade 3 infusion reaction that returns to Grade 1 in less than 6 hours
4.8.4
Definition of Hematologic DLT
Any of the following events will be considered a Hematologic DLT:
•
Grade 4 neutropenia that lasts longer than 5 days
•
Grade 4 thrombocytopenia
•
Grade 3 thrombocytopenia associated with clinically significant bleeding
•
Grade 3 febrile neutropenia that lasts longer than 48 hours
•
Grade 3 hemolysis
4.9
Guidelines for Dose Modification
Intra-subject dose escalation or reduction of lirilumab, nivolumab, and ipilimumab is not permitted
in this study in order to allow better evaluation of extended safety and efficacy at individual Dose 
Levels and schedules.
4.9.1
Intra-subject Dose Escalation
No intra-subject dose escalation is allowed.
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4.9.2
Dose Reductions
No dose reductions of lirilumab, nivolumab, and ipilimumab are permitted in this study.
4.9.3
Dose Delays Due To Toxicity
Subjects who experience a DLT must have therapy held. Subjects who are required to permanently
discontinue study drug administration are listed in Section 4.9.5. All other subjects will be
permitted to resume study drug administration at the same doses for all study drugs following
resolution of the AE to Grade 1 or less, or to baseline.
Study drug administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, and total bilirubin will require dose discontinuation (see Section 4.8)
•
Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of the 
investigator, warrants delaying the dose of study drug
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when retreatment criteria are met.
4.9.4
Criteria for Subsequent Dosing
Subsequent dosing may continue if subjects continue to meet laboratory criteria as listed in
Section 3.3.1. The investigator will determine if subsequent dosing is appropriate for subjects who
have laboratory or clinical abnormalities that do not meet DLT (Section 4.8) or discontinuation
criteria (Section 4.9.5). All related Grade 2 toxicities should be discussed with the BMS Medical 
Monitor prior to subsequent dosing.
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue.
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
•
For subjects 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.
•
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (Section 4.8) should have treatment permanently discontinued. 
•
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.
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•
Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor. Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
4.9.5
Guidelines for Permanent Discontinuation
Subjects will be required to permanently discontinue all study drugs for the following AEs:
1) Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the retreatment period OR requires 
systemic treatment 
2) For subjects receiving lirilumab in combination with nivolumab or nivolumab monotherapy 
(the Dose Escalation and Cohort Expansion [Part 1; completed] and the SCCHN Cohort 
Expansion [Part 2; completed], the SCCHN Randomized Cohorts [Part 3],): Any Grade 3 non-
skin, drug-related AE lasting > 7 days or recurs, with the following exceptions for laboratory 
abnormalities, drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, 
infusion reactions, and endocrinopathies:
a) Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation.
b) 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. 
c) Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
i)
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding
ii) Grade ≥3 drug-related AST, ALT, or total bilirubin*
iii) Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
3) For subjects receiving lirilumab in combination with nivolumab and ipilimumab (the Signal 
Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination [Part 5]): Any 
Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs with the following exceptions 
for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related uveitis, 
pneumonitis, 
bronchospasm, 
hypersensitivity 
reactions, 
infusion 
reactions, 
and 
endocrinopathies:
a) Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation.
b) 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. 
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c) Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
iv) Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding
v) Any drug-related liver function test abnormality that meets the following criteria:
(1) Grade ≥3 drug-related AST, ALT, or total bilirubin*
(2) Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
4) Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or total bilirubin), except for the following events, which do not require 
discontinuation:
a) 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
b) Grade 4 neutropenia ≤ 7 days
c) Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
d) Grade 4 lymphopenia < 5 days in duration
e) Grade 4 drug-related endocrinopathy AEs, such as hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids or thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
5) Any DLT as outlined in Section 4.8 will require permanent discontinuation with the following
exceptions:
a) Grade 3 diarrhea, nausea, vomiting, or abdominal pain that returns to Grade 1 or baseline
within 3 days with medical intervention
b) Grade 3 ALT or AST that returns to Grade 1 or baseline within 7 days with medical
intervention
c) Grade 3 pruritus or rash that returns to Grade 1 or baseline within 7 days or baseline with
medical intervention
6) Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
a) Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. 
b) Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor. 
c) Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks, the BMS 
Medical Monitor must be consulted. Tumor assessments should continue as per protocol 
even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
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should also continue Q6W or more frequently if clinically indicated during such dosing 
delays.
7) Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing.
The consideration to re-initiate study therapy under these exceptions will be made on a case by
case basis after considering the overall benefit/risk profile and in consultation between the
investigator and the study Sponsor.
In cases where the AE meets the criteria for permanent discontinuation from study therapy, but the
investigator and the Sponsor believe that re-initiation of study therapy may be potentially
beneficial and justified, details will be submitted in advance to the FDA or other relevant health 
authorities for review, prior to re-initiation of study therapy.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of lirilumab and/or ipilimumab. Although there is overlap among the 
discontinuation criteria, if discontinuation criteria are met for lirilumab and/or ipilimumab but not 
for nivolumab, treatment with nivolumab may continue if lirilumab and/or ipilimumab is 
discontinued.
If a subject in any of the study drug combination cohorts meets criteria for discontinuation and 
investigator is unable to determine whether the event is related to a single study drug, the subject
should discontinue all study drugs and be taken off the treatment phase of the study.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
5.1.1
Dose Escalation and Dose Expansion (Part 1; Completed) and the SCCHN Cohort Expansion (Part 2;
Completed)
Table 5.1.1-1:
Screening Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Screening
Visit
(D -28 to -1)
D -14
to -1
D -3 to -1
Visit
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol-specific informed
consent is signed.
Inclusion/Exclusion Criteria
X
Medical History
X
May include more detailed medical history of risk factors for potential events
such as pulmonary related events.
Archived tumor tissue samples
X
One paraffin block or 5 to 15 FFPE unstained slides identified prior to
enrollment/randomization.
For the SCCHN Cohort Expansion (Part 2), confirmation of tumor tissue 
receipt at central laboratory is required before subjects receive study drug.
Safety Assessments
Physical Examination
X
If the screening PE is performed within 24 hours of dosing on Cycle 1 Day 1 
then a single exam may count as both the screening and pre-dose evaluation.
Performance Status
X
ECOG Performance Status (see Appendix 7).
Physical Measurements
X
Includes height, weight.
Vital Signs
X
Includes body temperature, seated blood pressure, and heart rate. Blood 
pressure and heart rate should be measured after the subject has been seated 
quietly for at least 5 minutes.
Oxygen Saturation
Xa
Collected at rest. Oxygen levels will be used in combination with clinical 
signs and symptoms and radiographic images to evaluate 
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Table 5.1.1-1:
Screening Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Screening
Visit
(D -28 to -1)
D -14
to -1
D -3 to -1
Visit
Notes
pulmonary/respiratory status. Changes in oxygen levels will not be used in 
isolation to document or diagnose pulmonary toxicity.
Electrocardiogram
X
12-lead ECG.
Chest Radiograph
X
Laboratory Tests
X
Day -14 to -1 prior to Cycle 1 Day 1.
To include: CBC with differential, LFTs (to include a minimum of AST, 
ALT, alkaline phosphatase, total bilirubin, and LDH), BUN, creatinine, Ca, 
Mg, Na, K, carbon dioxide, Cl, phosphorous, glucose, albumin, amylase, 
lipase, CRP, TSH with reflex (free T3 and free T4), hepatitis B/C, and HIV 
testing
(Subjects with HCC only, PT, PTT, INR, and fibrinogen)
If performed within 72 hours of dosing on Cycle 1 Day 1, then Cycle 1 Day 1 
laboratories are not required.
HPV Status
X
The Dose Escalation and Dose Cohort (Part 1): SCCHN subjects only. Sites 
must submit and document prior HPV status and subtype, particularly HPV16 
and HPV18 (p16 immunohistochemistry positive or negative status is 
recommended).
The SCCHN Cohort Expansion (Part 2) Sites must submit prior HPV status if 
known. For subjects with unknown status, tumor tissue will be required, per 
inclusion criteria. Subjects must consent to HPV testing.
MSI Status
X
CRC subjects only. Sites must submit and document prior MSI testing and 
results. If MSI status is known prior to study entry, repeat testing will not be 
required during the screening period, but tissue must be available for repeat 
MSI testing if requested.
Child-Pugh Score
X
HCC subjects only. See Appendix 5
Serum Pregnancy Test
X a
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Table 5.1.1-1:
Screening Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Screening
Visit
(D -28 to -1)
D -14
to -1
D -3 to -1
Visit
Notes
Concomitant Medication
X
Collected for the period 2 weeks prior to Cycle 1 Day 1. (Note: 
Immunosuppressive medications are recorded on a separate log page.)
Assessment of Signs and Symptoms
X
Collected for the period 2 weeks prior to Cycle 1 Day 1.
Adverse Event Reporting
Monitor for Serious Adverse Events
X
All SAEs must be collected starting at the time the subject signs informed 
consent and through 150 days after discontinuation of dosing. SAEs should 
be approved in TAO within 4 days of entry
Efficacy Assessments
Diagnostic Imaging
X
CT with contrast is the preferred modality (MRI if CT is not feasible). 
Assessment should include the chest/abdomen/pelvis at a minimum; and 
should include other anatomic regions as indicated by individual subject 
disease histories.
Brain Imaging
X
Brain imaging (CT/MRI) for subjects with history or symptoms of brain 
metastases or who have not had brain imaging within 30 days of anticipated 
first study drug administration.
Bone Scan
X
As clinical indicated (ie, subjects with history or symptoms of bone 
metastases), but bone scans will not be considered a modality for assessment 
for measurable disease.
Serologic Tumor Markers
X
To include measuring for tumor types with known serologic markers 
(ie, CEA for subjects with CRC, PSA for subjects with prostate ca, CA-125 
for subjects with ovarian/breast cancer, alpha fetoprotein for subjects with 
HCC, hepatitis B DNA PCR for subjects with hepatitis B, and hepatitis C 
RNA PCR for subjects with hepatitis C, etc).
To be collected prior to the first dose of study drug.
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Table 5.1.1-1:
Screening Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Screening
Visit
(D -28 to -1)
D -14
to -1
D -3 to -1
Visit
Notes
Clinical Drug Supplies
Subject Registration
X
a May be obtained on Cycle 1 Day 1 with results evaluated prior to study drug administration.
BUN = blood urea nitrogen; Ca = calcium; CEA = carcinoembryonic antigen; CBC = complete blood count; Cl = chloride; CRP = C-reactive protein; D = Day; 
ECG = electrocardiogram; INR = international normalized ratio; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; Mg = magnesium; Na
= sodium; PE = physical examination; PSA = prostate-specific antigen; PT = prothrombin time; PTT = partial thromboplastin time; T3 = triiodothyronine; T4 = 
thyroxine; TAO = Trial Access Online; TSH = thyroid-stimulating hormone.
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BMS-986015
lirilumab
Table 5.1.1-2:
On-treatment Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and 
the SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Cycles 1 to 12
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
Safety Assessments
Physical Examination
X
A symptom directed physical examination performed by the
investigator or designee is required at each subsequent visit.
Performance Status
X
X
X
X
ECOG score (see Appendix 7)
Physical Measurements
X
X
X
X
Weight only.
Vital Signs
X
X
X
X
Vital signs will be obtained before the nivolumab infusion,
after the nivolumab infusion, and after the lirilumab infusion.
If any vital sign is abnormal at the final check, the subject
must be observed further for a period of time, as clinically
indicated.
The start and stop time of the study drug infusion should be
documented. If there are any new or worsening clinically
significant changes since the last examination, report changes
on the appropriate non-serious or serious adverse event page.
When slowing or restarting an infusion due to an infusion
reaction, vital signs should be monitored every 15 minutes
(± 5 minutes) or as directed by the investigator until the
infusion is completed and/or the subject is stabilized. If a
subject has an infusion reaction with nivolumab, the lirilumab
infusion can be given (without prophylactic medications) if
the infusion reaction resolves within 3 hours. For scheduling
purposes after a nivolumab infusion reaction, the lirilumab
infusion may be given the next day. Prophylactic pre-infusion
medications should be given prior to all subsequent
nivolumab infusions.
Electrocardiogram
X
12-lead ECG (if performed on same day as study drug
administration it is to be performed prior to dosing).
Not required on Cycle 1 Day 1
Revised Protocol No.: 12
Date: 08-May-2018
122
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.1-2:
On-treatment Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and 
the SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Cycles 1 to 12
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
Chest Radiograph
As clinically indicated.
Oxygen Saturation Levels
X
X
X
X
Collected at rest prior to dosing.
Laboratory Tests
X
X
X
X
On-study laboratory tests (including pregnancy testing) to be
done on site/local. Within 72 hours of re-dosing to include
CBC with differential, LFTs (to include a minimum of AST,
ALT, alkaline phosphatase, total bilirubin, and LDH), BUN,
creatinine, glucose, Ca, Mg, Na, K, carbon dioxide, Cl,
phosphorous, amylase, and lipase. Results should be
examined by the investigator or appropriate designee prior to
dose administration.
(Subjects with HCC only, PT, PTT, INR, and fibrinogen)
CBC with differential should also be collected at each
timepoint where samples for immunophenotyping are
collected as listed in Table 5.7.3.3-1, Table 5.7.3.3-3, and
Table 5.7.3.3-4.
Child-Pugh Score
X
HCC only. 
Endocrine Panel
X
To include TSH with reflex testing (free T3 and free T4).
Results should be examined by the investigator or appropriate
designee within 48 hours of dose administration.
Pregnancy Test
X
X
X
X
Serum or urine.
Adverse Event Reporting
Monitor for Non-serious 
Adverse Events
X
X
X
X
Non-serious AEs will be collected starting with the first dose 
of study drug and through 150 days after discontinuation of 
dosing or until the start of subsequent anti-cancer therapy.
Monitor for Serious Adverse 
Events
X
X
X
X
All SAEs must be collected starting at the time a subject signs 
informed consent and through 150 days after discontinuation 
Revised Protocol No.: 12
Date: 08-May-2018
123
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.1-2:
On-treatment Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and 
the SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Cycles 1 to 12
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
of dosing. SAEs should be approved in TAO within 4 days of 
entry
Sample Collection
PK Assessments
See Table 5.7.3.3-1, Table 5.7.3.3-2, Table 5.7.3.3-3, and 
Table 5.7.3.3-4. To be collected on Days 1, 2, 8, 15, 29, 85, 
86, 92, and 113.
Immunogenicity 
Assessments 
See Table 5.7.3.3-1, Table 5.7.3.3-2, Table 5.7.3.3-3, and 
Table 5.7.3.3-4. To be collected on Days 1, 2, 8, 15, 29, 85, 
86, 92, and 113
Biomarker Assessments
See Table 5.7.3.3-1, Table 5.7.3.3-2, Table 5.7.3.3-3, and 
Table 5.7.3.3-4. To be collected on Days 1, 2, 8, 15, 29, 85, 
86, 92, and 113. Subjects in Cohort Expansion (Part 1) with 
MEL and SCCHN must utilize Table 5.7.3.3-3.
Efficacy Assessments
Diagnostic Imaging
X
By methods used at baseline. Scans will be performed Q8W 
relative to the Cycle 1 Day 1 visit regardless of treatment 
delays.
Brain Imaging
X
As clinically indicated.
Bone Scan
X
As clinically indicated.
Serologic Tumor Markers
X
To include measuring for tumor types with known serologic 
markers (ie, CEA for subjects with CRC, PSA for subjects 
with prostate ca, CA-125 for subjects with ovarian/breast 
cancer, alpha fetoprotein for subjects with HCC, hepatitis B 
DNA PCR for subjects with hepatitis B, and hepatitis C RNA 
PCR for subjects with hepatitis C, etc).
Revised Protocol No.: 12
Date: 08-May-2018
124
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.1-2:
On-treatment Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and 
the SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Cycles 1 to 12
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
Clinical Drug Supplies
Nivolumab Administration
X
X
X
X
Lirilumab Administration
X
X
To be administered 30 minutes after completion of the 
nivolumab infusion.
BUN = blood urea nitrogen; Ca = calcium; CEA = carcinoembryonic antigen; CBC = complete blood count; Cl = chloride; D = Day; ECG = electrocardiogram; 
INR = international normalized ratio; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; Mg = magnesium; Na = sodium; PSA = prostate-
specific antigen; PT = prothrombin time; PTT = partial thromboplastin time; Q8W = every 8 weeks; T3 = triiodothyronine; T4 = thyroxine; TAO = Trial Access 
Online; TSH = thyroid-stimulating hormone.
Revised Protocol No.: 12
Date: 08-May-2018
125
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.1-3:
Follow-up Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-up
Notes
1
30 days
(± 5 days)
2
60 days
(± 5 days)
3
100 days
(± 5 days)
4
150 days a
(± 5 days)
Q12W
(± 2 weeks)
Safety Assessments
Physical Examination
X
X
X
Vital Signs
X
X
X
Includes body temperature, seated blood 
pressure, and heart rate. Blood pressure 
and heart rate should be measured after 
the subject has been seated quietly for at 
least 5 minutes.
Performance Status
X
X
X
ECOG score (see Appendix 7)
Laboratory Tests
X
CBC with differential, LFTs (to include a 
minimum of AST, ALT, alkaline 
phosphatase, total bilirubin, and LDH), 
BUN, creatinine, glucose, Ca, Mg, Na, K, 
carbon dioxide, Cl, phosphorous, amylase, 
and lipase.
Child-Pugh Score
X
HCC subjects only
Adverse Event Reporting
Monitor for Non-serious 
Adverse Events
X
X
X
X
Non-serious AEs will be collected starting 
with the first dose of study drug and 
through 150 days after discontinuation of 
dosing or until the start of subsequent anti-
cancer therapy.
Monitor for Serious Adverse 
Events
X
X
X
X
All SAEs must be collected starting at the 
time a subject signs informed consent and 
through 150 days after discontinuation of 
Revised Protocol No.: 12
Date: 08-May-2018
126
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.1-3:
Follow-up Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-up
Notes
1
30 days
(± 5 days)
2
60 days
(± 5 days)
3
100 days
(± 5 days)
4
150 days a
(± 5 days)
Q12W
(± 2 weeks)
dosing. SAEs should be approved in TAO 
within 4 days of entry.
Sample Collection
PK Assessments
X
X
X
See Table 5.7.3.3-1, Table 5.7.3.3-2, 
Table 5.7.3.3-3, and Table 5.7.3.3-4.
Immunogenicity (ADA) 
Assessments
X
X
X
See Table 5.7.3.3-1, Table 5.7.3.3-2, 
Table 5.7.3.3-3, and Table 5.7.3.3-4
Efficacy Assessments
Diagnostic Imaging
X
X
By method used at baseline. At the end of 
the clinical follow-up period, 
non-progressive subjects will continue to 
have scans Q12W for up to 1 year and 
then at a minimum of every 6 months 
thereafter until PD.
Imaging to include brain or bone imaging 
as clinically indicated.
Revised Protocol No.: 12
Date: 08-May-2018
127
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.1-3:
Follow-up Procedural Outline the Dose Escalation and Dose Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) (CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-up
Notes
1
30 days
(± 5 days)
2
60 days
(± 5 days)
3
100 days
(± 5 days)
4
150 days a
(± 5 days)
Q12W
(± 2 weeks)
Survival Status
Assessment Subject Survival 
Statusb
X
Subject status will be assessed by either a 
clinic visit or telephone contact Q12W 
(± 2 weeks) for up to 3 years following the 
first dose of study drug. The nature and 
start dates of any new therapies during this 
period will be recorded.
a 150-day follow-up may be performed via clinic visit or telephone contact.
b No longer required with Revised Protocol 12.
BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; 
Mg = magnesium; Na = sodium; TAO = Trial Access Online.
Revised Protocol No.: 12
Date: 08-May-2018
128
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.1.2
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)
Table 5.1.2-1:
Screening Procedural Outline the SCCHN Randomized Cohorts (Part 3 - closed to enrollment) 
(CA223001)
Procedure
Screening
Visit 
(D -35 to -1)
D -14 
to -1
D -3 to -1
Visit
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol-specific informed 
consent is signed.
Inclusion/Exclusion Criteria
X
Medical History
X
May include more detailed medical history of risk factors for potential events 
such as pulmonary related events.
Archived tumor tissue samples
X
One paraffin block or 10 to 15 FFPE unstained slides must be shipped to the 
testing laboratory at the same time as the biopsy samples. 
Mandatory Fresh Tumor Biopsy
X
All subjects will be required to provide fresh biopsies at baseline and 
on-treatment if a subject has accessible lesions and if the risks associated with 
obtaining biopsies are deemed acceptable. A minimum of 2 cores must be 
collected. Core 1 will be formalin fixed and paraffin embedded. This core 
must be submitted to analysis laboratory for PD-L1 testing as soon as 
possible. Core 2 will be placed into RNAlater immediately upon collection. 
Specific processing instructions will be provided in the laboratory manual.
Safety Assessments
Physical Examination
X
If the screening PE is performed within 24 hours of dosing on Cycle 1 Day 1 
then a single exam may count as both the screening and pre-dose evaluation. 
Performance Status
X
ECOG Performance Status (see Appendix 7).
Physical Measurements
X
Includes height, weight, BSA.
Vital Signs
X
Includes body temperature, seated blood pressure, and heart rate. Blood 
pressure and heart rate should be measured after the subject has been seated 
quietly for at least 5 minutes.
Oxygen Saturation
X a
Collected at rest.
Revised Protocol No.: 12
Date: 08-May-2018
129
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-1:
Screening Procedural Outline the SCCHN Randomized Cohorts (Part 3 - closed to enrollment) 
(CA223001)
Procedure
Screening
Visit 
(D -35 to -1)
D -14 
to -1
D -3 to -1
Visit
Notes
Electrocardiogram
X
12-lead ECG.
Chest Radiograph
X
Laboratory Tests
X
To include: CBC with differential, LFTs (to include a minimum of AST, 
ALT, alkaline phosphatase, total bilirubin, and LDH), BUN, creatinine, Ca, 
Mg, Na, K, carbon dioxide, Cl, phosphorous, glucose, albumin, amylase, 
lipase, CRP, TSH with reflex (free T3 and free T4), hepatitis B/C, HIV 
testing, and troponin.
If performed within 72 hours of dosing on Cycle 1 Day 1, then Cycle 1 Day 1 
laboratories are not required.
HPV Status
X
Oropharyngeal cancer sites are defined in Appendix 4. Sites must submit 
prior HPV status if known. For subjects with unknown status, tumor tissue 
will be required, per inclusion criteria. Subjects must consent to HPV testing.
Note: If results are not available, then a sample (tissue on microscopic slides, 
tissue block or a fresh tissue biopsy in formalin) should be sent to the central 
laboratory for analysis and confirmed as shipped.
Serum Pregnancy Test
X a
WOCBP only.
Concomitant Medication
X
(Note: Immunosuppressive medications are recorded on a separate log page.)
Assessment of Signs and Symptoms
X
Adverse Event Reporting
Monitor for Serious Adverse Events
X
All SAEs must be collected starting at the time the subject signs informed 
consent and through 150 days after discontinuation of dosing. SAEs should 
be approved in TAO within 4 days of entry.
Efficacy Assessments
Diagnostic Imaging
X
CT with contrast is the preferred modality (MRI if CT is not feasible). 
Assessment should include the chest/abdomen/pelvis at a minimum; and 
Revised Protocol No.: 12
Date: 08-May-2018
130
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-1:
Screening Procedural Outline the SCCHN Randomized Cohorts (Part 3 - closed to enrollment) 
(CA223001)
Procedure
Screening
Visit 
(D -35 to -1)
D -14 
to -1
D -3 to -1
Visit
Notes
should include other anatomic regions as indicated by individual subject 
disease histories.
Brain Imaging
X
Brain imaging (CT/MRI) for subjects with history or symptoms of brain 
metastases or who have not had brain imaging within 30 days of anticipated 
first study drug administration.
Bone Scan
X
As clinical indicated (ie, subjects with history or symptoms of bone 
metastases), but bone scans will not be considered a modality for assessment 
for measurable disease.
Clinical Drug Supplies
Subject Randomization
X
Within 3 days from vial allocation, the subject must receive the first dose of 
study drug.
a May be obtained on Cycle 1 Day 1 with results evaluated prior to study drug administration.
BSA = body surface area; BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; CRP = C-reactive protein; D = Day; 
ECG = electrocardiogram; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; Mg = magnesium; Na = sodium; PE = physical examination; 
T3 = triiodothyronine; T4 = thyroxine; TAO = Trial Access Online; TSH = thyroid-stimulating hormone.
Revised Protocol No.: 12
Date: 08-May-2018
131
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-2:
On-treatment Procedural Outline the SCCHN Randomized Cohorts (Part 3 - closed to enrollment) 
(CA223001)
Procedure
8-week Cycle, until PD
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
Safety Assessments
Physical Examination
X
A symptom directed physical examination performed by the 
investigator or designee is required at each subsequent visit.
Performance Status
X
X
X
X
ECOG score (see Appendix 7)
Physical Measurements
X
X
X
X
Weight only.
Vital Signs
X
X
X
X
Includes body temperature, seated blood pressure, and heart 
rate. Blood pressure and heart rate should be measured after 
the subject has been seated quietly for at least 5 minutes.
Vital signs will be obtained before the nivolumab infusion, 
after the nivolumab infusion, and after the lirilumab or 
placebo for lirilumab infusion.
Electrocardiogram
X
12-lead ECG (if performed on same day as study drug 
administration it is to be performed prior to dosing).
Not required on Cycle 1 Day 1
Chest Radiograph
As clinically indicated.
Oxygen Saturation Levels
X
X
X
X
Collected at rest and after mild to moderate exertion prior to 
dosing.
Laboratory Tests
X
X
X
X
On-study laboratory tests (including pregnancy testing) to be 
done on site/local. Within 72 hours of re-dosing to include 
CBC with differential, LFTs (to include a minimum of AST, 
ALT, alkaline phosphatase, total bilirubin, and LDH), BUN, 
creatinine, glucose, Ca, Mg, Na, K, carbon dioxide, Cl, 
phosphorous, amylase, lipase, and troponin. Results should be 
examined by the investigator or appropriate designee prior to 
dose administration.
Revised Protocol No.: 12
Date: 08-May-2018
132
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-2:
On-treatment Procedural Outline the SCCHN Randomized Cohorts (Part 3 - closed to enrollment) 
(CA223001)
Procedure
8-week Cycle, until PD
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
Endocrine Panel
X
To include TSH with reflex testing (free T3 and free T4). 
Results should be examined by the investigator or appropriate 
designee within 48 hours of dose administration.
Pregnancy Test
X
X
X
X
Serum or urine. WOCBP only.
Concomitant Medication
X
X
X
X
X
(Note: Immunosuppressive medications are recorded on a 
separate log page.)
On-treatment Tumor Biopsy
X
Fresh on-treatment tumor biopsy must be collected from the 
same lesion as screening biopsy if possible. A minimum of 
2 cores are required. Core 1 will be FFPE. Core 2 will be 
placed in RNAlater. Additional cores, if available, will 
alternate between FFPE and RNAlater. Specific processing 
instructions will be provided in the laboratory manual 
Adverse Event Reporting
Monitor for Non-serious 
Adverse Events
X
X
X
X
Non-serious AEs will be collected starting with the first dose 
of study drug and through 150 days after discontinuation of 
dosing or until the start of subsequent anti-cancer therapy..
Monitor for Serious Adverse 
Events
X
X
X
X
All SAEs must be collected starting at the time a subject signs 
informed consent and through 150 days after discontinuation 
of dosing. SAEs should be approved in TAO within 4 days of 
entry
Revised Protocol No.: 12
Date: 08-May-2018
133
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-2:
On-treatment Procedural Outline the SCCHN Randomized Cohorts (Part 3 - closed to enrollment) 
(CA223001)
Procedure
8-week Cycle, until PD
Notes
D1
(± 2 days)
D15
(± 2 days)
D29
(± 2 days)
D43
(± 2 days)
D49 to 
56
Efficacy Assessments
Diagnostic Imaging
X
By methods used at baseline. Scans will be performed Q8W 
relative to the Cycle 1 Day 1 visit regardless of treatment 
delays.
Brain Imaging
X
As clinically indicated.
Bone Scan
X
As clinically indicated.
Clinical Drug Supplies
Nivolumab Administration
X
X
X
X
Lirilumab Administration
X
X
For subjects on Arm A: To be administered 30 minutes after 
completion of the nivolumab infusion.
Placebo for Lirilumab 
Administration
X
X
For subjects on Arm B: To be administered 30 minutes after 
completion of the nivolumab infusion.
BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; D = Day; ECG = electrocardiogram; K = potassium; LDH = lactate 
dehydrogenase; LFT = liver function test; Mg = magnesium; Na = sodium; Q8W = every 8 weeks; T3 = triiodothyronine; T4 = thyroxine; TAO = Trial Access 
Online; TSH = thyroid-stimulating hormone.
Revised Protocol No.: 12
Date: 08-May-2018
134
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-3:
Follow-up Procedural Outline the SCCHN Randomized Cohorts (Part 3-closed to enrollment) 
(CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-upa
Notes
1
30 days b
(± 5 days)
2
60 days c
(± 5 days)
3
100 days d
(± 5 days)
4
150 days e
(± 5 days)
Q12W
(± 2 weeks)
Safety Assessments
Physical Examination
X
X
X
Vital Signs
X
X
X
Includes body temperature, seated blood 
pressure, and heart rate. Blood pressure 
and heart rate should be measured after 
the subject has been seated quietly for at 
least 5 minutes.
Performance Status
X
X
X
ECOG score (see Appendix 7)
Laboratory Tests
X
CBC with differential, LFTs (to include a 
minimum of AST, ALT, alkaline 
phosphatase, total bilirubin, and LDH), 
BUN, creatinine, glucose, Ca, Mg, Na, K, 
carbon dioxide, Cl, phosphorous, amylase, 
lipase, and troponin.
Adverse Event Reporting
Monitor for Non-serious 
Adverse Events
X
X
X
X
Non-serious AEs will be collected starting 
with the first dose of study drug and 
through 150 days after discontinuation of 
dosing or until the start of subsequent anti-
cancer therapy.
Monitor for Serious Adverse 
Events
X
X
X
X
All SAEs must be collected starting at the 
time a subject signs informed consent and 
through 150 days after discontinuation of 
Revised Protocol No.: 12
Date: 08-May-2018
135
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.2-3:
Follow-up Procedural Outline the SCCHN Randomized Cohorts (Part 3-closed to enrollment) 
(CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-upa
Notes
1
30 days b
(± 5 days)
2
60 days c
(± 5 days)
3
100 days d
(± 5 days)
4
150 days e
(± 5 days)
Q12W
(± 2 weeks)
dosing. SAEs should be approved in TAO 
within 4 days of entry.
Sample Collection
Efficacy Assessments
Diagnostic Imaging
X
X
By method used at baseline. At the end of 
the clinical follow-up period, 
non-progressive subjects will continue to 
have scans Q12W for up to 1 year and 
then at a minimum of every 6 months 
thereafter until PD.
Imaging to include brain or bone imaging 
as clinically indicated.
Survival Status
Assessment Subject Survival 
Statuse
X
Subject status will be assessed by either a 
clinic visit or telephone contact Q12W
(± 2 weeks) for up to 3 years following the 
first dose of study drug. The nature and 
start dates of any new therapies during this 
period will be recorded.
a Survival follow-up no longer applicable with Revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
136
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
b 30 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 30 days after last dose.
c 60 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 60 days after last dose.
d 100 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 100 days after last dose.
e 150 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 150 days after last dose. 150-day follow-up may be performed via clinic visit or telephone contact.
BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; 
Mg = magnesium; Na = sodium; TAO = Trial Access Online.
Revised Protocol No.: 12
Date: 08-May-2018
137
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.1.3
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12
Revised Protocol No.: 12
Date: 08-May-2018
138
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.1.4
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 -
closed to enrollment) and the Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 6 - removed with Revised Protocol 12)
Table 5.1.4-1:
Screening Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Screening
Visit 
(Day -35
to -1)
Day -14 
to -1
Day -3 to 
-1
Visit
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol-specific informed 
consent is signed.
Inclusion/Exclusion Criteria
X
Medical History
X
May include more detailed medical history of risk factors for potential events 
such as pulmonary-related events.
Archived Tumor Tissue Samples
X
One paraffin block or 10 to 15 FFPE unstained slides must be shipped to the 
testing laboratory at the same time as the biopsy samples.
Mandatory Fresh Tumor Biopsy 
X
All subjects will be required to provide fresh biopsies at baseline if a subject 
has accessible lesions and if the risks associated with obtaining biopsies are 
deemed acceptable (subjects in the Signal Detection in SCCHN with 
Lirilumab, nivolumab, and Ipilimumab Combination [Part 5] will also be 
required to have fresh on-treatment biopsies and if the risks associated with 
obtaining biopsies are deemed acceptable). A minimum of 2 cores must be 
collected. Core 1 will be FFPE. This core must be submitted to analysis 
laboratory for PD-L1 testing as soon as possible. Core 2 will be placed into 
RNAlater immediately upon collection. Specific processing instructions will 
be provided in the laboratory manual.
Safety Assessments
Physical Examination
X
If the screening PE is performed within 24 hours of dosing on Week 1 Day 1 
then a single exam may count as both the screening and pre-dose evaluation. 
Performance Status
X
ECOG Performance Status (see Appendix 7)
Revised Protocol No.: 12
Date: 08-May-2018
139
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-1:
Screening Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Screening
Visit 
(Day -35
to -1)
Day -14 
to -1
Day -3 to 
-1
Visit
Notes
Physical Measurements
X
Includes height, weight, BSA.
Vital Signs
X
Includes body temperature, seated blood pressure, and heart rate. Blood 
pressure and heart rate should be measured after the subject has been seated 
quietly for at least 5 minutes.
Oxygen Saturation
X a
Collected at rest. 
Electrocardiogram
X
12-lead ECG
Echocardiogram
X
Chest Radiograph
X
Laboratory Tests
X
Days -14 to -1 prior to Week 1 Day 1.
To include: CBC with differential, LFTs (to include a minimum of AST, 
ALT, alkaline phosphatase, total bilirubin, and LDH), BUN, creatinine, Ca, 
Mg, Na, K, carbon dioxide, Cl, phosphorous, glucose, albumin, amylase, 
lipase, CRP, TSH with reflex (free T3 and free T4), hepatitis B/C, HIV 
testing, and troponin.
If performed within 72 hours of dosing on Week 1 Day 1, then Week 1 Day 1 
laboratories are not required.
Mutation Status
X
Documentation of BRAF mutation status only for MEL
Serum Pregnancy Test
X a
WOCBP only.
Concomitant Medication
X
(Note: Immunosuppressive medications are recorded on a separate log page.)
Revised Protocol No.: 12
Date: 08-May-2018
140
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-1:
Screening Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Screening
Visit 
(Day -35
to -1)
Day -14 
to -1
Day -3 to 
-1
Visit
Notes
Assessment of Signs and Symptoms
X
Adverse Event Reporting
Monitor for Serious Adverse Events
X
All SAEs must be collected starting at the time the subject signs informed 
consent and through 150 days after discontinuation of dosing. SAEs should 
be approved in TAO within 4 days of entry.
Efficacy Assessments
Diagnostic Imaging
X
Must be performed within 28 days prior to first dose of study drug. CT with 
contrast is the preferred modality (MRI if CT is not feasible). Assessment 
should include the chest/abdomen/pelvis at a minimum and should include 
other anatomic regions as indicated by individual subject disease histories.
Brain Imaging
X
Brain imaging (CT/MRI) for subjects with history or symptoms of brain 
metastases or who have not had brain imaging within 30 days of anticipated 
first study drug administration.
Bone Scan
X
As clinical indicated (ie, subjects with history or symptoms of bone 
metastases), but bone scans will not be considered a modality for assessment 
for measurable disease.
Clinical Drug Supplies
Subject Randomization
X
Within 3 days from vial allocation, the subject must receive the first dose of 
study drug
a May be obtained on Week 1 Day 1 with results evaluated prior to study drug administration.
BSA = body surface area; BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; CRP = C-reactive protein; D = Day; 
ECG = electrocardiogram; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; Mg = magnesium; Na = sodium; PE = physical examination; 
T3 = triiodothyronine; T4 = thyroxine; TAO = Trial Access Online; TSH = thyroid-stimulating hormone.
Revised Protocol No.: 12
Date: 08-May-2018
141
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-2:
On-treatment Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Until PD
Notes
Week 1, 
13, 25, 
and 37
Day 1
(± 2 days)
Weeks 3, 
11, 15, 23, 
27, 35, 39, 
and 47
Day 1
(± 2 days)
Weeks 5, 
9, 17, 21, 
29, 33, 41, 
and 45
Day 1
(± 2 days)
Weeks 7, 
19, 31, 
and 43
Day 1
(± 2 days)
Part 5 Only
Weeks 9, 
17, 25, 33, 
41, and 49
Day 1 
(±7 days)
Safety Assessments
Physical Examination
X
A symptom-directed physical examination 
performed by the investigator or designee is 
required at each subsequent visit.
Performance Status
X
X
X
X
ECOG score (see Appendix 7)
Physical Measurements
X
X
X
X
Weight only
Vital Signs
X
X
X
X
Includes body temperature, seated blood pressure, 
and heart rate. Blood pressure and heart rate 
should be measured after the subject has been 
seated quietly for at least 5 minutes.
Vital signs will be obtained before the nivolumab 
infusion, before the ipilimumab infusion, before 
the lirilumab infusion, and after the lirilumab 
infusion.
Electrocardiogram
X
12-lead ECG (if performed on same day as study 
drug administration, it is to be performed prior to 
dosing).
Not required on Week 1 Day 1
Echocardiogram
As clinically indicated.
Chest Radiograph
As clinically indicated.
Revised Protocol No.: 12
Date: 08-May-2018
142
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-2:
On-treatment Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Until PD
Notes
Week 1, 
13, 25, 
and 37
Day 1
(± 2 days)
Weeks 3, 
11, 15, 23, 
27, 35, 39, 
and 47
Day 1
(± 2 days)
Weeks 5, 
9, 17, 21, 
29, 33, 41, 
and 45
Day 1
(± 2 days)
Weeks 7, 
19, 31, 
and 43
Day 1
(± 2 days)
Part 5 Only
Weeks 9, 
17, 25, 33, 
41, and 49
Day 1 
(±7 days)
Oxygen Saturation 
Levels
X
X
X
X
Collected at rest.
Laboratory Tests
X
X
X
X
On-study laboratory tests (including pregnancy 
testing) to be done on site/local. Within 72 hours 
of re-dosing to include CBC with differential, 
LFTs (to include a minimum of AST, ALT, 
alkaline phosphatase, total bilirubin, and LDH), 
BUN, creatinine, glucose, Ca, Mg, Na, K, carbon 
dioxide, Cl, phosphorous, amylase, lipase, and 
troponin. Results should be examined by the 
investigator or appropriate designee prior to dose 
administration.
CBC with differential should also be collected at 
each timepoint where samples for 
immunophenotyping are collected as listed in 
Table 5.7.3.3-7.
Endocrine Panel
X
To include TSH with reflex testing (free T3 and 
free T4). Results should be examined by the 
investigator or appropriate designee within 48 
hours of dose administration.
Pregnancy Test
X
X
X
X
Serum or urine. WOCBP only.
Concomitant Medication
X
X
X
X
X
(Note: Immunosuppressive medications are 
recorded on a separate log page.)
Revised Protocol No.: 12
Date: 08-May-2018
143
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-2:
On-treatment Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Until PD
Notes
Week 1, 
13, 25, 
and 37
Day 1
(± 2 days)
Weeks 3, 
11, 15, 23, 
27, 35, 39, 
and 47
Day 1
(± 2 days)
Weeks 5, 
9, 17, 21, 
29, 33, 41, 
and 45
Day 1
(± 2 days)
Weeks 7, 
19, 31, 
and 43
Day 1
(± 2 days)
Part 5 Only
Weeks 9, 
17, 25, 33, 
41, and 49
Day 1 
(±7 days)
On-treatment Tumor 
Biopsy
X
(See note)
The Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5) 
only: Day 15 on-treatment tumor biopsy must be 
collected from the same lesion as screening biopsy 
if possible. A minimum of 2 cores are required. 
Core 1 will be FFPE. Core 2 will be placed in 
RNAlater. Additional cores, if available, will 
alternate between FFPE and RNAlater. Specific 
processing instructions will be provided in the 
laboratory manual. 
Adverse Event 
Reporting
Monitor for Non-serious 
Adverse Events
X
X
X
X
X
Non-serious AEs will be collected starting with the 
first dose of study drug and through 150 days after 
discontinuation of dosing or until the start of 
subsequent anti-cancer therapy.
Monitor for Serious 
Adverse Events
X
X
X
X
X
All SAEs must be collected starting at the time a 
subject signs informed consent and through 150 
days after discontinuation of dosing. SAEs should 
be approved in TAO within 4 days of entry.
Revised Protocol No.: 12
Date: 08-May-2018
144
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-2:
On-treatment Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Until PD
Notes
Week 1, 
13, 25, 
and 37
Day 1
(± 2 days)
Weeks 3, 
11, 15, 23, 
27, 35, 39, 
and 47
Day 1
(± 2 days)
Weeks 5, 
9, 17, 21, 
29, 33, 41, 
and 45
Day 1
(± 2 days)
Weeks 7, 
19, 31, 
and 43
Day 1
(± 2 days)
Part 5 Only
Weeks 9, 
17, 25, 33, 
41, and 49
Day 1 
(±7 days)
Sample Collection
PK Assessments
See Table 5.7.3.3-7.
Immunogenicity 
Assessments 
See Table 5.7.3.3-7. 
Biomarker Assessments
See Table 5.7.3.3-7. 
Efficacy Assessments
Diagnostic Imaging
X
By methods used at baseline. 
The Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5): 
Scans will be performed Q8W relative to the Week 
1 Day 1 visit regardless of treatment delays for 1 
year (48 weeks), and then Q12W afterwards.
Brain Imaging
X
As clinically indicated.
Bone Scan
X
As clinically indicated.
Revised Protocol No.: 12
Date: 08-May-2018
145
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-2:
On-treatment Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Until PD
Notes
Week 1, 
13, 25, 
and 37
Day 1
(± 2 days)
Weeks 3, 
11, 15, 23, 
27, 35, 39, 
and 47
Day 1
(± 2 days)
Weeks 5, 
9, 17, 21, 
29, 33, 41, 
and 45
Day 1
(± 2 days)
Weeks 7, 
19, 31, 
and 43
Day 1
(± 2 days)
Part 5 Only
Weeks 9, 
17, 25, 33, 
41, and 49
Day 1 
(±7 days)
Clinical Drug Supplies
Nivolumab 
Administration
X
X
X
X
To be administered first on days when multiple 
study drugs are given.
Ipilimumab 
Administration
X
X
To be administered 30 minutes after completion of 
the nivolumab infusion.
Lirilumab 
Administration
X
X
On days when all 3 study drugs are given, 
lirilumab is to be administered 30 minutes after 
completion of the ipilimumab infusion. On days 
when nivolumab and lirilumab are given, lirilumab 
is to be administered 30 minutes after completion 
of the nivolumab infusion.
BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; D = Day; ECG = electrocardiogram; K = potassium; LDH = lactate 
dehydrogenase; LFT = liver function test; Mg = magnesium; Na = sodium; T3 = triiodothyronine; T4 = thyroxine; TAO = Trial Access Online; TSH = thyroid-
stimulating hormone.
Revised Protocol No.: 12
Date: 08-May-2018
146
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-3:
Follow-up Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-upa
Notes
1
30 days b
(± 5 days)
2
60 days c
(± 5 days)
3
100 days d
(± 5 days)
4
150 days e
(± 5 days)
Q12W 
(± 2 weeks)
Safety Assessments
Physical Examination
X
X
X
Vital Signs
X
X
X
Includes body temperature, seated blood 
pressure, and heart rate. Blood pressure 
and heart rate should be measured after 
the subject has been seated quietly for at 
least 5 minutes.
Performance Status
X
X
X
ECOG score (see Appendix 7)
Laboratory Tests
X
CBC with differential, LFTs (to include a 
minimum of AST, ALT, alkaline 
phosphatase, total bilirubin, and LDH), 
BUN, creatinine, glucose, Ca, Mg, Na, K, 
carbon dioxide, Cl, phosphorous, amylase, 
lipase, and troponin.
Adverse Event Reporting
Monitor for Non-serious 
Adverse Events
X
X
X
X
Non-serious AEs will be collected starting 
with the first dose of study drug and 
through 150 days after discontinuation of 
dosing or until the start of subsequent anti-
cancer therapy.
Monitor for Serious Adverse 
Events
X
X
X
X
All SAEs must be collected starting at the 
time a subject signs informed consent and 
through 150 days after discontinuation of 
Revised Protocol No.: 12
Date: 08-May-2018
147
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.1.4-3:
Follow-up Procedural Outline the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment) (CA223001)
Procedure
Clinical Follow-up
Survival 
Follow-upa
Notes
1
30 days b
(± 5 days)
2
60 days c
(± 5 days)
3
100 days d
(± 5 days)
4
150 days e
(± 5 days)
Q12W 
(± 2 weeks)
dosing. SAEs should be approved in TAO 
within 4 days of entry.
Sample Collection
PK Assessments
X
X
X
See Table 5.7.3.3-7.
Immunogenicity (ADA) 
Assessments
X
X
X
See Table 5.7.3.3-7.
Efficacy Assessments
Diagnostic Imaging
X
X
By method used at baseline. At the end of 
the clinical follow-up period, 
non-progressive subjects will continue to 
have scans Q12W for up to 1 year and 
then at a minimum of every 6 months 
thereafter until PD.
Imaging to include brain or bone imaging 
as clinically indicated.
Survival Status
Assessment Subject Survival 
Statuse
X
Subject status will be assessed by either a 
clinic visit or telephone contact Q12W
(± 2 weeks) for up to 3 years following the 
first dose of study drug. The nature and 
start dates of any new therapies during this 
period will be recorded.
a Survival follow-up no longer applicable with Revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
148
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
b 30 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 30 days after last dose.
c 60 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 60 days after last dose.
d 100 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 100 days after last dose.
e 150 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study 
drug is greater than 150 days after last dose. 150-day follow-up may be performed via clinic visit or telephone contact.
BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; Cl = chloride; K = potassium; LDH = lactate dehydrogenase; LFT = liver function test; 
Mg = magnesium; Na = sodium; TAO = Trial Access Online.
Revised Protocol No.: 12
Date: 08-May-2018
149
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.2
Study Materials
The following materials will be provided prior to the start of the study:
•
NCI CTCAE v4.03;
•
Lirilumab, nivolumab, and ipilimumab IBs;
•
Pharmacy binder;
•
Laboratory manuals for collection and handling of blood (including PKs, biomarker, and
immunogenicity) and tissue specimens;
•
Enrollment/randomization worksheets;
•
SAE forms;
•
Pregnancy surveillance forms.
•
Subject questionnaires: EORTC-QLQ-C30, EORTC-QLQ-H&N35, EQ-5D-3L (for the Signal 
Detection Randomized Cohorts [Part 3] only).
•
Dosing Procedure Manual.
5.3
Safety Assessments
AEs will be assessed continuously during the study and for 150 days after the last treatment or 
until the start of subsequent anti-cancer therapy. AEs will be coded using the most current version
of the Medical Dictionary for Regulatory Activities (MedDRA) and reviewed for potential
significance and importance. AEs will be evaluated according to the NCI CTCAE v4.03. Subjects
should be followed until all treatment-related AEs have recovered to baseline or are deemed
irreversible by the investigator.
Some of the assessments referred to in this section may not be captured as data in the CRF. They 
are intended to be used for safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
At baseline, a medical history will be obtained to capture relevant underlying conditions. Baseline
signs and symptoms are those that are assessed within 2 weeks prior to subject registration. The
baseline physical examination should include weight, height, heart rate, blood pressure,
temperature and ECOG status and should be performed within 28 days of treatment assignment
for the Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort Expansion (Part 2) 
and within 35 days of treatment assignment or randomization for all other study parts. Concomitant
medications will be collected from within 2 weeks prior to treatment assignment or randomization
through the study treatment period (see Section 5.1).
Subjects will be considered evaluable for safety if they have received any dose of either study
drug. Toxicity assessments will be continuous during the treatment period and the clinical follow-
up periods.
Body weight and performance status should be assessed at each on-study visit. Vital signs will be
obtained at timepoints according to Section 5.1. For further details related to infusion reactions, 
see Section 3.6.
Revised Protocol No.: 12
Date: 08-May-2018
150
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Additional measures including non-study required laboratory tests should be performed as
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug-
induced liver enzyme evaluations) will be monitored during the clinical follow-up period via on-
site/local laboratories until all study-drug-related toxicities resolve, return to baseline, or are 
deemed irreversible.
Clinical laboratory measures will be assessed (see Section 5.1). Sites should collect these samples
between -28 to -1 days from registration to insure that results required for eligibility purposes are
verified prior to registration (or between -35 to -1 days for subjects in the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination [Part 5]). Pregnancy testing
must be performed within 72 hours prior to the initial administration of investigational product at
baseline and then prior to administration of either study drug during study therapy and at the
3 clinical follow-up visits. Complete blood count plus differential and serum chemistry panel
should be drawn within 72 hours prior to each subsequent scheduled cycle. On-study laboratory
tests will be performed on site/locally. Laboratory tests may be obtained more frequently if
indicated. Additional laboratory tests should be performed as per standard of care.
If a subject shows pulmonary-related signs (eg, hypoxia or fever) or symptoms (eg, dyspnea, 
cough, or fever) consistent with possible pulmonary AEs, the subject should be immediately 
evaluated to rule out pulmonary toxicity according to the suspected pulmonary toxicity 
management algorithm in the nivolumab IB.19
5.3.1
Microsatellite Instability Testing
MSI-high in tumors refers to changes in 2 or more of the 5 NCI-recommended panels of
microsatellite markers in tumor tissue. The original (1997) Bethesda guidelines proposed a panel
of 5 microsatellite markers for the uniform analysis of MSI in hereditary non-polyposis CRC. This
panel, which is referred to as the Bethesda panel, included 2 mononucleotide (BAT-25 and BAT-
26) and 3 dinucleotide (D5S346, D2S123, and D17S250) repeats.40 Individual testing sites may
utilize a slightly different panel of markers incorporating alternative mononucleotide or
dinucleotide markers. Regardless of the panel of markers, samples with instability in zero or
1 marker are designated as non-MSI-high. Those with 1 unstable marker are designated as
MSI-low. Samples with no detectable alterations are MSI-stable. Samples with detectable
alterations in 2 or more markers are considered MSI-high.
5.4
Efficacy Assessments
Disease assessment with CT and/or MRI, as appropriate, will be performed at baseline and every 
8 weeks until disease progression, at the completion of clinical follow-up, or until subjects
withdraw from the study. Disease assessments at other timepoints may be performed if the
investigator is concerned about tumor progression. Tumor responses will be derived for
appropriate populations of subjects as defined by RECIST v1.141 (see Appendix 3) from tumor
measurements. For the Dose Escalation and Cohort Expansion (Part 1; completed) and the SCCHN 
Cohort Expansion (Part 2; completed), investigator-assessed responses and treatment decisions 
related to subject management will be based on irRECIST9 (see Appendix 2); all other study parts 
Revised Protocol No.: 12
Date: 08-May-2018
151
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
will use only RECIST v1.1. Radiographic
assessments may be submitted to the third-party 
radiology vendor for any part of the study as they are performed on an ongoing basis. Submission 
of radiographic scans to the third-party vendor is no longer required with Revised Protocol 12.
Changes in tumor measurements and tumor responses will be assessed by the investigator using
irRECIST criteria. Investigators will also report the number and size of new lesions that appear
while on-study. The timepoint tumor assessments will be reported on the CRF based on
investigators’ assessment using irRECIST criteria. The SCCHN Randomized Cohorts (Part 3), and 
the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination
(Part 5), however, will use only RECIST v1.1 for all assessments. Please refer to Appendix 3 for
specifics of RECIST v1.1 and Appendix 2 for specifics of irRECIST criteria to be utilized in this
study.
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)
The primary endpoint is ORR based on assessment in all subjects randomized to lirilumab plus 
nivolumab.
The secondary efficacy endpoints of the SCCHN Randomized Cohorts (Part 3) are DCR, DOR, 
time to response, depth of response, OS, PFS, , and ORR according to investigator-assessed 
response. All randomized subjects will be monitored by radiographic assessment Q8W (± 7 days)
beginning from the first dose date until Week 48 and Q12W (± 7 days) thereafter until PD or
treatment discontinuation (whichever occurs earlier), to determine changes in tumor size.
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
5.5
Pharmacokinetic Assessments
Serum samples for lirilumab, nivolumab, and/or ipilimumab PK assessments will be collected for
all subjects in both dose escalation and cohort expansion.
Revised Protocol No.: 12
Date: 08-May-2018
152
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
PK of lirilumab and ipilimumab will be derived from serum
concentration vs time. The PK parameters to be assessed include:
Cmax
Maximum observed concentration
Tmax
Time of maximum observed concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to the time of the last
quantifiable concentration
AUC(INF)
Area under the plasma concentration-time curve from time zero extrapolated to infinite
time
Ctrough
Trough observed serum concentration
AUC(TAU)
Area under the plasma concentration-time curve in 1 dosing interval
CL
Clearance
Vz
Apparent volume of distribution during terminal phase
T-HALF
Half-life
Individual subject PK parameter values will be derived by non-compartmental methods by a
validated PK analysis program. Actual times will be used for the analyses.
In addition, nivolumab end of infusion and trough (Cmin) concentrations will be calculated at
specified visits.
5.5.1
Pharmacokinetics: Collection and Processing
Further
details of blood collection and processing will be provided to the study site in the procedure
manual.
5.5.2
Pharmacokinetic Sample Analyses
Serum samples will be analyzed for lirilumab, nivolumab, and ipilimumab by a validated
immunoassay.
 
 
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the PK blood collection, labeling, processing, storage, and shipping will
be provided to the study site in the procedure manual.
5.6
Biomarker Assessments
No further biomarker samples are required to be collected with Revised Protocol 12. 
 
Revised Protocol No.: 12
Date: 08-May-2018
153
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.7
Biomarker Assessments
Blood/tissue will be collected at the times indicated in Section 5.7.3.3. Further details of blood
collection and processing will be provided to the study site in the procedure manual. The
pharmacodynamics of lirilumab, nivolumab, and ipilimumab in combination, as well as nivolumab 
monotherapy treatment, will be assessed by quantifying biomarkers from peripheral blood and 
serial tumor biopsies.
Revised Protocol No.: 12
Date: 08-May-2018
154
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.7.3
Assessments for Subjects Undergoing Tumor Biopsies
Blood will be drawn at the times indicated in Section 5.7.1 and will be used to perform all of the
studies listed for those subjects in dose escalation (see Section 5.7.1). Blood will be obtained for
all subjects in order to obtain tumor/normal pairs. Mandatory pre-treatment and on-treatment 
tumor biopsies will be obtained in a minimum of 10 subjects in the MEL and SCCHN cohorts of
Cohort Expansion (Part 1; completed). In the SCCHN Cohort Expansion (Part 2; completed), a
minimum of 15 subjects will be required to undergo mandatory pre-treatment and on-treatment
biopsies at acceptable clinical risk as judged by the investigator.
In 
 the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5); all subjects will be required to provide fresh 
biopsies at baseline if a subject has accessible lesions and if the risks associated with obtaining 
biopsies are deemed acceptable. In addition, all subjects in 
 the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5 - closed to enrollment) will be required to have a fresh on-
treatment biopsy if biopsy risk is acceptable. 
Revised Protocol No.: 12
Date: 08-May-2018
155
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
On-treatment biopsies will be collected at Day 29 ± 3 days for the SCCHN Cohort Expansion 
(Part 2; completed); and at Day 15 ± 3 days for
the 
Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5).
Post-treatment biopsies (following completion of all study therapy) will be optional.
 
 
5.7.3.1
PD-L1 Testing on Screening Tumor Biopsies
All subjects in the SCCHN Randomized Cohorts (Part 3); and the Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) must have PD-L1 testing 
performed on tumor biopsies obtained during screening. Subjects in the SCCHN Randomized 
Cohorts (Part 3) must be PD-L1+ on fresh biopsies by IHC testing performed by the central 
laboratory during the screening period to be enrolled in the study. All subjects in the Signal 
Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) must be 
tested for PD-L1 on the screening biopsy but will be enrolled regardless of PD-L1 status. 
PD-L1-stained tissue samples will be assessed by a pathologist at a central laboratory identified 
by the Sponsor and will be scored as PD-L1+ if membrane staining is observed in ≥1% of tumor 
cells among a minimum of 100 evaluable tumor cells. If the screening biopsy sample is not 
evaluable for PD-L1 testing, a second test of the screening biopsy will be performed. If the second 
test is not evaluable, the study site may submit archival tumor samples (minimum of 10 unstained 
FFPE slides or a FFPE tumor block). PD-L1 testing must be performed during screening period to 
determine eligibility.
Revised Protocol No.: 12
Date: 08-May-2018
156
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Revised Protocol No.: 12
Date: 08-May-2018
157
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
5.7.3.3
Pharmacokinetics, Immunogenicity (Anti-drug antibodies) and 
Biomarker Assessment Schedules
Detailed schedules of the PK, immunogenicity (ADA), and biomarker assessments are presented 
below for all study parts. Effective with Revised Protocol 12, PK and ADA samples will continue 
to be collected but will not be analyzed except as clinically indicated in specific cases such as 
Grade 3/4 toxicity, infusion reactions, etc.
Revised Protocol No.: 12
Date: 08-May-2018
158
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-1:
PK, Immunogenicity (ADA) and Biomarker Assessment Schedule: Dose Escalation (the Dose 
Escalation and Cohort Expansion [Part 1; completed])
Collection Timing
Serum
Tumor
Study 
Week
Study 
Day
Relative 
Study 
Day
Time 
(Event)
Time
PK 
anti-
KIR
PK 
anti-
PD-1
ADA
anti-
KIR
ADA
anti-
PD-1
Archived 
Tumor 
Sample
Screening
X
Week 1
C1D1
D1
0 h b
00:00
X
X
X
X
C1D1
Djj1
EOI c
X
X
C1D2
D2
24 h d
24:00
X
C1D8
D8
168 h d
168:00
X
Week 3
C1D15
D15
336 h b
336:00
X
X
X
X
Week 5
C1D29
D29
0 h b
00:00
X
X
X
X
Week 13
C2D29
D85
0 h b
00:00
X
X
X
X
C2D29
D85
EOI c
X
X
C2D30
D86
24 h d
24:00
X
C2D36
D92
168 h d
168:00
X
Week 17
C3D1
D113
0 h b
00:00
X
X
X
X
Week 33
C5D1
D225
0 h b
00:00
X
X
X
Week 49
C7D1
D337
0 h b
00:00
X
X
X
Week 65
C9D1
D449
0 h b
00:00
X
X
X
Revised Protocol No.: 12
Date: 08-May-2018
159
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-1:
PK, Immunogenicity (ADA) and Biomarker Assessment Schedule: Dose Escalation (the Dose 
Escalation and Cohort Expansion [Part 1; completed])
Collection Timing
Serum
Tumor
Study 
Week
Study 
Day
Relative 
Study 
Day
Time 
(Event)
Time
PK 
anti-
KIR
PK 
anti-
PD-1
ADA
anti-
KIR
ADA
anti-
PD-1
Archived 
Tumor 
Sample
Week 81
C11D1
D561
0 h b
00:00
X
X
X
EOT
X
X
X
X
Follow-
ups 1-3
X
X
X
b Samples to be collected prior to the infusion of nivolumab.
c Samples must be collected immediately following the end of lirilumab infusion. It is imperative that the actual time that the sample is obtained is recorded. All 
listed studies should be obtained prior to this point.
d Samples may be collected at any time during the day, but it is imperative that the actual time that the sample is obtained is recorded.
C = Cycle; CBC = complete blood count; D = Day; EOI = End of Infusion; EOT = End of Treatment.
Revised Protocol No.: 12
Date: 08-May-2018
160
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-2:
PK, Immunogenicity (ADA) and Biomarker Assessment Schedule: Cohort Expansion (except for 
subjects with MEL or SCCHN) (the Dose Escalation and Cohort Expansion [Part 1; completed])
Collection Timing
Serum
Tumor
Study 
Week
Study 
Day
Relative 
Study Day
Time 
(Event)
Time
(relative)
PK 
anti-
KIR
PK 
anti-
PD-1
ADA 
anti-KIR
ADA 
anti-PD-1
Archived Tumor Sample
Screening
X
Week 1
C1D1
D1
0 h a
00:00
X
X
X
X
C1D1
D1
EOI b
X
X
C1D2
D2
24 hc
24:00
X
C1D8
D8
168 hc
168:00
X
Week 3
C1D15
D15
336 ha
336:00
X
X
X
X
Week 5
C1D29
D29
0 ha
00:00
X
X
X
X
Week 13
C2D29
D85
0 ha
00:00
X
X
X
X
C2D29
D85
EOIb
X
X
C2D30
D86
24 hc
24:00
X
C2D36
D92
168 hc
168:00
X
Week 17
C3D1
D113
0 ha
00:00
X
X
X
X
Week 33
C5D1
D225
0 hb
00:00
X
X
X
X
Week 49
C7D1
D337
0 hb
00:00
X
X
X
X
Week 65
C9D1
D449
0 hb
00:00
X
X
X
X
Week 81
C11D1
D561
0 hb
00:00
X
X
X
X
Revised Protocol No.: 12
Date: 08-May-2018
161
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-2:
PK, Immunogenicity (ADA) and Biomarker Assessment Schedule: Cohort Expansion (except for 
subjects with MEL or SCCHN) (the Dose Escalation and Cohort Expansion [Part 1; completed])
Collection Timing
Serum
Tumor
Study 
Week
Study 
Day
Relative 
Study Day
Time 
(Event)
Time
(relative)
PK 
anti-
KIR
PK 
anti-
PD-1
ADA 
anti-KIR
ADA 
anti-PD-1
Archived Tumor Sample
EOT
X
X
X
X
Follow-up 
Visits 1-3
X
X
X
X
a Samples to be collected prior to the infusion of nivolumab.
b Samples must be collected immediately following the end of the lirilumab infusion. It is imperative that the actual time that the sample is obtained is recorded. 
All listed studies should be obtained at this point.
c Samples may be collected at any time during the day, but it is imperative that the active time that the sample is obtained is recorded.
C = Cycle; D = Day; EOI = End of Infusion; EOT = End of Treatment.
Revised Protocol No.: 12
Date: 08-May-2018
162
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-3:
Biomarker Assessment Schedule: MEL and SCCHN Cohort Expansions and Subjects Undergoing 
Tumor Biopsy in the Dose Escalation and Cohort Expansion (Part 1; Completed)
Collection Timing
Plasma
Serum
Tumor
Study Week
Study Day
Relative Study Day
Time (Event)
ctDNAa
PK anti-KIR
PK anti-PD-1
ADA anti-KIR & 
anti-PD-1
Tumor Biopsyd,e,f
Archived Tumor 
Sample
Screening
X
X
Week 1
C1D1
D1
0 hf
X
X
X
C1D1
D1
EOIg
X
X
C1D2
D2
24 hh
X
C1D8
D8
168 hh
X
Week 3
C1D15
D15
336 hf
X
X
X
Week 5
C1D29
D29
0 hf
X
X
X
Week 9
C2D1
D57
0 h
X
Week 13
C2D29
D85
0 hf
X
X
X
C2D29
D85
EOIg
X
X
C2D30
D86
24 hh
X
C2D36
D92
168 hh
X
Week 17
C3D1
D113
0 hd,f
X
X
X
Xi
Revised Protocol No.: 12
Date: 08-May-2018
163
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-3:
Biomarker Assessment Schedule: MEL and SCCHN Cohort Expansions and Subjects Undergoing 
Tumor Biopsy in the Dose Escalation and Cohort Expansion (Part 1; Completed)
Collection Timing
Plasma
Serum
Tumor
Study Week
Study Day
Relative Study Day
Time (Event)
ctDNAa
PK anti-KIR
PK anti-PD-1
ADA anti-KIR & 
anti-PD-1
Tumor Biopsyd,e,f
Archived Tumor 
Sample
Week 33
C5D1
D225
0 hb
X
X
X
Week 49
C7D1
D337
0 hb
X
X
X
Week 65
C9D1
D449
0 hb
X
X
X
Week 81
C11D1
D561
0 hb
X
X
X
EOT
X
X
X
Follow-up 
Visits 1-3
X
X
a For subjects in MEL cohort expansions only.
d A minimum of 10 subjects with MEL in the cohort expansion and a minimum of 10 subjects with SCCHN in the Cohort Expansion (Part 1) will be required to 
provide pre-treatment and on-treatment biopsies.
e Any subject who consents to biopsies is required to collect the biomarker assessments listed.
f Samples to be collected prior to the infusion of nivolumab.
g Samples must be collected immediately following the end of infusion of lirilumab. It is imperative that the actual time that the sample is obtained is recorded. 
All listed studies should be obtained at this point.
Revised Protocol No.: 12
Date: 08-May-2018
164
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
h Samples may be collected at any time during the day, but it is imperative that the actual time that the sample is obtained is recorded.
i
C3D1 biopsy should be collected prior to Week 17 drug administration.
C = Cycle; CBC = complete blood count; D = Day; EOI = End of Infusion; EOT = End of Treatment.
Revised Protocol No.: 12
Date: 08-May-2018
165
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-4:
Biomarker Assessment Schedule: the SCCHN Cohort Expansion (Part 2; completed)
Collection Timing
Serum
Tumor
Study Week
Study Day a
Relative Study 
Day
Time (Event)
PK anti-KIR
PK anti-PD-1
ADA anti-KIR 
& anti-PD-1
Tumor Biopsyc
Archived Tumor 
Sample
Screening
X
X
Week 1
C1D1
D1
0 h
X
X
X
C1D1
D1
EOI
X
X
C1D2
D2
24 h
X
C1D8
D8
168 h
X
Week 3
C1D15
D15
336 h
X
X
X
X d
Week 5
C1D29
D29
0 h
X
X
X
Week 9
C2D1
D57
0 h
Week 13
C2D29
D85
0 h
X
X
X
C2D29
D85
EOI
X
X
C2D30
D86
24 h
X
C2D36
D92
168 h
X
Week 17
C3D1
D113
0 h
X
X
X
Week 33
C5D1
D225
0 h
X
X
X
Revised Protocol No.: 12
Date: 08-May-2018
166
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-4:
Biomarker Assessment Schedule: the SCCHN Cohort Expansion (Part 2; completed)
Collection Timing
Serum
Tumor
Study Week
Study Day a
Relative Study 
Day
Time (Event)
PK anti-KIR
PK anti-PD-1
ADA anti-KIR 
& anti-PD-1
Tumor Biopsyc
Archived Tumor 
Sample
Week 49
C7D1
D337
0 h
X
X
X
Week 65
C9D1
D449
0 h
X
X
X
Week 81
C11D1
D561
0 h
X
X
X
EOT
X
X
X
Follow-up 
Visits 1-3
X
X
a On days where study drug is administered, samples should be collected before the nivolumab dose unless otherwise specified.
c
A minimum of 2 cores from a core needle biopsy should be collected at biopsy timepoints (1 core for FFPE, 1 core for nucleic acid analyses [RNAlater]). A 
minimum of 15 subjects with SCCHN in the SCCHN Cohort Expansion (Part 2) cohort expansion will be required to provide pre-treatment and on-treatment 
biopsies.
d C1D15 biopsy can be collected ± 3 days.
C = Cycle; CBC = complete blood count; D = Day; EOI = End of Infusion; EOT = End of Treatment.
Revised Protocol No.: 12
Date: 08-May-2018
167
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-5:
Biomarker, Pharmacokinetics, and Immunogenicity Assessment Schedule: the SCCHN Randomized 
Cohorts (Part 3 - closed for enrollment)
Collection Timing
Serum
Tumor
Study Week
Study Day a
Relative Study 
Day
Time (Event)
PK lirilumab
PK nivolumab
ADA anti-
lirilumab & anti-
nivolumab
Tumor Biopsy c
Archived Tumor 
Sample
Screenin
g
X
X
Week 1
C1D1
D1
0 h
X
X
X
C1D1
D1
EOI
X
X
C1D2
D2
24 h
X
C1D8
D8
168 h
X
Week 3
C1D15
D15
336 h
X
X
X
X d
Week 5
C1D29
D29
0 h
X
X
X
Week 9
C2D1
D57
0 h
Week 13
C2D29
D85
0 h
X
X
X
C2D29
D85
EOI
X
X
C2D30
D86
24 h
X
C2D36
D92
168 h
X
Week 17
C3D1
D113
0 h
X
X
X
Revised Protocol No.: 12
Date: 08-May-2018
168
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-5:
Biomarker, Pharmacokinetics, and Immunogenicity Assessment Schedule: the SCCHN Randomized 
Cohorts (Part 3 - closed for enrollment)
Collection Timing
Serum
Tumor
Study Week
Study Day a
Relative Study 
Day
Time (Event)
PK lirilumab
PK nivolumab
ADA anti-
lirilumab & anti-
nivolumab
Tumor Biopsy c
Archived Tumor 
Sample
Week 33
C5D1
D225
0 h
X
X
X
Week 49
C7D1
D337
0 h
X
X
X
Week 65
C9D1
D449
0 h
X
X
X
Week 81
C11D1
D561
0 h
X
X
X
Q16W
after 
Week 81 
until 
EOT
X
X
X
Follow-
up Visits 
1-3
X
X
X
a On days where study drug is administered; samples should be collected before the nivolumab dose unless otherwise specified.
Revised Protocol No.: 12
Date: 08-May-2018
169
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
c A minimum of 2 cores from a core needle biopsy should be collected at biopsy timepoints (1 core for FFPE, 1 core for nucleic acid analyses [RNAlater]). In the 
SCCHN Randomized Cohorts (Part 3), all subjects will be required to provide biopsies during screening and on-treatment if a subject has accessible lesions and 
if the risks associated with obtaining biopsies are deemed acceptable.
d C1D15 biopsy can be collected ± 3 days.
C = Cycle; CBC = complete blood count; D = Day; EOI = End of Infusion; Q16W = every 16 weeks.
Revised Protocol No.: 12
Date: 08-May-2018
170
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-6:
Biomarker, Pharmacokinetics, and Immunogenicity Assessment Schedule: the Signal Detection Cohort 
Expansion (Part 4)
Removed with Revised Protocol 12.
Revised Protocol No.: 12
Date: 08-May-2018
171
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-7:
Pharmacokinetics, Immunogenicity, and Biomarker Assessment Schedule: the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed for enrollment) and 
in the Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6 - removed)
Effective with Revised Protocol 12, PK and ADA samples will continue to be collected but will not be analyzed except as clinically 
indicated in specific cases such as Grade 3/4 toxicity, infusion reactions, etc.
Collection Timing
Serum
Tumor
Study Week
Relative Study 
Day a
Time (Event)
PK Lirilumab
PK Nivolumab
PK Ipilimumab
ADA Anti-
lirilumab, Anti-
nivolumab, and 
Anti-Ipilimumab
Tumor Biopsy c
Archived Tumor 
Sample
Screening
X
X
Week 1
D1
0 h
X
X
X
X
D1
EOI
X
X
X
D2
24 h
X
D8
168 h
X
Week 3
D15
336 h
X
X
X
X d
Week 5
D29
0 h
X
X
X
Week 13
D85
0 h
X
X
X
X
D85
EOI
X
X
X
D86
24 h
X
D92
168 h
X
Week 17
D113
0 h
X
X
X
X
Revised Protocol No.: 12
Date: 08-May-2018
172
Approved
13.0
v
Approved
1.0
v


Clinical Protocol (MAD)
CA223001
BMS-986015
lirilumab
Table 5.7.3.3-7:
Pharmacokinetics, Immunogenicity, and Biomarker Assessment Schedule: the Signal Detection in 
SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed for enrollment) and 
in the Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 6 - removed)
Effective with Revised Protocol 12, PK and ADA samples will continue to be collected but will not be analyzed except as clinically 
indicated in specific cases such as Grade 3/4 toxicity, infusion reactions, etc.
Collection Timing
Serum
Tumor
Study Week
Relative Study 
Day a
Time (Event)
PK Lirilumab
PK Nivolumab
PK Ipilimumab
ADA Anti-
lirilumab, Anti-
nivolumab, and 
Anti-Ipilimumab
Tumor Biopsy c
Archived Tumor 
Sample
Week 25
D169
0 h
X
X
X
X
Week 37
D253
0 h
X
X
X
X
Q12W after 
Week 37 until 
EOT
X
X
X
X
Follow-up 
Visits 1-3
X
X
X
X
a On days where study drug is administered; samples should be collected before the nivolumab dose unless otherwise specified.
c A minimum of 2 cores from a core needle biopsy should be collected at biopsy timepoints (1 core for FFPE, 1 core for nucleic acid analyses [RNAlater]). In the 
Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), all subjects will be required to provide biopsies at screening if 
a subject has accessible lesions and if the risks associated with obtaining biopsies are deemed acceptable. Subjects in the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) will also be required to provide on-treatment biopsies if a subject has accessible lesions and if the 
risks associated with obtaining biopsies are deemed acceptable.
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d For the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) only, C1D15 biopsy can be collected ± 3 days.
C = Cycle; CBC = complete blood count; D = Day; EOI = End of Infusion.
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5.8
Outcomes Research Assessments
No additional QLQ collection is required with Revised Protocol 12.
5.9
Other Assessments
5.9.1
Immunogenicity Assessments
Serum samples for analysis of development of ADA will be drawn in conjunction with analysis of
lirilumab, nivolumab, and ipilimumab serum concentrations and will be collected from all as
indicated in Section 5.7.3.3. These serum samples will be analyzed for ADA by a validated
immunoassay.
Samples designated for PK analysis (Section 5.5) 
may be used for immunogenicity analysis in the event of insufficient volume, to complete the 
immunogenicity assessment, or to follow up on suspected immunogenicity-related AEs. Effective 
with Revised Protocol 12, PK and ADA samples will continue to be collected but will not be 
analyzed except as clinically indicated in specific cases such as Grade 3/4 toxicity, infusion 
reactions, etc.
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a
pre-existing medical condition in a clinical investigation subject administered an investigational
(medicinal) product 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 investigational product,
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess all
AEs. The casual 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.
AEs 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.)
Immune-mediated AEs 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 
subject’s CRF.
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 1 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
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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 non-pathogenic) via the study
drug is an SAE.
Although pregnancy, overdose, cancer, and potential 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 remedying ill health state 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,
care-giver respite, family circumstances, administrative).
−
admission for administration of anti-cancer therapy in the absence of any other SAEs
6.1.1
Serious Adverse Event Collection and 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
150 days of discontinuation of dosing. If applicable, SAEs must be collected that relate to any later
protocol-specified procedure (eg, a follow-up skin biopsy).
The investigator should report any SAE occurring after these time periods that is believed to be
related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its status of
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. SAEs must be recorded on the SAE Report Form; pregnancies on a
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Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports are
to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies 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): See 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 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
Non-serious Adverse Events
A Non-serious Adverse Event is an AE not classified as serious.
6.2.1
Non-serious Adverse Event Collection and Reporting
The collection of non-serious AE information should begin at initiation of study drug. Non-serious
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.
Non-serious 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 non-serious AEs that cause
interruption or discontinuation of study drug and for those that are present at the end of study
treatment as appropriate. All identified non-serious AEs must be recorded and described on the
non-serious AE page of the CRF (paper or electronic).
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that
are reported/identified during the course of the study.
Every AE must be assessed by the investigator with regard to whether it is considered immune
mediated. For events that are potentially immune mediated, additional information will be 
collected on the subject’s CRF.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious 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
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•
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 vs low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is discovered that a study subject is
pregnant or may have been pregnant at the time of investigational product exposure, including
during at least 6 half-lives after product administration, the investigational product will be
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject
safety).
The investigator must immediately notify BMS (or designee) Medical Monitor of this event and
complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 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 subject should be reported to BMS.
Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that
is considered both excessive and medically important. All occurrences of overdose must be
reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug-induced Liver Injury
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 DILI is defined as:
1) Aminotransferase (ALT or AST) elevation > 3 × ULN
AND
2) Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline
phosphatase),
AND
3) No other immediately apparent possible causes of aminotransaminases 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.
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6.6.1
Potential Drug-induced Liver Injury for Subjects with HCC
Potential DILI for this study is defined as:
Hepatotoxicity as evidenced by any of the following:
•
AST or ALT > 10 × ULN for > 2 weeks,
•
AST or ALT > 15 × ULN irrespective of duration,
•
Total bilirubin > 8 × ULN irrespective of duration for subjects with elevated total bilirubin at
study entry or > 5 × ULN for those with normal total bilirubin at entry,
Clinical deterioration manifested by drug-related hepatic decompensation not identified above.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiograms
(ECGs), x-ray films, any other potential safety assessments required or not required by the protocol
should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
6.8
Treatment Algorithms for Drug-related Adverse Events
Treatment algorithms for the management of potential drug-related AEs are located in Appendix 1
of this protocol and in the IB for nivolumab.19
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL
COMMITTEES
For all parts of the study, a blinded independent review committee will review all available tumor 
assessment scans to determine response using RECIST v1.1 criteria. When required, adjudicated 
events will be submitted to health authorities for review on a specified timeframe in accordance 
with the adjudication documentation.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
8.1.1
Dose Escalation (Part 1; Completed)
As this is a Phase 1/2 dose escalation cohort, the sample size at each dose cannot be determined
exactly, as it depends on the number of observed toxicities. Between 3 and 12 subjects
approximately are expected to be treated during dose escalation in each Dose Level, and up to
15 subjects may be dosed at selected Dose Levels.
8.1.2
Cohort Expansion (Part 1; Completed)
During cohort expansion, approximately 18 subjects are expected to be enrolled in each of the
3 unknown or low historic response cohort expansions and approximately 35 subjects in the
2 cohorts with higher historic ORR and treated at the previously determined MTD, MAD, or at an
alternative dose that is not to exceed the MAD.
CRC, SCCHN, and HCC cohorts: The sample size for each tumor cohort will be guided by a
2-stage Gehan design.38 In order to determine whether a target ORR is likely in a tumor cohort,
9 subjects will be treated at Stage 1 in each tumor type, as outlined in Table 3.1.1.2-1. For a tumor
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type in which no responses are observed, it will be concluded that the true ORR is unlikely to be
greater than or equal to the target ORR and no more subjects will be enrolled in these tumor 
cohorts. Otherwise, for the tumor cohort(s) in which at least 1 response among the first 9 subjects
is observed, up to an additional 9 subjects will be enrolled as guided by Table 3.1.1.2-2. With
9 subjects in Stage 1, per tumor there is no more than a 10% chance of declaring that there is no
therapeutic effect when actually there is an effect. A total of up to 18 subjects across the 2 stages
per tumor will guarantee an estimate of the true ORR with 12% precision.
NSCLC and MEL cohorts: A total of approximately 35 subjects will be enrolled in each of these
tumor cohorts based on achieving a higher precision with a reasonable control on the type I error.
In a cohort of approximately 35 subjects, if 12, 14, or 16 responses are observed, then the lower
limit of the 1-sided 90% CI for the ORR is 24%, 29%, or 34%, respectively. In addition,
19 responses would need to be observed in approximately 35 subjects so that the 90% 1-sided CI
for the ORR is entirely above 20%. These calculations are based on the lower limit of the Clopper-
Pearson method for exact CIs. If the true ORR in a tumor type is 45%, then with approximately
35 subjects in a cohort there is 96% chance of observing at least 10 responses, and 93% chance of
observing at least 11 responses, and there is 7% chance of observing 10 or fewer responses (false
negative rate). If the true ORR for a tumor is only 30% rather than 45%, then there is a 35% and
14% chance, respectively, that there will be at least 12 or at least 14 responses in approximately
35 subjects (false positive rate).
The above numbers are approximate, as subjects treated during dose escalation with a tumor under
the same setting (eg, dose and population) as in cohort expansion may be included in the total n
per tumor.
8.1.3
The SCCHN Cohort Expansion (Part 2; Completed)
A total of approximately 35 subjects will be enrolled in the SCCHN Cohort Expansion (Part 2).
The null hypothesis that the true ORR is 25% will be tested against a 1-sided alternative: ORR =
40%. The null hypothesis will be rejected if 12 or more responses are observed in 35 subjects. This 
design gives a 1-sided type 1 error rate of 0.15 and a power of 0.81.
8.1.4
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)
The SCCHN Randomized Cohorts (Part 3) has a primary endpoint of ORR. A total of 225 subjects 
will be randomized in a 2:1 ratio to the 2 treatment arms, nivolumab combined with lirilumab 
(Arm A) and nivolumab monotherapy (Arm B), stratified by PD-L1 ≥50% expression (yes/no) 
and prior treatment with cetuximab (yes/no).
Objective Response Rate:
The sample size is calculated to assess the ORR of lirilumab in combination with nivolumab. The 
type 1 error is set to 0.10 (2-sided) with no planned interim analysis. The final analysis for ORR 
will take place approximately 6 months after the last subject is randomized and treated. With 
150 subjects in Arm A, if 50 responses are observed, the estimated ORR will be 33% and the 90% 
CI will be [26%, 41%]. In Study CA209041, the 90% CI for the nivolumab arm in PD-L1+ (> 1%) 
subjects was [9%, 25%].
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The above sample size calculation was performed using EAST® 6 and SAS 9.2.
8.1.5
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
8.1.7
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
8.2
Population for Analyses
•
All Enrolled Data set: subjects who signed informed consent and registered in the study.
•
All Treated Data set: all subjects who received at least 1 dose of any study drug.
•
Response-Evaluable Data Set: all treated subjects who receive any study drug, have a baseline
tumor assessment with measurable disease, and 1 of the following:
−
at least 1 evaluable on-treatment tumor assessment,
−
clinical progression, or
−
death prior to the first on-treatment tumor evaluation.
•
Lirilumab PK Data Set: all subjects who receive at least 1 dose of lirilumab and have adequate
serum concentration data for lirilumab PK.
•
Nivolumab PK Data Set: all subjects who receive at least 1 dose of nivolumab and have
adequate nivolumab PK.
•
Lirilumab Immunogenicity Data Set: all subjects who receive at least 1 dose of lirilumab and
have at least 1 ADA sample available.
•
Nivolumab Immunogenicity Data Set: all subjects who receive at least 1 dose of nivolumab
and have at least 1 ADA sample available.
•
Ipilimumab Immunogenicity Data Set: all subjects who receive at least 1 dose of ipilimumab 
and have at least 1 ADA sample available. 
•
Biomarker Data Set: all treated subjects who have biomarker data available.
•
For the SCCHN Randomized Cohorts (Part 3), Randomized Subjects Data Set: All enrolled
subjects who were randomized. This is the dataset for baseline demographics and efficacy
analyses for this cohort.
•
For the SCCHN Randomized Cohorts (Part 3), PRO subjects: All randomized subjects with
baseline and at least 1 post-baseline PRO assessment.
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8.3
Endpoint Definitions
Endpoints are defined as follows. 
Safety Endpoint Definitions
Safety is the primary endpoint in this study except for the SCCHN Randomized Cohorts (Part 3). 
All subjects who receive at least 1 dose of study drug will be evaluated for safety as measured by 
the occurrence of AEs, SAEs, deaths, and laboratory abnormalities, assessed during treatment and 
for 150 days in follow-up.
Study level endpoints used to assess the safety objective will be based on AE reports and the results 
of vital sign measurements, ECGs, physical examinations, imaging studies, and clinical laboratory 
tests. AEs will be categorized using the most current version of MedDRA; both AEs and laboratory 
tests will be graded using NCI CTCAE v4.03. All subjects who receive study drug therapy will be 
evaluated for safety as measured by the rate of AEs, and SAEs, and will be assessed during 
treatment and for 150 days in follow-up.
Safety will be measured by the following: 
•
Incidence of AEs: all non-serious AEs will be collected from Day 1 until 150 days after the 
subject’s last dose of study drug or until they discontinue the study as per Section 3.5 and all 
SAEs must be collected from the date of the subject’s written consent until 150 days after 
discontinuation of dosing or until they discontinue the study as per Section 3.5.
•
Incidence of clinical laboratory test abnormalities including hematology and serum chemistry, 
and thyroid panel abnormalities, assessed at specified timepoints as designated in the Time and 
Events Section (5.1).
Efficacy Endpoint Definitions
Study level endpoints used to assess the anti-tumor activity objective are defined as follows: 
ORR is defined as the total number of subjects whose BOR is either CR or PR divided by the total 
number of subjects in the population of interest.
PFS rate is defined as the probability of a subject remaining progression-free and surviving to 24 
weeks. The probability will be computed based on the number of days between the first dose of 
study drug and PD or death, as defined by each criterion. For those subjects who remain alive and 
have not progressed, PFS will be censored on the date of the last tumor assessment. The above 
will be calculated based on tumor measurements occurring Q8W during treatment and at planned 
timepoints during the clinical follow-up period.
BOR is the best response designation recorded from the start of the study treatment until the end 
of treatment taking into account any requirement for confirmation, based on RECIST v1.1 criteria. 
CR or PR determinations included in the BOR assessment must be confirmed by a consecutive 
second (confirmatory) evaluation meeting the criteria for response that is performed at least 4 
weeks after the criteria for response are first met. The above will be determined based on tumor 
measurements occurring Q8W (± 7days) during the treatment period (or Q6W (± 7days) for 1 year 
[48 weeks] and Q12W (± 7days) afterwards for the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination [Part 5] and once during the clinical follow-up period.
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Other efficacy endpoints include the following:
OS is defined as the time from randomization to the date of death. A subject who has not died will 
be censored at last known date alive. OS will be followed continuously while subjects are on the 
study drug and every 3 months for up to 3 years following the first dose of study drug via in-person 
or phone contact after subjects discontinue the study drug.
PFS is defined as the time from randomization to the date of the first documented tumor 
progression (per RECIST v1.1). 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 evaluable tumor assessment. Subjects who did not have any 
on-study tumor assessments and did not die will be censored on the date they were randomized. 
Subjects who started any subsequent anti-cancer therapy without a prior reported progression will 
be censored at the last evaluable tumor assessment prior to initiation of the subsequent anti-cancer 
therapy. 
DOR is defined as the time between the date of first confirmed response to the date of the first 
documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs 
first. Subjects who neither progress nor die will be censored on the date of their last evaluable 
tumor assessment. Subjects who started any subsequent anti-cancer therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to or on 
initiation of the subsequent anti-cancer therapy. DOR will be evaluated for responders (confirmed 
CR or PR) only.
Time to response is defined as the time from randomization to the date of the first confirmed CR 
or PR. DOR will be evaluated for responders (confirmed CR or PR) only.
DCR is defined as the proportion of subjects with BOR equal to CR, unconfirmed CR, PR, 
unconfirmed PR, or SD.
Depth of response is defined as the target tumor burden percent change from baseline at nadir for 
each subject as measured by the percent of subjects with ≥50% and ≥80% tumor reduction
Pharmacokinetic Endpoint Definitions 
PK endpoints (Cmax [μg/mL], Tmax [hr], AUC[0-T] [μg.hr/mL], Ctrough [μg/mL], AUC[TAU] 
[μg.hr/mL], AUC[INF] [μg.hr/mL], CL [L/day], T-HALF, Vz, and Cmin [μg/mL]) will be 
evaluated using non-compartmental analysis, where feasible. In addition, nivolumab end of 
infusion and trough (Cmin) concentrations will be calculated at specified visits for certain study 
parts
.
Immunogenicity Endpoint Definitions 
Endpoints for the study are incidence rates of persistent positive ADA as well as neutralizing 
positive ADA from initiation of each drug treatment and up to and including the follow-up period 
of the last study drug dosing. Based on recommendation from BMS Immunogenicity Council, 
Harmonization of Clinical Immunogenicity Reporting by an Initiative of the Therapeutic Protein 
Immunogenicity Focus Group of the American Association Pharmaceutical Scientists, and the 
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FDA Guidance for Industry Immunogenicity Assessment for Therapeutic Protein Products, the 
following definitions will be applied.
ADA Status of a Subject:
•
Baseline ADA Positive Subject: A subject with baseline ADA positive sample 
•
ADA Positive Subject: A subject with at least 1 ADA positive sample relative to baseline at 
any time after initiation of treatment during the defined observation time period. 
•
ADA Negative Subject: A subject with no ADA positive sample after the initiation of treatment
Definitions for ADA Status of a Sample (Baseline ADA Positive, ADA Positive, or ADA 
Negative), as well as sub-categories of ADA Positive Subject such as Persistent Positive, Only the 
Last Sample Positive, Other Positive and Neutralizing Positive will be provided in the statistical 
analysis plan.
Biomarker Endpoint Definitions 
Measures of TILs, PD-L1, 
 expression using IHC, including baseline and changes 
from baseline outcomes, on mandatory tumor biopsies from the subjects specified in each study 
part.
Quality of Life Endpoint Definitions
Quality of life endpoints are discussed in detail in Section 5.8.
8.3.1
Primary Endpoint(s)
Refer to Section 8.3 for endpoint definitions.
8.3.1.1
Dose Escalation and Cohort Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed)
•
The primary endpoints are safety measures (the Dose Escalation and Cohort Expansion [Part 1] 
the SCCHN Cohort Expansion [Part 2]), and assessment of preliminary anti-tumor activity (for 
the SCCHN Cohort Expansion [Part 2]).
−
For the SCCHN Cohort Expansion (Part 2), assessment of preliminary anti-tumor activity 
will be based on using irRECIST for the purposes of subject management. Timepoint tumor 
response evaluations will be recorded on the CRF based on investigators’ assessments 
using irRECIST criteria. Statistical analysis and reporting will be based primarily on 
RECIST v1.1 criteria. 
8.3.1.2
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)
•
The primary endpoint is ORR in subjects randomized to lirilumab plus nivolumab.
−
Tumor assessments are scheduled to be performed at Week 8 (± 7 days) from first dose 
date, Q8W (± 7 days) until Week 48, and then Q12W (± 7 days) until PD or treatment 
discontinuation, whichever occurs earlier.
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8.3.1.3
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
8.3.1.4
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment)
•
The primary endpoints are safety measures and assessment of preliminary anti-tumor activity.
−
The assessment of preliminary anti-tumor activity will be based on using RECIST v1.1.
Timepoint tumor response evaluations will be recorded on the CRF based on investigators’ 
assessments using RECIST v1.1 criteria. Statistical analysis and reporting will be based 
primarily on RECIST v1.1 criteria. Investigator-assessed BOR based on RECIST v1.1 will 
be listed.
8.3.1.5
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
8.3.2
Secondary Endpoints
8.3.2.1
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed)
The secondary endpoints are PK, ADAs, and biomarkers.
•
The secondary endpoint of occurrence of specific ADAs to lirilumab and nivolumab will be 
determined from measurements on Weeks 1, 3, 5, 13, 17, 33, 49, 65, and 81; end of treatment;
and all 3 clinical follow-up visits (please see Table 5.7.3.3-1, Table 5.7.3.3-2, Table 5.7.3.3-3, 
and Table 5.7.3.3-4).
•
Biomarker endpoint measures will be taken from a minimum of 10 MEL cohort expansion 
subjects and a minimum of 10 SCCHN (the Dose Escalation and Dose Expansion [Part 1]) 
cohort expansion subjects or other additional subjects included in the biomarker analysis data 
sets.
•
Biomarker endpoint measures will be taken from a minimum of 15 subjects in the SCCHN 
Cohort Expansion (Part 2) or other additional subjects included in the biomarker analysis data 
sets.
8.3.2.2
The SCCHN Randomized Cohorts (Part 3 - closed to enrollment)
The secondary endpoints are DCR, DOR, time to response, depth of response, OS, PFS, ORR 
according to investigator-assessed response, and safety measures.
•
Tumor assessments are scheduled to be performed at Week 8 (± 7 days) from first dose date, 
Q8W (± 7 days) until Week 48, and then Q12W (± 7 days) until PD or treatment 
discontinuation, whichever occurs earlier.
8.3.2.3
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
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8.3.2.4
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment)
The secondary endpoints are DOR, depth of response, PK, ADAs, immunomodulatory properties, 
and biomarkers.
•
Tumor assessments are scheduled to be performed at Week 8 (± 7 days) from first dose date, 
Q8W (± 7 days) for 1 year (48 weeks), and then Q12W (± 7 days) until PD or treatment 
discontinuation, whichever occurs earlier.
•
The secondary endpoint of occurrence of specific ADAs to lirilumab, nivolumab, and 
ipilimumab, will be determined from measurements specified in Table 5.7.3.3-7).
•
Biomarker endpoint measures will be included from all subjects in the biomarker analysis data 
sets.
8.3.2.5
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated. Summary statistics for age, body
weight, and height will be collected, and body mass index will be derived.
Subject
characteristics
including
demographics,
baseline
performance
status,
disease
characteristics and baseline laboratory parameters will be summarized by treatment arm and/or 
tumor types, if applicable, as well as pooled across treatment arm and/or tumor types, if applicable.
8.4.2
Efficacy Analyses
8.4.2.1
The SCCHN Randomized Cohorts (Part 3) Primary Endpoint Analysis
The primary endpoint of ORR in subjects randomized to lirilumab plus nivolumab will be analyzed
for the SCCHN Randomized Cohorts (Part 3). Subjects will be enrolled if PD-L1 is expressed in 
≥1% of tumor cells.
CIs will be provided separately for each treatment arm using the Clopper-Pearson method.
8.4.2.2
Secondary Endpoints Analysis
Individual BOR, DOR, and PFS will be listed using RECIST v1.1 criteria. Summary tables will 
be presented on efficacy endpoints for each randomized treatment arm. The OS and PFS rates at 
specific timepoints (eg, at 24 weeks) and corresponding CI will be estimated by KM methodology 
depending on data availability. ORR, DOR and PFS analyses will include subjects in the cohort 
expansion phase and subjects in dose escalation matching those in cohort expansion by disease 
type and treatment. Individual changes in the tumor burden over time will be presented graphically 
within a disease type.
 
The number and percentage of subjects in each category of BOR (CR, PR, SD, PD, or unable to 
determine) will be presented by treatment arm and/or tumor types, if applicable. Finally, a waterfall 
plot showing the biggest reduction in the sum of target lesions will be produced for response-
evaluable subjects.
8.4.3
Safety Analyses
All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment.
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any
significant physical examination findings, and clinical laboratory results will be listed. ECG
readings will be evaluated by the investigator and abnormalities, if present, will be listed.
Summary tables will be presented on safety parameters for each treatment arm and/or tumor types, 
if applicable.
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8.4.4
Pharmacokinetic Analyses
Summary statistics will be tabulated for the PK parameters of lirilumab by dose and study 
day/week. For 
 the Signal Detection in SCCHN 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), summary tables will also be 
presented by each treatment arm. To describe the dependency on dose of anti-KIR, scatter plots of 
Cmax and AUC(TAU) vs dose will be provided for each day measured. Dose proportionality of 
lirilumab when co-administered with nivolumab will be assessed based on a power model. Dose 
proportionality of lirilumab when co-administered with nivolumab, and of lirilumab when co-
administered with nivolumab and ipilimumab will be assessed based on a power model.
Nivolumab end of infusion and trough (Cmin) concentration will be tabulated by summary
statistics. These data may also be pooled with other datasets for population PK analysis, which
will be part of a separate report.
8.4.5
Biomarker Analyses
The pharmacodynamic effect of lirilumab on TILs and expression of tumor markers including PD-
L1
will be assessed by summary statistics, and investigated graphically to explore
patterns of change, eg, with drug exposure for corresponding subjects included in the biomarker 
analysis data set. In addition, the correlation of TIL changes and tumor marker expression with
measures of peripheral blood markers will be explored graphically, or by appropriate statistical
methods based on data availability, for assessing associations.
8.4.7
Outcomes Research Analyses
Removed with Revised Protocol 12.
8.4.8
Other Analyses
A listing will be provided of all available immunogenicity data. Additionally, a listing of
immunogenicity data from those subjects with at least 1 positive ADA at any timepoint will be
provided by treatment for each analyte. The number (%) of subjects with the following anti-drug
responses will be reported for each analyte if applicable, by dose, and overall: Baseline ADA
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Positive, ADA Positive (Persistent Positive, Only the Last Sample Positive), ADA Positive with
Neutralizing Positive, and ADA Negative.
To examine the potential relationship between immunogenicity and safety, the frequency and type
of AEs of special interest may be examined by overall immunogenicity status. Associations
between trough concentrations of lirilumab (or nivolumab or ipilimumab) and corresponding ADA
assessments may be explored.
8.5
Interim Analyses
Data emerging from the unblinded parts of this study may be needed for timely decisions about
adjustments to procedures in subsequent parts of the study. Therefore, data may be reviewed prior
to the final lock of the study database. While the study is still ongoing, additional interim analyses
may also be performed for administrative purposes or publications. In that case, analyses will only
consist of listings, summaries, and graphs of the available data, and no formal inferences requiring
any adjustment to statistical significance level will be performed. Efficacy analyses based on
interim data may use response-evaluable or all-treated populations depending on the purpose of
the analysis.
The Dose Escalation and Cohort Expansion (Part 1; completed) of the study is the dose-escalation 
study and includes expansion cohorts in specific tumor types. In the dose expansion portion of the 
Dose Escalation and Cohort Expansion (Part 1; completed), in order to assess if the target response
rate is likely for tumor cohorts with unknown or low historic ORR, the tumor response will be
initially based on the tumor measurements from the first approximately 9 subjects in each cohort
to facilitate decisions on continuing enrollment in that tumor. If no responses are observed in
approximately the first approximately 9 subjects with tumor measurements, enrollment in that
tumor cohort will not continue. However, accrual to these tumor types may continue, while the
Stage I response assessments are performed.
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
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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 an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the
data quality and study integrity. On-site, they will review study records and directly compare them
with source documents, discuss the conduct of the study with the investigator, and verify that the
facilities remain acceptable.
In addition, the study may be evaluated by BMS internal auditors and government inspectors who
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities,
and promptly forward copies of inspection reports to BMS.
9.1.3
Investigational Site Training
BMS 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 
investigational product (those supplied by BMS) is maintained at each study site where study drug 
are inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:
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•
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/study site for dispensing or storage
•
non-study disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the study 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. 
For study sites using the BMS EDC 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 a qualified physician who is an investigator or qualified physician 
who is a sub-investigator 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 EDC 
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 EDC tool using the unique user account provided by BMS. User 
accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
A Signatory investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory investigator will be selected considering the following criteria.
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in study design
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the 
investigator or BMS as related to the investigational 
product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator’s Brochure for an unapproved 
investigational product)
Serious Adverse Event
Serious adverse event defined as 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, 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 1 of the other serious 
outcomes listed in the definition above). Examples of 
such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization). For reporting purposes 
only, BMS also considers the occurrence of pregnancy, 
overdose (regardless of association with an AE), and 
cancer as important medical events.
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11
LIST OF ABBREVIATIONS
Term
Definition
%CV
coefficient of variation
AE
adverse event
ADA
anti-drug antibody
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC(INF)
area under the plasma concentration-time curve from time zero 
extrapolated to infinite time
AUC(0-T)
area under the plasma concentration-time curve from time zero to 
the time of the last quantifiable concentration
AUC(TAU)
area under the plasma concentration-time curve in 1 dosing 
interval
BC
bladder cancer
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BOR
best overall response
BSA
body surface area
BTLA
B- and T-lymphocyte attenuator
BUN
blood urea nitrogen
C
Cycle
C30
30-item core
Ca
calcium
CEA
carcinoembryonic antigen
Cavgss
time-averaged concentration at dosing interval
CBC
complete blood count
CD
cluster of differentiation
cHL
classical Hodgkin lymphoma
CI
confidence interval
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Term
Definition
CL
clearance
C1
chloride
Cmax
maximum observed concentration
Cmaxss
steady-state peak concentration
Cmin
trough observed concentration
Cminss
steady-state trough concentration
CMV
cytomegalovirus
CNS
central nervous system
CR
complete response
CRC
colorectal cancer
CRF
case report form, paper or electronic
CRP
C-reactive protein
CT
computed tomography
CTA
clinical trial agreement
CTL
cytotoxic T lymphocyte
ctDNA
circulating tumor deoxyribonucleic acid
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte antigen 4
Ctrough
trough observed serum concentration
D
Day
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
EC50
concentration required for 50% efficacy
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
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Term
Definition
EGFR
epidermal growth factor receptor
EOI
End of Infusion
EORTC
European Organisation for Research and Treatment of Cancer
EOT
End of Treatment
EQ-5D
EuroQol 5 dimensions questionnaire
ESCC
squamous cell esophageal cancer
Fab
fragment antigen-binding
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
Geo
geometric
H&N35
head and neck specific module
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HPV
human papillomavirus
HR
hazard ratio
HRT
hormone replacement therapy
HSCT
hematopoietic stem cell transplant
IB
Investigator’s Brochure
IC50
concentration required for 50% inhibition
ICH
International Conference on Harmonisation
ICOS
inducible T-cell co-stimulator
IEC
Independent Ethics Committee
IFN-γ
interferon-gamma
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
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Term
Definition
IO
immuno-oncology
INR
international normalized ratio
ir
immune-related
IRB
Institutional Review Board
IRC
independent review committee
IRT
Interactive Response Technology
IV
intravenous
IVRS
Interactive Voice Response System
K
potassium
KIR
killer cell immunoglobulin-like receptors
KM
Kaplan-Meier
KRAS
Kirsten Ras
LDH
lactate dehydrogenase
LFT
liver function test
mAb
monoclonal antibody
MAD
maximum administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MEL
melanoma
Mg
magnesium
mIgG
murine immunoglobulin
MRI
magnetic resonance imaging
MSI
microsatellite instability
MTD
maximum tolerated dose
mWHO
modified World Health Organization
Na
sodium
N/A
not applicable
NCI
National Cancer Institute
NK
natural killer
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Term
Definition
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L1+
programmed cell death ligand 1 positive
PD-L2
programmed cell death ligand 2
PE
physical examination
PFS
progression-free survival
PID
patient identification number
PK
pharmacokinetic(s)
PPK
population pharmacokinetics
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
QLQ
quality of life questionnaire
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
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Term
Definition
RNA
ribonucleic acid
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SHP-1, -2
Src homology region 2 domain-containing phosphatase-1, -2
sqNSCLC
squamous cell non-small cell lung cancer
T3
triiodothyronine
T4
thyroxine
TAO
Trial Access Online, the BMS implementation of an EDC 
capability
TCGA
The Cancer Genome Atlas
TF
tumor free
T-HALF
half-life
TIL
tumor-infiltrating lymphocyte
Tmax
time of maximum observed concentration
TRAE
treatment-related adverse event
Treg
regulatory T cell
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
v1.1
version 1.1
v4.03
version 4.03
VAS
visual analog rating scale
Vc
volume of central compartment
Vss
apparent volume of distribution at steady state
Vz
apparent volume of distribution during terminal phase
WBC
white blood cell
WOCBP
women of childbearing potential
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REFERENCES
1
Leidner R, Kang H, Haddad R, et al. Preliminary efficacy from a phase 1/2 study of the natural 
killer cell–targeted antibody, lirilumab in combination with nivolumab in squamous cell 
carcinoma of the head and neck [abstract 456]. SITC Annual Meeting; 2016 Nov 9-13; 
National Harbor, MD.
2
Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell 
carcinoma of the head and neck [published online ahead of print 2016 Oct 8]. N Engl J Med 
2016 Oct 8. doi:10.1056/NEJMoa1602252.
3
Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy 
in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results 
from the phase II CheckMate-275 study [Abstract LBA31]. 2016 ESMO Congress; 
2016 Oct 7-11; Copenhagen, Denmark.
4
Poli A, Michel T, Thérésine M, et al. CD56bright natural killer (NK) cells: an important NK 
cell subset. Immunology 2009;126(4):458-65.
5
Senbabaoglu Y, Winer AG, Gejman RS, et al. The landscape of T-cell infiltration in human 
cancer its association with antigen presenting gene expression [published online ahead of print 
2015 Sep 1]. Available from: URL: http://biorxiv.org/content/early/2015/09/01/025908. 
doi:http://dx.doi.org/10.1101/025908. 
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Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2004;23:515-48.
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Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000;192(7):1027-34.
8
Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol 2007;8:237-45.
9
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20.
10 Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: Releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012;18:153-9.
11 Effect of anti-Ly49 in Combination with anti-PD-1 or anti-CTLA4 on the rejection of the 
C1498 AML tumor: Study 1. Bristol-Myers Squibb Company; 2012. Document Control No. 
.
12 Segal NH, Infante JR, Sanborn RE, et al. Safety of the natural killer (NK) cell-targeted 
anti-KIR antibody, lirilumab (liri), in combination with nivolumab (nivo) or ipilimumab (ipi) 
in two phase I studies in advanced refractory solid tumors [poster 1086P]. 2016 ESMO 
Congress; 2016 Oct 7-11; Copenhagen, Denmark. 
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13 Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 
6(2):69-90.
14 NCI 
SEER 
Statistics 
Review. 
Available 
from: 
URL: 
http://seer.cancer.gov/statfacts/html/oralcav.html. Accessed March 5, 2016.
15 Leemans CR, Braakhuis B, Brakenhoff R. Molecular biology of head and neck cancer. Nat 
Rev Cancer 2011;11(1):9-22.
16 Mehra R, Seiwert TY, Mahipal A, et al. Efficacy safety of pembrolizumab in 
recurrent/metastatic head neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after 
long-term follow-up in KEYNOTE-012 [abstract 6012]. J Clin Oncol 2016:34(Suppl).
17 Gillison ML, Blumenschein G, Fayette J. Nivolumab (nivo) vs investigator’s choice (IC) for 
recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 
CheckMate141 [abstract CT099]. Cancer Research 2016;76(14 Suppl):CT099-CT099.
18 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.
19 Nivolumab (BMS-936558) Investigator Brochure Version 16. Bristol-Myers Squibb 
Company; 2017. Document Control No. 
20 An open-label, trial of nivolumab, or nivolumab plus ipilimumab, or nivolumab plus platinum-
doublet chemotherapy versus platinum doublet chemotherapy in subjects with stage IV non-
small cell lung cancer (NSCLC) (CheckMate 227). ClinicalTrials.gov Identifier: 
NCT02477826. Available from: URL: https://clinicaltrials.gov/ct2/show/NCT02477826.
21 BMS-986015 (lirilumab) Investigator Brochure, Version 08. Bristol-Myers Squibb Company; 
2017. Document Control No. 
22 Ipilimumab (BMS-734016) Investigator Brochure Version 19. Bristol-Myers Squibb
Company; 2016. Document Control No. 
23 Non-clinical Expedited Safety Report for Nivolumab (Ad Hoc CARES #54344.1). 
Bristol-Myers Squibb Company. Document Control No. 
 
24 Repeated-dose (q3d x 3, 14-day) toxicity study of anti-CTLA-4/10D1 administered via 
intravenous injection to cynomolgus monkeys (Study 126-002), Report. Redfield Laboratories; 
2000. Document Control No.
25 Study SBi 0919-128: A 2-week toxicity study of human anti-CTLA4 administered by 
intravenous injection to cynomolgus monkeys. Bristol-Myers Squibb Company; 2000. 
Document Control No.
26 Covance Study 7114-100: Fourteen day intravenous toxicity study with mAb 10D1 in 
cynomolgus monkeys. Bristol-Myers Squibb Company; 2000. Document Control No. 
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27 Study DS06064: BMS-663513 and BMS-734016 (MDX-010): One month intravenous 
combination toxicity study in monkeys. Bristol-Myers Squibb Company; 2007. Document 
Control No. 
28 Study SBi 1416-128: A repeat dose toxicology and efficacy study MDX-010 or 
MDX-010-HYB in combination with HBsAg and SKMel vaccines in cynomolgus monkeys. 
Bristol-Myers Squibb Company; 2003. Document Control No. 
29 Study SBi 0992-128: An immunogenic study following combined intravenous/intramuscular 
administration of MAb10D1/HBsAg, respectively, to cynomolgus monkeys. Bristol-Myers 
Squibb Company; 2001. Document Control No. 
30 Study 01-3460: MDX-CTLA4: A 6-month intravenous toxicology study in cynomolgus 
monkeys. Bristol-Myers Squibb Company; 2002. Document Control No. 
31 Ipilimumab population pharmacokinetics and exposure-response analyses in subjects with 
advanced melanoma (CA184004, CA184007, CA184008, and CA184022). Bristol-Myers 
Squibb; 2010. Document Control No. 
32 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:122-33.
33 Waterhouse D, Horn L, Reynolds C, et al. Safety profile of nivolumab administered as 
30-minute infusion: analysis of data from CheckMate 153 [abstract 3059]. American Society 
of Clinical Oncology 2016 Annual Meeting; 2016 Jun 3-7; Chicago, IL.
34 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. Abstract 1297O.
35 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.
36 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.
37 Jin S, Deng Y, Hao J-W, et al. NK cell phenotypic modulation in lung cancer environment. 
PLoS ONE 2014;9(10):e109976.
38 Gehan, EA. The determination of the number of patients required in a preliminary and a follow-
up trial of a new chemotherapeutic agent. Therapeutics 1961;13:4,346-53.
39 Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal 
cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 
2012;36:945-54.
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40 Umar A, Boland Cr, Terdiman JP, et al. Revised Bethesda Guidelines for Hereditary 
Non-polyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Nat 
Cancer Inst 2004;96:261-68.
41 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
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Source: Appendix 3, BMS936558 IB v15
APPENDIX 1
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology (I-O) agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for I-O drug-related adverse events (AE). The oral 
equivalent of the recommended intravenous doses may be considered for ambulatory patients 
with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related AEs covered by these algorithms will depend on the 
I-O agent or regimen being used.
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Figure 1:
Gastrointestinal Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. 
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
ADL = activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute.
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Figure 2:
Renal Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; ULN = upper limit of normal.
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Source: Appendix 3, BMS936558 IB v15
Figure 3:
Pulmonary Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging and 
pulmonary consultation.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
CTCAE = Common Terminology Criteria for Adverse Events; ID = infectious disease; IV = intravenous; NCI = National Cancer Institute.
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Figure 4:
Hepatic Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 × ULN and total bilirubin ≤ 5 × ULN. 
**The recommended starting dose for Grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; CTCAE = Common Terminology Criteria for Adverse Events; 
IV = intravenous; LFT = liver function test; NCI = National Cancer Institute; ULN = upper limit of normal.
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Figure 5:
Endocrinopathy Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field 
testing, endocrinology consultation, and imaging.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
IV = intravenous; MRI = magnetic resonance imaging; PO = oral; TSH = thyroid stimulating hormones; ULN = upper limit of normal.
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Figure 6:
Skin Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific grading criteria.
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is diagnosed, permanently 
discontinue I-O therapy.
BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; SJS = Stevens 
Johnson Syndrome; TEN = toxic epidermal necrolysis.
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Source: Appendix 3, BMS936558 IB v15
Figure 7:
Neurological Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
ADL = activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; IVIG = intravenous immunoglobulin therapy; 
NCI = National Cancer Institute; PO = oral.
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APPENDIX 2
irRECIST
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
Subjects must have measureable disease to be eligible for this study.
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT scans have
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
•
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). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable lesions
•
All other lesions, including small lesions (longest diameter < 10 mm 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 in not 
measurable by reproducible imaging techniques.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or
disappearance of bone lesions.
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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.3.2
Cystic lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
•
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Measurable lesions may be in an irradiated field as long as there is 
documented progression and the lesion(s) can be reproducibly measured.
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung.
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1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
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.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
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 below, 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.
2.1.1
Lymph nodes
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. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
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2.2
Non-target lesions
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’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION 
3.1
Evaluation of target lesions
Immune-related Complete Response (irCR):  Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis to <
10 mm.
Immune-related Partial Response (irPR):  At least a 30% decrease in the sum of diameters of 
target lesions and all new measurable lesions (ie Percentage Change in Tumor Burden), taking 
as reference the baseline sum diameters.
Note: the appearance of new measurable lesions is factored into the overall Tumor Burden, but 
does not automatically qualify as progressive disease until the sum of the diameters increases by 
≥20% when compared to nadir.
Immune-related Progressive Disease (irPD):  At least a 20% increase in Tumor Burden  (ie the 
sum of diameters of target lesions, and any new measurable 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. Tumor assessments using immune-related criteria for progressive disease incorporates the 
contribution of new measurable lesions. Each net percentage change in tumor burden per 
assessment accounts for the size and growth kinetics of both old and new lesions as they appear.
Immune-related Stable Disease (irSD):  Neither sufficient shrinkage to qualify for irPR nor 
sufficient increase to qualify for irPD, taking as reference the smallest sum diameters while on 
study.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
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. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
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3.1.1.2
Target lesions that become ‘too small to measure’  
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
•
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: in case of a lymph node believed to be present and 
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).
3.1.1.3
Target 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. 
•
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’.
3.2
Evaluation 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.
Immune-related Complete Response (irCR):  Disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (< 10 mm short axis).
Immune-related Progressive Disease (irPD):  Increases in number or size of non-target lesion(s) 
does not constitute progressive disease unless/until Tumor Burden increases by 20% (ie the 
sum of the diameters at nadir of target lesions and any new measurable lesions increases by the 
required amount) 
Note: Non-target lesions are not considered in the definition of Stable Disease and Partial 
Response.
3.3
New lesions
The appearance of new lesions alone does not denote disease progression. However their 
contribution to total tumor burden is included in the sum of the diameters which in turn feeds 
into the irRECIST assessment of tumor response.
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4
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
•
Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions 
(target and non-target), together with no new measurable or unmeasurable lesions, for at least 
4 weeks from the date of documentation of irCR. All lymph nodes short axes must be 
< 10 mm.
•
Immune-related Partial Response (irPR): The sum of the diameters of all target lesions is 
measured and captured as the sum of diameters at baseline. At each subsequent tumor 
assessment, the sum of the diameters of all target lesions and of new measurable lesions are 
added together to provide the Immune Response Sum of the Diameters (irSD). A decrease, 
relative to baseline of the irSD of 30% or greater is considered an irPR, in the absence of 
irCR. Must be confirmed no less than 4 weeks from the first irPR.
•
Immune-related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease.
•
Immune-related Progressive Disease (irPD): It is recommended in difficult cases 
(eg, increase in the sum of the diameters accompanied with significant individual lesion 
regression, “mixed response”, or in presence of stable or improving performance 
status/clinical condition) to confirm PD at the following tumor assessment. Any of the 
following will constitute progressive disease:
−
At least 20% increase in the Sum of the Diameters of all target lesions over the nadir Sum 
of the Diameters calculated for these lesions.
−
At least a 20% increase in the Sum of the Diameters of all target lesions and new 
measurable lesions over the nadir Sum of the Diameters calculated for the target lesions.
Table 1.
irRECIST Definitions.
Target 
Lesion 
Response
Non-
target 
Lesion 
Response
New 
Measurable 
Lesions
New Non-
measurable 
Lesions
% Change in Tumor 
Burden 
(including measurable 
new lesions when 
present)
Overall ir-
response
CR
CR
Any
Any
-100%
irCR
PR
Any
Any
Any
≤-30%
irPR
> -30% to < +20%
irSD
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Table 1.
irRECIST Definitions.
Target 
Lesion 
Response
Non-
target 
Lesion 
Response
New 
Measurable 
Lesions
New Non-
measurable 
Lesions
% Change in Tumor 
Burden 
(including measurable 
new lesions when 
present)
Overall ir-
response
≥+20%
irPD
SD
Any
Any
Any
> -30% to < +20%
irSD
≥+20%
irPD
PD
Any
Any
Any
≥+20%
irPD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ir = Immune 
response
4.1.1
Confirmation Scans 
•
Verification of Response: irPR must be confirmed no less than 4 weeks from the initial 
irPR.
4.2
Best overall response: All timepoints
Best Overall Response and Date of Progression Using irRECIST (irBOR): The investigator will 
be asked to provide all responses on study and date(s) of progression, if applicable, and the best 
overall response will be calculated by the sponsor or designee based on the time point responses 
and tumor measurements provided by the investigators.
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APPENDIX 3
RECIST V1.1
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
Subjects must have measureable disease to be eligible for this study.
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least one measurable tumor lesion. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
•
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). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable lesions
•
All other lesions, including small lesions (longest diameter < 10 mm 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 in not 
measurable by reproducible imaging techniques.  
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
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•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.3.2
Cystic lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
•
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion.  Measurable lesions may be in an irradiated field as long as there is documented 
progression and the lesion(s) can be reproducibly measured.
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated
lung.
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1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
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.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
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 below, 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.
2.1.1
Lymph nodes
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. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed.
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2.2
Non-target lesions
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’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION 
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.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
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. Nodes 
that have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed.
3.1.1.2
Target lesions that become ‘too small to measure’
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
•
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: in case of a lymph node believed to be present and 
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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).
3.1.1.3
Target 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.
•
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’
3.2
Evaluation of non-target lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s).
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subject also has measurable disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.
•
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status.
3.2.1.2
When the subject has only non-measurable disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.
•
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status.
•
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing subjects 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: i.e. an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
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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 subject should be considered to have had overall PD 
at that point. 
3.2.1.3
Tumor markers
Tumor markers will not be used to assess objective tumor responses.
3.3
New lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal: i.e. 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 subject’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 subject
who has visceral disease at baseline and while on study has a CT or MRI brain scan ordered which 
reveals metastases. The subject’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.
4
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline Table 1 provides a summary of the overall 
response status calculation at each time point.
Table 1.
Time point response: subjects 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
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Table 1.
Time point response: subjects with target (+/– non-target) 
disease.
Target lesions
Non-target lesions
New lesions
Overall response
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, NE =not evaluable.
4.1.1
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
4.1.2
Confirmation Scans
•
Verification of Response: Confirmation of PR and CR is required within 4 weeks to ensure 
responses identified are not the result of measurement error.
4.2
Best Overall Response: all time points
The best overall response is determined once all the data for the subject is known. It 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 subject’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions.
Best response is defined as the best response across all time points with subsequent confirmation. 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later).
In this circumstance, the best overall response can be interpreted as specified in Table 2. When SD 
is believed to be best response, it must meet the protocol specified minimum time from baseline.
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Measurements must have met the SD criteria at least once after study entry at a minimum interval 
(in general not less than 6–8 weeks) that is defined in the study protocol.
Table 2.
Best overall response when confirmation of CR and PR IS required.
Overall 
response
Overall response
BEST overall response
First time 
point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable.
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 subject 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.
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4.3
Duration of response
4.3.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
4.3.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
Eisenhauer et al.  New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1).  European Journal of Cancer.  2009.  Vol 45, p 228-247.
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APPENDIX 4
HEAD AND NECK SQUAMOUS CELL CARCINOMAS 
CLASSIFICATIONS
Head and neck squamous cell carcinomas will be classified as follows:
•
oral cavity: 
−
anterior two-thirds of the tongue 
−
tongue unspecified 
−
lip 
−
gum 
−
floor of the mouth 
−
hard palate 
−
palate unspecified
−
other oral cavity (including buccal mucosa and retromolar area)
−
oral cavity unspecified 
•
oropharynx: 
−
base of the tongue 
−
soft palate 
−
tonsil 
−
uvula 
−
other parts of the oropharynx 
−
Waldeyer’s ring   
−
oropharynx unspecified
•
larynx: 
−
glottis
−
supraglottis
−
subglottis 
−
other and unspecified larynx subsites 
−
hypopharynx cases are classified as belonging to the larynx, including pyriform sinus
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APPENDIX 5
CHILD-PUGH SCORE
Score
Points
Child-Pugh A
5 - 6
Child-Pugh B
7 - 9
Child-Pugh C
> 9
Scoring
Score
Measure
1 Point
2 Points
3 Points
Ascites
Absent
Slight
Moderate
Serum bilirubin (mg/dl)
< 2.0
2.0 - 3.0
> 3.0
Serum albumin (g/dl)
> 3.5
2.8 - 3.5
< 2.8
PT prolongation
or INR
< 4 sec
< 1.7
4 - 6 sec
1.7 - 2.3
> 6 sec
> 2.3
Encephalopathy grade
None
1 - 2
3 - 4
Encephalopathy Grading
Encephalopathy
Grade
Clinical Definition
Grade 0
Normal consciousness, personality, and neurological examination
Grade 1
Restless, sleep disturbed, irritable/agitated, tremor, and impaired 
handwriting
Grade 2
Lethargic, time-disoriented, inappropriate, asterixis, and ataxia
Grade 3
Somnolent, stuporous, place-disoriented, hyperactive reflexes, and 
rigidity
Grade 4
Unrousable coma, no personality/behavior, decerebrate
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APPENDIX 6
GUIDANCE ON CONTRACEPTION
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. Male subjects must inform 
their female partners who are WOCBP of the contraceptive requirements of the protocol and are
expected to adhere to using contraception with their partner.
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
For WOCBP
Highly effective methods of birth control include the following:
•
Progestogen only hormonal contraception associated with inhibition of ovulation
•
Hormonal methods of contraception including oral contraceptive pills
•
(combination of estrogen and progesterone), vaginal ring, injectables, or implants
•
Intrauterine devices (IUDs) (hormonal or non-hormonal)
•
Intrauterine Hormone-releasing System (IUS)
•
Bilateral tubal ligation
•
Vasectomy
•
Complete abstinence (complete avoidance of heterosexual intercourse
For male subjects with partners that are WOCBP
•
Condom
All male subjects who have partners who are WOCBP must use condoms as their second method 
of contraception.
In countries where spermicide is not available or its use is not considered compatible with male 
condoms, use of a male condom without spermicide in conjunction with a hormonal method, 
IUD, or tubal ligation will be acceptable to fulfill this recommendation.  Any barrier method 
when used alone (without spermicide) or the concomitant use of a female and male condom, is 
not considered a sufficient method of contraception, as each carries a failure rate of >1%.
Women of childbearing potential (WOCBP) receiving BMS-936558 (nivolumab) will be 
instructed to adhere to contraception for the duration of study treatment with nivolumab and 
5 months after the last dose of study drug (ie, 30 days [duration of ovulatory cycle] plus the time 
required for the study drug to undergo approximately 5 half-lives). Men receiving nivolumab and 
who are sexually active with WOCBP will be instructed to adhere to contraception for the 
duration of study treatment with nivolumab and 7 months after the last dose of study drug 
(ie, 90 days [duration of sperm turnover] plus the time required for the study drug to undergo 
approximately 5 half-lives.)
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APPENDIX 7
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS1
Grade
ECOG
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care 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
                                                       
1 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;5:649-55.
Revised Protocol No.: 12
Date: 08-May-2018
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SAP_001.pdf: 
Official Title of Study: 
A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or Lirilumab 
Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors 
NCT Number: NCT01714739 
Document Date (Date in which document was last revised): August 24, 2020 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 1/2 STUDY OF THE COMBINATION OF LIRILUMAB (ANTI-KIR) PLUS 
NIVOLUMAB (ANTI-PD-1) OR LIRILUMAB PLUS NIVOLUMAB AND IPILIMUMAB IN 
ADVANCED REFRACTORY SOLID TUMORS
PROTOCOL(S) CA223001
VERSION # 2.1
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................7
1
BACKGROUND AND RATIONALE......................................................................8
1.1
Study Rationale ......................................................................................................14
1.1.1
Rationale for the Dose Escalation and Cohort Expansion (Part 1; 
Completed) and the SCCHN Cohort Expansion (Part 2; Completed)......................14
1.1.2
Rationale for the SCCHN Randomized Cohorts (Part 3).........................................15
1.1.3
Rationale for the Signal Detection Cohort Expansion (Part 4)................................16
1.1.4
Rationale for the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5 - closed to enrollment) and the Signal 
Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6 - removed)...........................................................16
1.1.4.1
Experience with Nivolumab and Ipilimumab Combination Treatment.....................18
1.2
Research Hypothesis:..............................................................................................20
1.2.1
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed) .....................................................20
1.2.2
The SCCHN Randomized Cohorts (Part 3 - Closed to enrollment)..........................20
1.2.3
The Signal Detection Cohort Expansion (Part 4) ....................................................20
1.2.4
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5 - Closed to enrollment) ..........................................................20
1.2.5
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .................................................20
1.3
Schedule of Analyses:.............................................................................................20
2
STUDY DESCRIPTION ........................................................................................21
2.1
Study Design ..........................................................................................................21
2.1.1
The Dose Escalation and Cohort Expansion (Part 1; Completed)...........................24
2.1.1.1
Dose Escalation (Completed)..................................................................................25
2.1.1.2
Cohort Expansion (Completed)...............................................................................26
2.1.2
The SCCHN Cohort Expansion (Part 2; Completed)...............................................28
2.1.3
The SCCHN Randomized Cohorts (Part 3 closed to enrollment).............................29
2.1.4
The Signal Detection Cohort Expansion (Part 4) ....................................................31
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2.1.5
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5 - closed to enrollment)...........................................................32
2.1.6
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6) .................................................36
2.2
Treatment Assignment............................................................................................36
2.3
Blinding and Unblinding.........................................................................................37
2.4
Protocol Amendments.............................................................................................38
2.5
Data Monitoring Committee ...................................................................................38
3
OBJECTIVES ........................................................................................................38
3.1
Primary Objective...................................................................................................38
3.1.1
Primary Objective for the Dose Escalation and Cohort Expansion (Part 1; 
Completed) and the SCCHN Cohort Expansion (Part 2; Completed)......................38
3.1.2
Primary Objective for the SCCHN Randomized Cohorts (Part 3 - closed to 
enrollment).............................................................................................................38
3.1.3
Primary Objective for the Signal Detection Cohort Expansion (Part 4) ..................38
3.1.4
Primary Objective for the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5 - closed to enrollment)...............38
3.1.5
Primary Objective for the Signal Detection in Previously Untreated MEL 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6).........................38
3.2
Secondary Objectives .............................................................................................39
3.2.1
Secondary Objectives for the Dose Escalation and Cohort Expansion (Part 1; 
Completed) and the SCCHN Cohort Expansion (Part 2; Completed)......................39
3.2.2
Secondary Objectives for the SCCHN Randomized Cohorts (Part 3 - closed 
to enrollment).........................................................................................................39
3.2.3
Secondary Objectives for the Signal Detection Cohort Expansion (Part 4) .............39
3.2.4
Secondary Objectives for the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5 - closed to enrollment)...............39
3.2.5
Secondary Objectives for the Signal Detection in Previously Untreated MEL 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6).........................40
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4
ENDPOINTS..........................................................................................................41
4.1
Primary Endpoints..................................................................................................41
4.2
Secondary Endpoints ..............................................................................................42
4.2.1
Preliminary Antitumor Activity...............................................................................42
4.2.1.1
Objective Response Rate (ORR)..............................................................................42
4.2.1.2
Median Time to Response (mTTR) ..........................................................................42
4.2.1.3
Median Duration of Response (mDOR)...................................................................42
4.2.1.4
Progression Free Survival Rate (PFSR)..................................................................43
4.2.2
Pharmacokinetic Endpoints....................................................................................46
4.2.3
Biomarker Endpoints..............................................................................................47
4.2.4
Immunogenicity ......................................................................................................47
5
SAMPLE SIZE AND POWER...............................................................................48
5.1
Dose Escalation (Part 1; Completed).......................................................................48
5.2
Cohort Expansion (Part 1; Completed)....................................................................48
5.3
The SCCHN Cohort Expansion (Part 2; Completed)...............................................49
5.4
The SCCHN Randomized Cohorts (Part 3).............................................................49
5.5
The Signal Detection Cohort Expansion (Part 4).....................................................49
5.6
The Signal Detection in First-line SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5) ...........................................................................49
5.7
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)..................................................49
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................49
6.1
Study Periods..........................................................................................................49
6.2
Treatment Regimens...............................................................................................50
6.3
Populations for Analyses ........................................................................................50
7
STATISTICAL ANALYSES..................................................................................50
7.1
General Methods ....................................................................................................50
7.2
Study Conduct........................................................................................................51
7.2.1
Study Information...................................................................................................51
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7.2.2
Accrual...................................................................................................................51
7.2.3
Relevant Protocol Deviations..................................................................................51
7.3
Study Population ....................................................................................................52
7.3.1
Subject Disposition.................................................................................................52
7.3.2
Demographic and Other Baseline Characteristics ..................................................53
7.4
Extent of Exposure .................................................................................................53
7.4.1
Study Therapy.........................................................................................................53
7.4.2
Modification of Study Therapy................................................................................54
7.4.3
Prior and Concomitant Medications .......................................................................54
7.5
Efficacy..................................................................................................................54
7.6
Safety.....................................................................................................................55
7.6.1
Adverse Events .......................................................................................................56
7.6.2
Deaths ....................................................................................................................56
7.6.3
Serious Adverse Events...........................................................................................56
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy.................................57
7.6.5
Select Adverse Events .............................................................................................57
7.6.6
Immune-Mediated Adverse Events ..........................................................................57
7.6.7
Multiple Events.......................................................................................................57
7.6.8
Clinical Laboratory Evaluations.............................................................................58
7.6.8.1
Abnormal Thyroid Test...........................................................................................58
7.6.8.2
Vital Signs and Other Safety Evaluation .................................................................59
7.6.8.3
Physical Examination Findings...............................................................................59
7.7
Pharmacokinetics....................................................................................................59
7.8
Immunogenicity (ADA)..........................................................................................60
7.9
Biomarkers .............................................................................................................61
8
CONVENTIONS....................................................................................................61
8.1
Pharmacokinetic Summaries...................................................................................61
9
CONTENT OF REPORTS .....................................................................................62
10
CONVENTION FOR SELECT AES AND IMAES DATA ANALYSIS ................62
11
DOCUMENT HISTORY........................................................................................64
12
REFERENCES.......................................................................................................64
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LIST OF TABLES
Table 2.1.1.1-1:
Dosages During Dose Escalation ............................................................26
Table 2.1.1.2-1:
Table 3.1.1.21:Tumor Types Eligible for Cohort Expansion ...................27
Table 2.1.1.2-2:
Table 3.1.1.22:Cohort Expansion Sample Sizes by n of Responses 
in Stage I for CRC, SCCHN, and HCC Tumors......................................27
Table 4.2.1.4-1:
Censoring Scheme for PFS.....................................................................43
Table 4.2.2-1:
PK Parameters, Naming Conventions and Definitions ............................46
Table 10-1:
Derivation of clustered AE .....................................................................63
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LIST OF FIGURES
Figure 1-1:
Anti-PD-1 and Anti-Ly49C/I (5E6 F(ab’)2) in MC38 Murine Colon 
Carcinoma Model...................................................................................12
Figure 2.1-1:
Overall Study Design for All Study Arms (Study CA223001) ................23
Figure 2.1.1-1:
Study Period Schematic for the Dose Escalation and Cohort 
Expansion (Part 1; Completed)...............................................................25
Figure 2.1.2-1:
Study Period Schematic for Part 2 (Completed)......................................29
Figure 2.1.3-1:
Study Design Schematic for the SCCHN Randomized Cohorts 
(Part 3) ...................................................................................................31
Figure 2.1.3-2:
Study Period Schematic for the SCCHN Randomized Cohorts (Part 
3)............................................................................................................31
Figure 2.1.5-1:
Study Schematic for the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) ................34
Figure 2.1.5-2:
Study Period Schematic for the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5) ................35
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1
BACKGROUND AND RATIONALE
Lirilumab (BMS-986015) is a fully human monoclonal antibody that is designed to act as a 
checkpoint inhibitor by blocking the interaction between killer cell immunoglobulin-like receptor 
(KIR)2DL-1,-2,-3 inhibitory receptors and their ligands facilitating activation of natural killer 
(NK) cells and, potentially some subsets of T cells, ultimately leading to anti-tumor activity.
The Dose Escalation and Cohort Expansion (Part 1) and the squamous cell carcinoma of the head 
and neck (SCCHN) Cohort Expansion (Part 2) have both completed enrollment and are not 
applicable starting with Amendment 13 and all subsequent amendments. For preliminary safety 
and efficacy results, see Section 1 “Clinical Experience with Lirilumab and Nivolumab 
Combination Treatment” of the protocol body.
At the time of Amendment 13, preliminary data from an initial cohort of subjects in 
Study CA223001 suggested a signal of potential efficacy in in recurrent or metastatic SCCHN 
subjects with disease progression on or after platinum-based therapy. Specifically, preliminary 
data in 29 evaluable subjects treated with the combination of lirilumab plus nivolumab showed an 
objective response rate (ORR) of 24% (7/29) in the all-comer population and an ORR of 41% 
(7/17) in the programmed cell death ligand 1 positive (PD-L1+) population.1. Whereas, nivolumab 
monotherapy, in a similar population of patients with previously treated SCCHN, showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥1% 
programmed cell death ligand 1 (PD-L1) expression. 2 Preliminary data also indicated the 
combination of lirilumab plus nivolumab is safe, with the addition of lirilumab to nivolumab 
adding little additional toxicity to that typically observed with nivolumab alone. Based on these 
results, the protocol was revised to add additional cohorts (Parts 3-6; see description in Section 3.1 
of the protocol).
Subsequent efficacy analysis of additional recurrent or metastatic SCCHN subjects with disease 
progression on or after platinum-based therapy treated with the combination of lirilumab and 
nivolumab did not demonstrate a differential efficacy signal as compared to nivolumab 
monotherapy treatment in a similar population of SCCHN subjects. Based on the review of these 
data, Revised Protocol 12 will implement the following:
•
Enrollment permanently closed in Part 3, a single-blinded, placebo-controlled, randomized 
cohort expansion of lirilumab in combination with nivolumab vs nivolumab monotherapy 
in subjects with platinum-refractory recurrent or metastatic SCCHN who are PD-L1+.
•
Removal of Part 4, a signal detection cohort expansion of nivolumab and lirilumab at a flat 
dose in subjects with sqNSCLC, ESCC, BC, and other squamous histologies and in 
subjects with SCCHN who have received prior PD-1/PD-L1 directed therapy. No subjects 
were enrolled.
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•
Enrollment permanently closed in Part 5, a safety and signal detection with a triplet
regimen of lirilumab in combination with nivolumab and ipilimumab in subjects with 
platinum-refractory recurrent or metastatic SCCHN.
•
Removal of Part 6, a safety and signal detection with a triplet regimen of lirilumab in 
combination with nivolumab and ipilimumab in subjects with previously untreated 
metastatic melanoma. No subjects were enrolled.
•
Removal of overall survival visits for all subjects, select sample collection and study visits, 
additional subjects entering treatment beyond progression and retreatment at the time of 
disease progression.
•
All subjects will be permitted a maximum of up to 2 years of treatment as specified in the 
individual study parts.
Background of NK Cells and KIR in Inflamed Tumors
An analysis of the immune infiltration in a large cohort of head and neck tumors, integrating 
genetic data with RNA-seq–based deconvolution of immune cell populations and 
effector/regulatory molecules was done3 and found that SCCHN is one of the most highly immune-
infiltrated cancer types, and in fact, the most highly NK cell– and Treg-infiltrated cancer type. 
These tumors are poised to benefit from immunotherapy that includes Treg and NK checkpoint-
targeted approaches that may have unique applicability in head and neck cancer.
Analysis of the levels of NK-cell infiltration in SCCHN showed that the CD56bright subpopulation 
is predominantly found in lymph nodes and peripheral blood and believed to be the likely precursor 
to CD56dim cells, which are far more cytotoxic and play a critical role in antitumor immunity.4
Strikingly, SCCHN tumors had the numerically highest levels of infiltration with CD56dim NK 
cells, compared with other highly immune-infiltrated cancer types. CD56dim NK cells are inhibited 
by KIRs, which are absent on CD56bright NK cells. CD56dim NK-cell infiltration correlated 
strongly with overexpression of the KIR inhibitory receptor genes KIR2DL1 and KIR2DL3. These 
data suggest that SCCHN tumors are prime candidates for trials of anti-KIR antibodies.
It has been shown that there are high levels of immunoregulatory influence in SCCHNs, which 
harbor the highest levels of Treg infiltration and the highest Treg/CD8+ T-cell ratio across all 
cancers, suggesting that these tumors are poised to respond to immunotherapeutic modalities that 
relieve inhibitory pathways. Treg function and proliferation rely on a number of targetable 
pathways. CTLA-4 is highly constitutively expressed on Tregs. Its activation is necessary for Treg 
function and proliferation. CTLA-4 inhibitors have clearly been shown to promote antitumor 
immunity in MEL. Blockade of the CTLA-4 receptor on activated Tregs may therefore dampen 
the immunosuppressive function of these cells in head and neck tumors. A growing body of 
evidence suggests that CTLA-4 blockade does, in some contexts, repress Treg function and 
accumulation in the tumor microenvironment.
Analysis of immune-cell infiltration and levels of immune activation in other highly inflamed 
cancer types, namely MEL, prostate, kidney clear cell, cervical/endometrial, sqNSCLC, adeno 
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NSCLC, breast, bladder, and thyroid5 showed that the levels of CD56bright NK-cell infiltration was 
predominantly found in lymph nodes and peripheral blood and is believed to be the likely precursor 
to CD56dim cells, which are far more cytotoxic and play a critical role in antitumor immunity.
Taken together, these data reveal that inflamed tumors such as SCCHN and MEL are infiltrated 
with Tregs and KIR-overexpressing CD56dim NK cells, to a higher degree than other cancer types. 
These findings suggest these tumors possess an immune landscape that is poised to respond to 
immunotherapeutic approaches that block inhibitory signals to T cells and NK cells. 
Background of Anti-KIR Antibody Lirilumab (BMS-986015)
Lirilumab binds specifically and with high affinity to subsets of KIRs (ie, KIR2DL1, -2, and -3 
and KIR2DS1 and -2), thus preventing the interaction between KIR and HLA-C. Therefore 
NK-cell activation is determined by the balance of activating (positive) and inhibitory (negative) 
receptor stimulation. Tumor cells are able to evade innate immunity through the interaction of KIR 
with HLA-C. By blocking this interaction, lirilumab facilitates the activation of NK cells and 
subsequent killing of the tumor cell. Blockade of inhibitory KIR by lirilumab is, thus, a promising 
mechanism to promote killing of tumor cells by the innate immune system.
Lirilumab is being studied as a potential immunotherapy alone and in combination with other 
agents in subjects with various hematologic malignancies and solid tumors. A total of 550 subjects 
have been treated with lirilumab across 5 studies as of 13-Jul-2017 assessing safety, 
pharmacokinetics (PK), biomarker modulation, and clinical activity. The first (Study CA223003, 
IPH2102-101) is a monotherapy, dose-escalation, Phase 1 trial to determine the safety and 
maximum tolerated dose (MTD) of BMS-986015 (IPH2102) and is completed. The second (Study 
CA223004, IPH2102-201) is a double-blind, placebo-controlled, Phase 2 trial of lirilumab 
evaluating the relapse-free survival in subjects with AML in complete remission but ineligible for 
allogeneic transplant and is completed. One-third of subjects in this study received placebo. The 
third (Study CA223001), fourth (Study CA223002), and fifth (Study CA223028) are Phase 1 (or 
Phase 1/2) trials of lirilumab in combination with the anti-PD-1 antibody nivolumab (Study 
CA223001), the anti-CTLA-4 antibody ipilimumab (Study CA223002), and the Signaling 
Lymphocytic Activation Molecule Family Member 7 antibody elotuzumab (Study CA223028) 
were initiated to determine if coordinate modulation of the innate and adaptive immune systems 
results in greater clinical benefit. Study CA223002 was terminated early, Study CA223028 is 
completed and study CA223001 is ongoing.
The majority of adverse events (AEs) in these 5 trials were mild or moderate (Grade 1 or 2), 
self-limiting, and manageable. The most common related AEs in the monotherapy trials were 
asthenia, bronchitis, diarrhea, headache, fatigue, pruritus, and thrombocytopenia. The most 
common related AEs in the combination trials were fatigue, infusion-related reaction, pruritus, 
rash, nausea, chills, diarrhea, rash maculo-papular, and pyrexia. The data to date support a positive 
safety profile of lirilumab.
Background of Nivolumab: Mechanism of Action
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Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.6 Collectively, these signals govern the 
balance between T-cell activation and tolerance.
PD-1 is a member of the cluster of differentiation (CD) 28 family of T-cell co-stimulatory 
receptors, which also include CD28, CTLA-4, inducible T-cell co-stimulator (ICOS), and B- and 
T-lymphocyte attenuator (BTLA).7 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of interleukin (IL)-2, IL-10, IL-13, interferon-gamma (IFN-γ), and B-cell lymphoma-
extra large. PD-1 expression has also been noted to inhibit T-cell activation and expansion of 
previously activated cells. Evidence for a negative regulatory role of PD-1 comes from studies of 
PD-1-deficient mice, which develop a variety of autoimmune phenotypes.8 These results suggest 
that PD-1 blockade has the potential to activate anti-self T-cell responses, but these responses are 
variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is 
not accompanied by a universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (concentration required for 
50% efficacy [EC50]: 0.39 to 2.62 nM) and inhibits the binding of PD-1 to its ligands PD-L1 and 
programmed cell death ligand 2 (PD-L2) (concentration required for 50% inhibition 
[IC50] ± 1 nM). Nivolumab binds specifically to PD-1 and not to related members of the CD28 
family such as CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 pathway by nivolumab 
results in a reproducible enhancement of both proliferation and IFN-γ release in the mixed 
lymphocyte reaction. Using a cytomegalovirus (CMV) re-stimulation assay with human peripheral 
blood mononuclear cell (PBMC), the effect of nivolumab on antigen-specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV-specific memory T cells in a 
dose-dependent manner vs isotype-matched control. In vivo blockade of PD-1 by a murine analog 
of nivolumab enhances the anti-tumor immune response and results in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).9
Pre-clinical Results Utilizing Murine Anti-PD-1 and Anti-KIR Antibodies
Pre-clinical studies tested the hypothesis that the combination of anti-KIR and anti-PD-1 would 
potentiate anti-tumor efficacy in a murine solid tumor model. Both nivolumab (human anti-PD-1 
antibody) and lirilumab recognize only human sequences. Thus, a murine-specific PD-1 antibody 
and anti-Ly49 antibody, an F(ab)2 that recognizes Ly49C/I, which is the KIR homologue in mice, 
were used to test this hypothesis. Mice were injected with the syngeneic MC38 murine colon 
carcinoma cell line and, following the formation of palpable tumors, they were randomized to 1 of 
4 cohorts to receive control IgG, anti-Ly49 antibody, anti-PD-1 antibody, or both antibodies. Mice 
treated with a control IgG antibody had rapid growth of tumors (upper left panel of Figure 1-1). 
Mice treated with anti-Ly49 antibody (lower left panel of Figure 1-1) did not differ significantly 
from control animals. Those treated with a murine anti-PD-1 antibody (upper right panel of
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Figure 1-1) showed latency in tumor progression, and 30% of mice continued to be free of tumor. 
Those treated with both antibodies (lower right panel of Figure 1-1) also had latency in tumor 
progression and 60% of mice continued to be free of tumor.
Figure 1-1:
Anti-PD-1 and Anti-Ly49C/I (5E6 F(ab’)2) in MC38 Murine Colon 
Carcinoma Model
Female C57BL/6 mice were injected subcutaneously with 2e6 (2 × 106) MC38 tumor cells. After randomization of 
animals, treatments began 7 days later. Mice were treated intraperitoneally on Days 7, 10, and 14 with control mAb, 
anti-PD-1, and/or anti-Ly49C/I (5E6 F[ab’]2). Animals receiving anti-Ly49C/I (5E6 F[ab’]2) were dosed 
additionally on Days 17, 21, and 24. Tumor measurements were taken twice weekly. Shown here are data from 
individual animals.
Fab = fragment antigen-binding; mAb = monoclonal antibody; mIgG = murine immunoglobulin; TF = tumor free.
These results provide pre-clinical evidence of the additive benefit of anti-KIR antibody to 
potentiate the efficacy of an anti-PD-1 antibody in a murine solid tumor model. 
Clinical Experience with Lirilumab and Nivolumab Combination Treatment 
As of 13-Jul-2017, a total of 322 subjects have been treated with the combination of lirilumab and 
nivolumab in the current study (Study CA223001). AEs evaluated as related to the combination of 
lirilumab and nivolumab were reported in 217 (67.4%) exposed subjects. The most common 
related AEs reported in > 10% subjects were fatigue, 62 (19.3%) subjects; and pruritus, 43 (13.4%) 
subjects; infusion-related reaction, 43 (13.4%) subjects each. Thirty-six (11.2%) subjects reported 
a related Grade 3 or 4 event. Lipase increased were reported in 5 (1.6%) subjects and amylase 
increased, aspartate aminotransferase increased, and infusion related reaction were reported in 4 
(1.2%) subjects each. There were no related Grade 5 events reported. Fourteen (4.3%) subjects 
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reported related events leading to study discontinuation. With continued enrollment and follow-up 
of treated subjects, no new safety signals have been identified.
At the time of Amendment 13, preliminary data from an initial cohort of subjects in 
Study CA223001 suggested a signal of potential efficacy in recurrent or metastatic SCCHN 
subjects with disease progression on or after platinum-based therapy. Specifically, preliminary 
data in 29 evaluable subjects treated with the combination of lirilumab plus nivolumab showed an 
ORR of 24% (7/29) in the all-comer population and an ORR of 41% (7/17) in the PD-L1+ 
population.1 No responses (0/12) were observed in the PD-L1 negative population. To put into 
context nivolumab monotherapy in a similar population of patients with previously treated 
SCCHN (recently approved by the US FDA for the treatment of patients with recurrent or 
metastatic SCCHN with disease progression on or after platinum-based therapy) showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥1% 
PD-L1 expression.2 Also of note, in 5 out of the 7 lirilumab plus nivolumab responders, the 
reduction in tumor burden was substantial, exceeding greater than 80%.1 Responses appeared 
durable, with the median DOR not reached.
Subsequent efficacy analysis of additional SCCHN subjects treated with the combination of
lirilumab and nivolumab did not demonstrate a differential efficacy signal as compared to
nivolumab monotherapy treatment in a similar population of SCCHN subjects. Efficacy
parameters analyzed included ORR regardless of tumor PD-L1 status, ORR in PD-L1+ population,
median PFS and median duration of responses.
Background: Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 Ig 
superfamily that competes with CD28 for B7. CTLA-4-mediated signals are inhibitory and turn 
off T-cell-dependent immune responses.10 Ipilimumab is a fully human monoclonal IgG1κ that 
binds to the CTLA-4 antigen expressed on a subset of T cells from human and non-human 
primates. The proposed mechanism of action for ipilimumab is interference of the interaction of 
CTLA-4 with B7 molecules on antigen-presenting cells, with subsequent blockade of the 
inhibitory modulation of T-cell activation promoted by the CTLA-4/B7 interaction.
Background: Anti-KIR Antibody in Combination with Anti-CTLA-4 Antibodies
Pre-clinical studies tested the hypothesis that the combination of anti-KIR and anti-CTLA-4 
antibodies would potentiate anti-tumor efficacy in a murine AML model. Both lirilumab and 
ipilimumab (human anti-CTLA-4 antibody) recognize only human receptors. Thus, a 
murine-specific anti-CTLA-4 antibody and anti-Ly49C/I (5E6 F(ab’)2) were used to test this 
hypothesis. Mice were infused with the murine leukemia C1498 cell line and randomized to 
1 of 4 cohorts to receive control immunoglobulin (Ig)G antibody, anti-CTLA-4 monoclonal 
antibody, anti-Ly49C/I (5E6 F(ab’)2), or both anti-CTLA-4 monoclonal antibody and 
anti-Ly49C/I (5E6 F(ab’)2). Mice treated with control antibody had a median survival of 25.5 days. 
Mice treated with anti-CTLA-4 did not differ significantly from control animals (median 
26.0 days, P = 0.37). Those treated with anti-Ly49C/I (5E6 F(ab’)2) had prolonged survival 
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(median 27.0 days, P = 0.016). Those treated with both antibodies had further prolonged survival 
(median 29.5 days, P < 0.001). It is possible that the combination of the 2 antibodies has a more 
potent effect than either alone. However, the difference in survival between anti-Ly49C/I (5E6 
F(ab’)2) alone and both antibodies (27.0 days vs 29.5 days, respectively) did not reach statistical 
significance (P = 0.17). It is possible that a prolonged dosing schedule will yield more robust 
results, and that this combination of antibodies will be efficacious in other cancer models. These 
results provide pre-clinical evidence of the benefit of an anti-KIR antibody to potentiate the 
efficacy of an anti-CTLA-4 antibody in a murine AML model.11
Clinical Experience with Lirilumab and Ipilimumab Combination Treatment
CA223002 was primarily designed to evaluate the safety, tolerability, and MTD of lirilumab, an 
anti-KIR monoclonal antibody, when administered in combination with an approved dose of 
ipilimumab in subjects with select advanced tumors. The study was to be conducted in 2 parts, 
with a dose-escalation phase followed by a dose-expansion phase. During the dose-escalation 
phase, subjects received BMS-986015 (0.1, 0.3, 1, or 3 mg/kg) and ipilimumab (3 mg/kg) as 
Induction therapy (every 3 weeks [Q3W] for 4 doses) and then Maintenance therapy (every 
12 weeks [Q12W] for 4 doses) for a total of up to 1.4 years of therapy. 
During the conduct of the dose-escalation phase, the study was terminated for business reasons 
that were unrelated to any AEs associated with the use of lirilumab in this or any other ongoing 
clinical study. No further subjects were enrolled after termination of the study, but subjects already 
receiving treatment in the study were permitted to complete treatment and clinical follow-up as 
per protocol. This report presents results of the evaluation of safety and tolerability (the primary 
objective), as well as preliminary anti-tumor activity (a secondary objective). 
AEs were reported for all 22 (100%) of the subjects treated in this study. The most frequently 
reported AEs (> 25% of all treated subjects) were fatigue (45.5%), nausea (40.9%), malignant 
neoplasm progression (36.4%), back pain (27.3%), diarrhea (27.3%), pneumonia (27.3%), pyrexia 
(27.3%), and vomiting (27.3%). There were no apparent dose-related trends in the occurrence of 
any AEs. Of the 16 subjects for whom best overall response (BOR) was evaluable, 3 subjects had 
a partial response, 5 subjects had stable disease (SD), and 8 subjects had progressive disease (PD). 
In conclusion, lirilumab was generally well tolerated when administered at doses of 0.1 to 1 mg/kg 
in combination with an approved dose of ipilimumab (3 mg/kg) in subjects with advanced or 
metastatic solid tumors.12
To date, the cumulative safety data support a manageable safety profile for lirilumab that is 
consistent with the profile of other immunotherapies.
1.1
Study Rationale
1.1.1
Rationale for the Dose Escalation and Cohort Expansion (Part 1; 
Completed) and the SCCHN Cohort Expansion (Part 2; Completed)
Anti-PD-1 monoclonal antibody (nivolumab) is an activator of T-cell responsiveness (ie, adaptive 
immunity) and has demonstrated activity in clinical studies for subjects with refractory and 
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metastatic solid tumors, including NSCLC, renal cell carcinoma (RCC), MEL, and possibly other 
tumor types. The safety profile of this agent is tolerable. KIR plays an important role in regulating 
NK-cell activation, and diminution of KIR function is likely to potentiate the innate immune 
response. Lirilumab is a fully human anti-KIR monoclonal antibody that has shown minimal side 
effects in a Phase 1 study. The aim of this study is to coordinately potentiate adaptive and innate 
immunity to enhance the anti-tumor activity of anti-PD-1 antibody by the addition of an anti-KIR 
antibody in subjects with advanced solid tumors who currently have poor prognosis and limited 
treatment options. The Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort 
Expansion (Part 2) of this study will address the feasibility and safety and preliminary efficacy of 
the combined administration of lirilumab and nivolumab. The Dose Escalation and Cohort 
Expansion (Part 1) has completed enrollment, and the SCCHN Cohort Expansion (Part 2) 
of this study will close to enrollment as the SCCHN Randomized Cohorts (Part 3) opens.
1.1.2
Rationale for the SCCHN Randomized Cohorts (Part 3)
With Revised Protocol 12, enrollment in Part 3 is closed.
This cohort will formally assess the efficacy and safety of lirilumab and nivolumab combination 
therapy and nivolumab monotherapy in subjects with advanced or metastatic SCCHN in a 
randomized expansion. 
Head and neck cancers are among the most common cancers worldwide, accounting for more than 
550,000 cases and around 300,000 deaths each year13 and these trends are increasing. In the US, 
~48,330 new cases of oral cavity and pharynx cancer were reported; and ~9,570 people were 
predicted to die of this disease in 2016.14 About ~90% of all head and neck cancers are squamous 
cell. Most SCCHNs arise from the epithelial lining of the oral cavity, oropharynx, larynx, and 
hypopharynx. The most important risk factors identified in SCCHNs include tobacco and alcohol 
use, and in a subgroup of SCCHNs (particularly oropharynx tumors), human papilloma virus 
(HPV) is a strong independent prognostic factor.15 Metastatic and recurrent SCCHN that is no 
longer amenable to local surgical/radiation therapy causes substantial morbidity and high 
mortality, with a median progression-free survival (PFS) of < 6 months and median overall 
survival (OS) of less than 12 months.
Ongoing trials with immune checkpoint inhibitors in SCCHN have shown promising preliminary 
results. A 17.7% ORR has been observed in the ongoing KEYNOTE 012 (NCT01848834) clinical 
trial of 192 subjects with the recurrent/metastatic SCCHN treated with the anti-PD-1 agent 
pembrolizumab.16 Recently, nivolumab was approved by the US FDA for the treatment of patients 
with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. 
The approval was based on results from the Phase 3, CheckMate-141 trial in which nivolumab 
demonstrated statistically significant and clinically meaningful superior OS vs the comparator arm 
(the investigator’s choice of methotrexate, docetaxel, or cetuximab), with a 30% reduction in the 
risk of death (HR = 0.70 [95% CI: 0.53 to 0.92; P = 0.0101]).17 The median OS was 7.5 months 
(95% CI: 5.5 to 9.1) for nivolumab compared to 5.1 months (95% CI: 4.0 to 6.0) for the 
investigator’s choice.2,17 Despite this recent data, patients with recurrent or metastatic SCCHN are 
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a population with unmet medical need and combination immunotherapy agents remains an area of 
active clinical evaluation.
At the time of Amendment 13, preliminary data from an initial cohort of subjects in 
Study CA223001 suggested a signal of potential efficacy in recurrent or metastatic SCCHN
subjects with disease progression on or after platinum-based therapy. Specifically, preliminary 
data in 29 evaluable subjects treated with the combination of lirilumab plus nivolumab showed an 
ORR of 24% (7/29) in the all-comer population and an ORR of 41% (7/17) in the PD-L1+ 
population.1 No responses (0/12) were observed in the PD-L1 negative population. To put into 
context nivolumab monotherapy in a similar population of patients with previously treated 
SCCHN (recently approved by the US FDA for the treatment of patients with recurrent or 
metastatic SCCHN with disease progression on or after platinum-based therapy) showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥1% 
PD-L1 expression.2 Also of note, in 5 out of the 7 lirilumab plus nivolumab responders, the 
reduction in tumor burden was substantial, exceeding greater than 80%. Responses appeared 
durable, with the median DOR not reached. These results indicate lirilumab plus nivolumab may 
have clinically meaningful greater clinical activity than nivolumab alone, particularly in inflamed 
(PD-L1+) tumors and with little added toxicity.
Furthermore, lirilumab in combination with nivolumab has an acceptable safety profile in subjects 
with advanced refractory solid tumors. The safety profile associated with lirilumab in combination 
with nivolumab was generally consistent with that observed with nivolumab monotherapy. Overall 
treatment-related adverse events (TRAEs) was reported in 114 (72%) subjects, and Grade 3 to 4 
TRAEs were reported in 24 (15%) subjects. Discontinuations due to TRAEs occurred in 12 (8%) 
subjects.12
Evaluating lirilumab in combination with nivolumab in subjects with tumor PD-L1+, 
platinum-refractory SCCHN will potentially provide further treatment options for patients with a 
high unmet medical need.
1.1.3
Rationale for the Signal Detection Cohort Expansion (Part 4)
With Revised Protocol 12, Part 4 is removed.
1.1.4
Rationale for the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5 - closed to enrollment) and the 
Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6 - removed)
With Revised Protocol 12, Part 5 is closed to enrollment and Part 6 is removed.
The combination of nivolumab and ipilimumab has a well-established regimen and safety profile.
Nivolumab and ipilimumab clinical activity is well established in multiple tumor types including 
MEL and NSCLC and are described in Section 1.1.4.1. This combination continues to be evaluated 
in a range of tumor types including RCC, BC, SCCHN. 
The safety profile of nivolumab and ipilimumab is well characterized from a large safety database 
at different dose and schedules as monotherapy or in combination. Consistent with the mechanism 
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of action of nivolumab and ipilimumab, the most frequently reported drug-related AEs observed 
in clinical trials are those associated with activation of the immune system. The most common 
types of immune-mediated AEs include endocrinopathies, diarrhea/colitis, hepatitis, pneumonitis, 
nephritis, and rash. In the combination regimen, the frequency and intensity of these events may 
vary and will depend on the specific dose and schedule used. Study CA209012 evaluating multiple 
dose regimens of nivolumab in combination with ipilimumab showed numerically higher response 
rates in cohorts evaluating the approved dose of nivolumab 3 mg/kg and the safety of combination 
improved with the lower dose of ipilimumab, 1 mg/kg was given less frequently (Q6W or Q12W) 
(See Section 1.1.4.1). Therefore the combination dosing schedule selected for this study 
(nivolumab 3 mg/kg every 2 weeks [Q2W] plus ipilimumab 1 mg/kg every 6 weeks [Q6W]) 
utilizes the approved nivolumab dose and provides the highest dose and frequency of ipilimumab 
feasible in a combination regimen where the immune-mediated AEs were mostly low grade and 
manageable with prompt use of corticosteroids (see Section 1.1.4.1). 
Safety Profile of Lirilumab in Combination with Nivolumab and with Ipilimumab
Safety and preliminary efficacy of lirilumab in combination with nivolumab and ipilimumab have 
been described in Section 1 “Clinical Experience with Lirilumab and Ipilimumab Combination 
Treatment” and “Clinical Experience with Lirilumab and Nivolumab Combination Treatment.” To 
date, the cumulative safety data support a manageable safety profile for lirilumab in combination 
with nivolumab and ipilimumab that is consistent with the profile of other immunotherapies. 
Therefore, it is not expected that the addition of lirilumab will add additional toxicities to the 
known safety profile of nivolumab and ipilimumab.
As an additional safety measure, initially approximately 10 subjects will be enrolled and followed 
for at least 4 weeks of safety assessment from the start of study drug administration before 
additional subjects are enrolled in the study to ensure there is no major safety signal with the 
combination. Any findings will be discussed between the BMS Medical Monitor and investigators 
and an agreement will be reached as to whether a lower dose or an alternate dose schedule should 
be examined or whether any additional treatment guidelines should be implemented prior to 
enrollment of additional subjects on study.
Biological Rationale for the Combination of Lirilumab with Nivolumab and Ipilimumab
As described in Section 1 “Background of NK cells and KIR in Inflamed Tumors,” immune 
infiltrate analysis in the inflamed tumors such as SCCHN and MEL, show infiltration with Tregs 
and KIR-overexpressing CD56dim NK cells, to a higher degree than other cancer types. These 
findings suggest that head and neck tumors possess an immune landscape that is poised to respond 
to immunotherapeutic approaches that block inhibitory signals to T cells and NK cells, such as 
immune checkpoint inhibitors (nivolumab and ipilimumab), including antibodies blocking KIR 
signaling (lirilumab).
Therefore, the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5) will evaluate if the addition of ipilimumab, a Treg-targeted agent will 
enhance the efficacy seen with the combination of lirilumab and nivolumab in SCCHN. 
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1.1.4.1
Experience with Nivolumab and Ipilimumab Combination Treatment
Pre-clinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve anti-tumor 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 
anti-tumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer 
models. In a murine MEL 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 
Tregs, as compared to either agent alone.18
Clinical activity of nivolumab and ipilimumab combination was evaluated in subjects with 
stage IV non-squamous cell lung cancer (NSCLC) as first line treatment in CA209012 study.19
This was a large phase 1, multi-arm safety study of nivolumab monotherapy and nivolumab in 
combination with various systemic anticancer therapies like ipilimumab, platinum based 
chemotherapies and EGFR tyrosine kinase inhibitor.
The regimens for these cohorts were:
•
Arm N (n=31): nivolumab 1 mg/kg + ipilimumab 1 mg/kg Q3W for 4 cycles, followed by 
nivolumab 3 mg/kg Q2W
•
Arm O (n=40): nivolumab 1 mg/kg Q2W + ipilimumab 1 mg/kg Q6W
•
Arm P (n=38): nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q12W
•
Arm Q (n=39): nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W
The most frequently reported drug-related AEs in the newer nivolumab plus ipilimumab cohorts 
were fatigue (29.0%), diarrhea (25.0%), pruritus (23.7%), and fatigue (23.1%) in arms N, O, P, 
and Q, respectively. Drug-related SAEs reported in more than 2 subjects/cohort treated in the 
newer nivolumab plus ipilimumab cohorts were adrenal insufficiency, hypophysitis, pneumonitis, 
autoimmune hepatitis, diarrhea, colitis, and acute kidney injury. Drug-related Grade 3 to 4 AEs 
were reported in 9 (29.0%) subjects in Arm N, 16 (40.0%) subjects in Arm O, 14 (36.8%) subjects 
in Arm P, and 13 (33.3%) subjects in Arm Q. Drug-related AEs leading to discontinuation 
reported in more than 1 subject treated in the new nivolumab plus ipilimumab arms included 
alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, colitis, 
myalgia, pneumonitis, rash, autoimmune hepatitis, infusion-related reaction, facial nerve disorder, 
esophagitis, and transaminases increased. Most deaths in CA209012 were due to disease 
progression. The only deaths reported due to study drug toxicity were in the nivolumab + 
ipilimumab original treatment groups (respiratory failure following Grade 3 colitis, pulmonary 
hemorrhage, and toxic epidermal necrolysis in a subject with a history of ulcerative colitis). 
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Clinical activity was observed in all combination cohorts but numerically higher response rates 
were observed in cohorts evaluating the approved dose of nivolumab 3 mg/kg, with confirmed 
response rates ≥ 39% (cohorts P and Q).19 With comparable efficacy and safety data from cohorts 
P and Q, the nivolumab plus ipilimumab every 6 week (Q6W) dosing schedule (cohort Q) was the 
selected regimen moving forward.20 Aside from utilizing the approved nivolumab dose in NSCLC, 
it would also provide the highest dose and frequency of ipilimumab feasible in a combination 
regimen.
To date, there are no data on the combination of nivolumab and ipilimumab in SCCHN. CA209714 
and CA209651 are studies evaluating this combination of nivolumab 3 mg/kg Q2W and 
ipilimumab 1 mg/kg Q6W in SCCHN and are ongoing.
Given the similarity in patient profiles of NSCLC and SCCHN, and that nivolumab 3 mg/kg Q2W 
and ipilimumab 1 mg/kg Q6W have shown adequate safety and increased efficacy compared to 
single agent nivolumab in CA209012, our hypothesis is that we will see a similar effect in SCCHN. 
Given that the safety profile of lirilumab in combination with nivolumab (see Section 1 “Clinical 
Experience with Lirilumab and Nivolumab Combination Treatment” of the protocol body) and 
ipilimumab is not different as compared to nivolumab or ipilimumab monotherapy, respectively, 
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with the exception of infusion reactions, which were only Grade 1 and 2, easily manageable, and 
did not lead to discontinuations, it is not anticipated that the addition of lirilumab at 3 mg/kg every 
4 weeks (Q4W) to the combination of nivolumab 3 mg/kg Q2W and ipilimumab 1 mg/kg Q6W 
will increase the toxicity of the regimen.
Similarly, clinical activity of lirilumab when added to nivolumab plus ipilimumab has the potential 
to enhance the activity seen with nivolumab and ipilimumab in MEL. Nivolumab and ipilimumab 
in combination in subjects with previously untreated, unresectable or metastatic MEL evaluated in 
CA209067, a randomized Phase 3 study, demonstrated improved PFS; the median PFS was 11.5 
months (95% CI, 8.9 to 16.7) in the nivolumab-plus-ipilimumab group, 6.9 months (95% 
confidence interval [CI], 4.3 to 9.5) in the nivolumab group, and 2.9 months (95% CI, 2.8 to 3.4) 
in the ipilimumab group.
1.2
Research Hypothesis:
1.2.1
The Dose Escalation and Cohort Expansion (Part 1; Completed) and the 
SCCHN Cohort Expansion (Part 2; Completed)
It is anticipated that the combination of anti-KIR antibody (lirilumab) and anti-PD-1 antibody 
(nivolumab) will demonstrate adequate safety and tolerability at pharmacologically relevant doses 
and suggest preliminary signs of clinical activity so as to permit further clinical testing. 
1.2.2
The SCCHN Randomized Cohorts (Part 3 - Closed to enrollment)
It is anticipated that treatment with nivolumab alone or in combination with lirilumab will lead to 
clinically meaningful tumor reductions, as measured by ORR, in subjects with platinum-refractory 
recurrent or metastatic SCCHN who are PD-L1+. 
1.2.3
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
1.2.4
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - Closed to enrollment)
It is anticipated that the triplet regimen of anti-KIR antibody (lirilumab), anti-PD-1 antibody 
(nivolumab), and anti-CTLA-4 antibody (ipilimumab) to treat subjects with platinum-refractory 
recurrent or metastatic SCCHN will demonstrate adequate safety and tolerability at 
pharmacologically relevant doses for further clinical testing. 
1.2.5
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
1.3
Schedule of Analyses:
Data emerging from the unblinded parts of this study may be needed for timely decisions about 
adjustments to procedures in subsequent parts of the study. Therefore, data may be reviewed prior 
to the final lock of the study database. While the study is still ongoing, additional interim analyses 
may also be performed for administrative purposes or publications. In that case, analyses will only 
consist of listings, summaries, and graphs of the available data, and no formal inferences requiring 
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any adjustment to statistical significance level will be performed. Efficacy analyses based on 
interim data may use response-evaluable or all-treated populations depending on the purpose of 
the analysis. 
The Dose Escalation and Cohort Expansion (Part 1; completed) of the study is the dose-escalation 
study and includes expansion cohorts in specific tumor types. In the dose expansion portion of the 
Dose Escalation and Cohort Expansion (Part 1; completed), in order to assess if the target response 
rate is likely for tumor cohorts with unknown or low historic ORR, the tumor response will be 
initially based on the tumor measurements from the first approximately 9 subjects in each cohort 
to facilitate decisions on continuing enrollment in that tumor. If no responses are observed in 
approximately the first approximately 9 subjects with tumor measurements, enrollment in that 
tumor cohort will not continue. However, accrual to these tumor types may continue, while the 
Stage I response assessments are performed.
2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 1/2 study that will be conducted in 6 parts. A brief overview of the study parts 
follows below.
Please note that the Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort 
Expansion (Part 2) have both completed enrollment and are not applicable starting with 
Amendment 13 and all subsequent amendments. For preliminary safety results, see Section 1
“Clinical Experience with Lirilumab and Nivolumab Combination Treatment.” of the protocol 
body.
•
Part 1 (Completed): The Dose Escalation and Cohort Expansion of the study will consist of a 
dose escalation assessment of the safety and tolerability of lirilumab administered in 
combination with nivolumab in subjects with advanced solid tumors and 5 cohort expansions 
at either the MTD, maximum administered dose (MAD), or at an alternative dose as 
determined by the investigators and the Sponsor. 
•
Part 2 (Completed): The SCCHN Cohort Expansion will be an additional cohort expansion at 
Dose Level 4 in subjects with platinum-refractory recurrent or metastatic SCCHN. 
•
Part 3 (Closed to enrollment): The SCCHN Randomized Cohorts will involve a single-blinded,
placebo-controlled, randomized cohort expansion of lirilumab in combination with nivolumab 
vs nivolumab monotherapy in subjects with platinum-refractory recurrent or metastatic 
SCCHN who are PD-L1+. 
•
Part 4 (Removed): The Signal Detection Cohort Expansion will be an additional cohort 
expansion of nivolumab and lirilumab at a flat dose in subjects with sqNSCLC, ESCC, BC, 
and other squamous histologies (including squamous cell cancers of the skin, cervix, vulva, 
vagina, penis, anorectal and of unknown primary site) and in subjects with SCCHN who have 
received prior PD-1/PD-L1 directed therapy.
•
Part 5 (Closed to enrollment): The Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination will be an open-label safety and signal detection cohort with a 
triplet regimen of lirilumab in combination with nivolumab and ipilimumab in subjects with 
platinum-refractory recurrent or metastatic SCCHN.
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•
Part 6 (Removed): The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination will be a safety and signal detection cohort with a 
first-line triplet regimen of lirilumab in combination with nivolumab and ipilimumab in 
subjects with previously untreated metastatic MEL.
Subjects will not be allowed to crossover between any parts or allowed to crossover to other BMS 
studies, including CA209714 and CA209651 for SCCHN. 
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Figure 2.1-1:
Overall Study Design for All Study Arms (Study CA223001)
a
Treatment period is until PD, treatment discontinuation, or a maximum of up to 2 years of treatment as specified in the individual study parts, whichever occurs earlier.
b
Subjects must have PD-L1+ tumors. PD-L1+, defined as PD-L1 expressed in > 1% of tumor cells.
c
150 days from the last dose of study drug (± 5 days) or coinciding with the date of discontinuation of study drug (± 5 days) if date of discontinuation of study drug is greater than 150 days after last dose.
d
No longer required with Revised Protocol 12.
CRC=colorectal cancer; HCC=hepatocellular carcinoma; R=randomization.
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2.1.1
The Dose Escalation and Cohort Expansion (Part 1; Completed)
Subjects in the dose escalation and cohort expansion periods of the Dose Escalation and Cohort 
Expansion (Part 1) will complete up to 4 study periods: screening, treatment, clinical follow-up, 
and survival follow-up. Screening (up to 28 days). Treatment (up to maximum of 2 years). 
Clinical follow-up (150 days). Survival follow-up (up to 3 years following the first dose of study 
drug). Survival follow-up is no longer applicable with Revised Protocol 12 and no further visits
should be conducted. With revised protocol 12, the total time on study for any individual subject 
will not exceed approximately 2.5 years.
The treatment period will last up to twelve 8-week treatment cycles. For subjects receiving 
lirilumab and nivolumab combination therapy in the Dose Escalation and Cohort Expansion 
(Part 1), each treatment cycle is composed of 4 doses of nivolumab and 2 doses of lirilumab. 
Nivolumab will be administered on Days 1, 15, 29, and 43 of each treatment cycle, and lirilumab 
will be administered on Days 1 and 29 of each treatment cycle.
Following each treatment cycle (for all assigned treatments), the decision to treat a subject with 
additional cycles of study therapy will be based on tumor assessment (evaluation performed 
between Days 49 and 56 and completed before the first dose in the next cycle). Treatment decisions 
related to subject management will be based exclusively on irRECIST for the Dose Escalation and 
Cohort Expansion (Part 1) (see Section 1 of the protocol for the rationale and Appendix 2 of the 
protocol for definitions).
For the Dose Escalation and Cohort Expansion (Part 1), subjects with an overall response of irPD-
unconfirmed, irSD, irPR, or irCR-unconfirmed at the end of a given cycle will continue to the next 
treatment cycle. Subjects will generally be allowed to continue study therapy until the first 
occurrence of any of the following: 1) achievement of irCR-confirmed; 2) completion of 
12 cycles; 3) confirmation of irPD; 4) clinical deterioration suggesting that no further benefit from 
treatment is likely; 5) intolerability to therapy; or 6) meeting criteria for discontinuation of study 
therapy as outlined in Sections 3.5 and 4.9.5 of the protocol. 
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30, 
60, 100, and 150 to monitor for AEs.
A study schematic is presented below in Figure 2.1.1-1.
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Figure 2.1.1-1:
Study Period Schematic for the Dose Escalation and Cohort 
Expansion (Part 1; Completed)
a Survival follow-up no longer applicable with Revised Protocol 12
2.1.1.1
Dose Escalation (Completed)
A 3 + 3 + 3 design will be used to assess the safety of lirilumab given in combination with 
nivolumab. The dosages during dose escalation are provided in Table 2.1.1.1-1. The DLT 
observation period will last for 8 weeks or until the completion of Cycle 1, whichever is longer. 
Three subjects will be treated initially at each Dose Level. If 0 DLTs occur in a cohort of 3 subjects, 
a new cohort of 3 subjects will be treated at the next higher Dose Level. If 1 of 3 subjects 
experiences a DLT, that cohort will be expanded to 6 subjects. If 1 of 6 subjects experiences a 
DLT, a new cohort of 3 subjects will be treated at the next higher Dose Level. If 2 of 6 DLT 
subjects experience a DLT, that cohort will be expanded to 9 subjects. If 2 of 3, 3 of 6, or 3 of 9 
subjects experience DLTs within a cohort, then that Dose Level will be determined to have 
exceeded the MTD. If no MTD is reached through Cohort 4, then additional cohorts at lirilumab 
6 mg/kg and lirilumab 10 mg/kg, given in combination with nivolumab 3 mg/kg, may be 
considered based on the aggregate safety experience during dose escalation and in consultation 
and agreement between investigators and Sponsor via a protocol amendment.
After determining the MTD, MAD, or completion of dose escalation without identifying the MTD 
and to further explore pharmacodynamic/biomarker objectives, 3 to 12 additional subjects may be 
enrolled in each Dose Level for a total of up to 15 subjects at any Dose Level (original 3 to 
12 subjects from dose escalation plus additional subjects required to have a total cohort size of 15).
No intra-subject dose escalation or reduction is allowed. Subjects who withdraw from the study 
during the DLT period for reasons other than a DLT may be replaced within the same Dose Level. 
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For the purpose of making decisions on dose escalation from a safety perspective, subjects will be 
considered evaluable if they have received 3 out of the 4 scheduled nivolumab doses through the 
8-week observation period only if the 1 missed dose was secondary to non-medical reasons. In 
addition, subjects with dosing delays of ≥ 3 weeks in Cycle 1 for non-DLT events will be 
considered not evaluable for making decisions on dose escalation and should be replaced.
Dose escalation will be based on the number of DLTs experienced during Cycle 1.
The initial 6 subjects at each Dose Level will have peripheral blood evaluations for 
pharmacodynamic markers.
Table 2.1.1.1-1:
Dosages During Dose Escalation
Dose Level 
Number
Total Subjects a
Lirilumab 
(IV; mg/kg)
Nivolumab
(IV; mg/kg)
1
n = approximately 3 to 15
0.1
3
2
n = approximately 3 to 15
0.3
3
3
n = approximately 3 to 15
1
3
4
n = approximately 3 to 15
3
3
Total
n = approximately 12 to 60
a 3 to 12 subjects will be enrolled during dose escalation. Additional subjects may be added to each Dose Level after 
completion of the dose escalation period of the study for a total of up to 15 subjects per Dose Level.
All available clinical and laboratory data and the nature, time of onset, and time to resolution of 
DLTs observed during dose escalation will be reviewed to determine whether an alternative dose 
schedule should be examined after consultation between the investigators and the Sponsor, if 
needed. If agreed upon, the alternative schedule will be identified by a protocol amendment.
2.1.1.2
Cohort Expansion (Completed) 
The purpose of the cohort expansions is to gather additional safety, tolerability, preliminary 
efficacy, and pharmacodynamic information regarding the combination of lirilumab and 
nivolumab. Once the safety profile of all doses tested has been characterized and the MTD of 
combined administration of lirilumab and nivolumab has been defined, the cohort expansion will 
be initiated at the MTD, the MAD, or an alternate dose, if recommended by the investigators and 
the Sponsor. Treatment doses in the cohort expansion groups will not exceed the MAD. Five cohort 
expansions will be restricted to the tumor types listed in Table 2.1.1.2-1. The NSCLC and MEL 
cohorts, which have demonstrated activity with nivolumab monotherapy, will be used to assess 
increased activity of the combination therapy. The colorectal cancer (CRC), SCCHN, and 
hepatocellular carcinoma (HCC) cohorts will explore activity of the combination therapy in tumors 
with unknown or historically low responses to nivolumab monotherapy. Continuous evaluation of 
toxicity events in the cohort expansions will be performed throughout enrollment in the cohort 
expansions. If the rate of DLTs exceeds 33%, then the findings will be discussed and further 
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enrollment may be interrupted. If a cohort expansion is discontinued due to toxicity, a new cohort 
may be initiated at a previously tested lower Dose Level.
In each of the NSCLC and MEL cohorts, approximately 35 subjects will be enrolled to allow for 
a more precise estimate of the ORR in these tumors following combination treatment. The sample 
size for the other 3 cohorts will be guided by Gehan21 design. In order to determine if a target 
response rate (eg, 25 to 30%) is likely, an initial number of subjects (eg, 9) will be treated at first 
(Stage I) in a cohort, as outlined in Table 2.1.1.2-1. In the tumor cohort in which no responses are 
observed, it will be concluded that the true response rate is unlikely to be greater than or equal to 
the target rate and no more subjects will be enrolled in that cohort. Otherwise, in the cohorts in 
which at least 1 response among the Stage I subjects is observed, up to 9 additional subjects will 
be treated for a total of 18 subjects per tumor type, as guided by Table 2.1.1.2-2. In Stage I, 
approximately 9 subjects will be enrolled per tumor type. The number of subjects enrolled in Stage 
II per tumor cohort will be guided by the number of responders observed in Stage I and the required 
precision of the ORR estimate. This is summarized in Table 2.1.1.2-2 below, using a precision of 
12% around the ORR point estimate.
Table 2.1.1.2-1:
Table 3.1.1.21:Tumor Types Eligible for Cohort Expansion
Tumor Type
Stage I Subjects
Stage II Subjects
Total Subjects
NSCLC
N/A
N/A
Approx. 35
MEL
N/A
N/A
Approx. 35
CRC
9
4 to 9
Approx. 9 to 18
SCCHN
9
4 to 9
Approx. 9 to 18
HCC
9
4 to 9
Approx. 9 to 19
Totals
Approx. 97 to 124
Approx. = approximately; N/A = not applicable.
The actual sample size per cohort in Stage II to achieve desired precision (standard error) of 12% 
for the ORR estimate, as guided by the Gehan design, depends on the number of responses 
observed in Stage I (see Table 2.1.1.2-2), assuming a target ORR of 25% to 30%. 
Table 2.1.1.2-2:
Table 3.1.1.22:Cohort Expansion Sample Sizes by n of Responses in 
Stage I for CRC, SCCHN, and HCC Tumors
Stage I Number of Responses 
in the First 9 Subjects
Stage II n a
Total n/Cohort 
0
0
9
1
4
13
2
8
17
3
9
18
4
8
17
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Table 2.1.1.2-2:
Table 3.1.1.22:Cohort Expansion Sample Sizes by n of Responses in 
Stage I for CRC, SCCHN, and HCC Tumors
Stage I Number of Responses 
in the First 9 Subjects
Stage II n a
Total n/Cohort 
5
5
14
6
0
9
a Based on 12% precision for the ORR estimates and a target ORR of 25% to 30%.
2.1.2
The SCCHN Cohort Expansion (Part 2; Completed)
To further explore emerging efficacy and safety data in subjects with SCCHN; an additional cohort 
of approximately 35 subjects will be treated at Dose Level 4. The null hypothesis that the true 
ORR is 25% will be tested against a one-sided alternative: ORR = 40%. The null hypothesis will 
be rejected if 12 or more responses are observed in 35 subjects. This design gives a 1-sided type I 
error rate of 0.15 and a power of 0.81. 
Subjects will complete up to 4 study periods: screening, treatment, clinical follow-up, and survival 
follow-up. Screening (up to 28 days). Treatment (up to maximum of 2 years). Clinical follow-
up (150 days). Survival follow-up (up to 3 years following the first dose of study drug). Survival 
follow-up is no longer applicable with Revised Protocol 12 and no further visits should be 
conducted. With revised protocol 12, the total time on study for any individual subject will not 
exceed approximately 2.5 years.
The treatment period will last up to twelve 8-week treatment cycles for the SCCHN Cohort 
Expansion (Part 2). For subjects receiving lirilumab and nivolumab combination therapy in the 
SCCHN Cohort Expansion (Part 2), each treatment cycle is composed of 4 doses of nivolumab 
and 2 doses of lirilumab. Nivolumab will be administered on Days 1, 15, 29, and 43 of each 
treatment cycle, and lirilumab will be administered on Days 1 and 29 of each treatment cycle. 
Following each treatment cycle (for all assigned treatments), the decision to treat a subject with 
additional cycles of study therapy will be based on tumor assessment (evaluation performed 
between Days 49 and 56 and completed before the first dose in the next cycle). Treatment decisions 
related to subject management will be based exclusively on irRECIST for the SCCHN Cohort 
Expansion (Part 2) (see Section 1.4.14 of the protocol for the rationale and Appendix 2 of the 
protocol for definitions). For the SCCHN Cohort Expansion (Part 2), subjects with an overall 
response of irPD-unconfirmed, irSD, irPR, or irCR-unconfirmed at the end of a given cycle will 
continue to the next treatment cycle. Subjects will generally be allowed to continue study therapy 
until the first occurrence of any of the following: 1) achievement of irCR-confirmed; 
2) completion of 12 cycles; 3) confirmation of irPD; 4) clinical deterioration suggesting that no 
further benefit from treatment is likely; 5) intolerability to therapy; or 6) meeting criteria for 
discontinuation of study therapy as outlined in Sections 3.5 and 4.9.5 of the protocol.
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 30, 
60, 100, and 150 to monitor for AEs.
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A study schematic is presented below in Figure 2.1.2-1.
The SCCHN Cohort Expansion (Part 2) of this study closed to enrollment when the SCCHN 
Randomized Cohorts (Part 3) opened.
Figure 2.1.2-1:
Study Period Schematic for Part 2 (Completed)
a Survival follow-up no longer applicable with Revised Protocol 12
2.1.3
The SCCHN Randomized Cohorts (Part 3 closed to enrollment)
To further explore emerging efficacy and safety data in subjects with SCCHN, lirilumab in 
combination with nivolumab and nivolumab monotherapy will be evaluated in a single-blind, 
placebo-controlled, randomized, expansion study. All subjects will submit fresh tumor biopsies 
that will be tested for PD-L1 status, and subjects will be enrolled if they have PD-L1+ tumors. 
(Refer to Section 5.7.3.1 of the protocol for the definition of PD-L1+.)
Subjects will be treated with 1 of the following:
•
Arm A: flat dose of lirilumab 240 mg Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg 
Q2W (Days 1, 15, 29, 43) until PD
•
Arm B: placebo for lirilumab Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg Q2W 
monotherapy (Days 1, 15, 29, 43) until PD
Approximately 225 subjects will be randomized to the 2 treatment arms in a 2:1 ratio (150 subjects 
to Arm A and 75 subjects to Arm B) and stratified by the following factors: PD-L1 ≥ 50% 
expression and prior treatment with cetuximab.
Subjects will complete up to 4 study periods: screening, treatment, clinical follow-up, and survival 
follow-up. Screening (up to 35 days). Treatment (until PD, treatment discontinuation, or a
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maximum of up to 12 cycles of treatment, whichever occurs earliest). Clinical follow-up
(150 days). Survival follow-up (up to 3 years following the first dose of study drug). With revised 
protocol 12, the total time on study for any individual subject will not exceed approximately 
2.5 years. Survival follow-up is no longer applicable with Revised Protocol 12.
The treatment begins with the contact to the Interactive Voice Response System (IVRS) to 
randomize the subject. Randomization should take place within approximately 35 days of 
enrollment. The treatment period will last up until PD for the SCCHN Randomized Cohorts 
(Part 3). For subjects receiving lirilumab and nivolumab combination therapy in Arm A of the 
SCCHN Randomized Cohorts (Part 3), each 8-week treatment cycle is composed of 4 doses of 
nivolumab and 2 doses of lirilumab. Nivolumab will be administered on Days 1, 15, 29, and 43 of 
each treatment cycle, and lirilumab will be administered on Days 1 and 29 of each treatment cycle. 
For subjects in Arm B receiving nivolumab monotherapy, each treatment cycle is composed of 
4 doses of nivolumab and 2 doses of placebo for lirilumab. Nivolumab will be administered on 
Days 1, 15, 29, and 43 of each treatment cycle, and placebo for lirilumab will be administered on 
Days 1 and 29 of each treatment cycle. 
Following each 8-week treatment cycle (for all assigned treatments), the decision to treat a subject 
with additional cycles of study therapy will be based on tumor assessment (evaluation performed 
between Days 49 and 56 and completed before the first dose in the next cycle). Treatment decisions 
related to subject management will be based on RECIST v1.1 (see Appendix 3 of the protocol). 
Subjects will generally be allowed to continue study therapy until the first occurrence of any of 
the following: 1) PD (confirmed or unconfirmed); 2) clinical deterioration suggesting that no 
further benefit from treatment is likely; 3) intolerability to therapy; 4) meeting criteria for 
discontinuation of study therapy as outlined in Sections 3.5 and 4.9.5 of the protocol or 5) 
maximum treatment duration of 12 treatment cycles.
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 
30, 60, 100, and 150 to monitor for AEs.
A study schematic of the study period is presented below in Figure 2.1.3-1.
Tumor progression or response endpoints will be assessed using a centralized imaging review 
(independent radiologic review committee) and the RECIST v1.1 criteria. With Revised Protocol
12, submission of scans to centralized imaging review is no longer required. For the purposes of 
subject management, clinical decision making will be based on investigator-assessed radiographic 
assessment using RECIST v1.1. Therefore timepoint tumor response evaluations will be recorded 
on the case report form (CRF) based on investigators’ assessments using RECIST v1.1 criteria. 
Dose reductions will be not be allowed for lirilumab or nivolumab. Crossover will not be 
permitted.
The primary endpoint is ORR based on IRC assessment. 
The study design schematic is presented in Figure 2.1.3-2. See Section 3.1 of the protocol for a 
description of the study phases for this cohort.
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Figure 2.1.3-1:
Study Design Schematic for the SCCHN Randomized Cohorts 
(Part 3)
Figure 2.1.3-2:
Study Period Schematic for the SCCHN Randomized Cohorts (Part 3) 
a Biopsy will be taken at screening and at Day 15 (± 3days).
b Survival follow-up no longer applicable with Revised Protocol 12
2.1.4
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
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2.1.5
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5 - closed to enrollment)
The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 
5) is an open-label, Phase 2 cohort expansion study in subjects ≥18 years old with 
platinum-refractory recurrent or metastatic SCCHN that is not amenable to curative therapy 
evaluating lirilumab in combination with nivolumab and ipilimumab as a treatment. There will be 
continuous monitoring of safety via a safety lead-in, described in detail later in this section. 
Subjects must have tumor progression or recurrence after prior platinum-containing systemic 
therapy for recurrent or metastatic disease. In addition, subjects who have progressed within 
6 months of platinum-based therapy used as part of concurrent chemoradiation (definitive or 
adjuvant therapy) are also eligible.
All subjects in this cohort with be tested for PD-L1 status. All testing for PD-L1 status will be 
performed on a fresh biopsy obtained during screening, and results must be available prior to 
randomization. In the event that the biopsy sample collected during screening is not evaluable for 
PD-L1, the site will be notified and an archival specimen may be submitted for PD-L1 testing. 
Additional subjects may be enrolled, if necessary, to ensure an adequate representation of the 
patient population (ie, non-, lower-, and higher-PD-L1 expressers).
 
 
(see 
Sections 5.7.3.1 
 of the protocol). Subjects will undergo PD-L1 
 
screening evaluations to determine eligibility within 35 days prior to enrollment.
Subjects will be treated with lirilumab, nivolumab, and ipilimumab combination (see Table 5.1.4-
2 of the protocol for dosing schedule) as follows:
−
Nivolumab 3 mg/kg IV Q2W (± 3 days)
−
Ipilimumab 1 mg/kg IV Q6W (± 3 days) following the administration of nivolumab
−
Lirilumab 3 mg/kg IV Q4W (± 3 days) will be the final drug administered on any specific 
treatment day
Approximately 40 subjects will be enrolled. 
The total duration of the study from enrollment to primary endpoint ORR analysis is expected to 
be approximately 21 months, assuming 12 to 15 months accrual duration. 
Subjects will complete up to 4 study periods: screening, treatment, clinical follow-up, and survival 
follow-up. Screening (up to 35 days). Treatment (until PD, treatment discontinuation, or a
maximum of 8 cycles of treatment, whichever occurs earlier). Clinical follow-up (150 days). 
Survival follow-up (up to 3 years following the first dose of study drug). With revised protocol
12, the total time on study for any individual subject will not exceed approximately 2.5 years.
Survival follow-up is no longer applicable with Revised Protocol 12.
The treatment begins with the contact to the IVRS to assign the subject’s treatment. The first dose 
of study drug should take place within approximately 35 days of enrollment. The treatment period 
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will last up until PD for the Signal Detection in SCCHN with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 5). Nivolumab will be administered Q2W, ipilimumab will be 
administered Q6W, and lirilumab will be administered Q4W in all subjects. 
Safety lead-in: There will be continuous monitoring of safety. Initially approximately 10 subjects 
will be enrolled and followed for at least 4 weeks of safety assessment from the start of study drug 
administration before additional subjects are enrolled in the study to ensure there is no major safety 
signal with the combination. Any findings will be discussed between the BMS Medical Monitor 
and investigators and an agreement will be reached as to whether a lower dose or an alternate dose 
schedule should be examined or whether any additional treatment guidelines should be 
implemented prior to enrollment of additional subjects on study.
Following each treatment cycle (12 weeks of study therapy consisting of 6 doses of nivolumab 
given Q2W, 2 doses of ipilimumab given Q6W, and 3 doses of lirilumab given Q4W), the decision 
to treat a subject with additional study therapy will be based on tumor assessment done Q8W
(evaluation performed Q8W and completed before study therapy is continued). Treatment 
decisions related to subject management will be based on investigator-assessed radiographic 
assessment using RECIST v1.1 (see Appendix 3 of the protocol). Subjects with an overall response 
of SD, PR, or CR-unconfirmed at the time of each assessment may continue study drug. Subjects 
will generally be allowed to continue study drug until the first occurrence of any of the following: 
1) achievement of CR-confirmed; 2) PD (confirmed or unconfirmed); 3) clinical deterioration 
suggesting that no further benefit from treatment is likely; 4) intolerability to therapy; 5) meeting 
criteria for discontinuation of study therapy as outlined in Sections 3.5 and 4.9.5 of the protocol. 
or 6) maximum treatment duration of 8 treatment cycles (See Section 3.5.1 of the protocol).
The subjects listed above will enter the clinical follow-up period, with visits scheduled on Days 
30, 60, 100, and 150 to monitor for AEs.
A study period schematic is presented below in Figure 2.1.5-1 and Figure 2.1.5-2.
For the purposes of subject management, clinical decision-making will be based on RECIST v1.1. 
Therefore, timepoint tumor response evaluations will be recorded on the CRF based on 
investigators’ assessments using RECIST v1.1 criteria. 
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Figure 2.1.5-1:
Study Schematic for the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5)
a Biopsy will be taken at screening. Initially approximately 10 subjects will be enrolled and followed for at least 4 weeks of safety assessment from the start of 
study drug administration before additional subjects are enrolled in the study to ensure there is no major safety signal with the combination.
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Figure 2.1.5-2:
Study Period Schematic for the Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab 
Combination (Part 5)
a Biopsy will be taken at screening and Day 15 (± 3 days). Initially approximately 10 subjects will be enrolled and followed for at least 4 weeks of safety assessment 
from the start of study drug administration before additional subjects are enrolled in the study to ensure there is no major safety signal with the combination.
b Until PD, treatment discontinuation, or a maximum of 8 cycles of treatment, whichever occurs earliest.
c Survival follow-up no longer applicable with Revised Protocol 12
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2.1.6
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
2.2
Treatment Assignment
CA223001 is an open-label study with the exception of the SCCHN Randomized Cohorts (Part 3), 
which is site- and subject-blind. Subjects will undergo screening evaluations to determine 
eligibility within 28 days prior to dosing for the Dose Escalation and Cohort Expansion (Part 1) 
and the SCCHN Cohort Expansion (Part 2) and 35 days for all other study parts. Enrolled subjects 
will be assigned a subject number, 
 increasing sequentially with each 
additional enrolled subject. The subject number will be assigned by the Sponsor via IVRS once 
the subject signs the informed consent form. Each subject will then be identified by a distinct 
patient identification number (PID) which is composed of the study site number and the subject 
number. For example, the first subject screened (ie, enrolled) at study site number 1, will have a 
PID 
. The investigator or designee will register the subject following the enrollment 
procedures established by BMS. The following information is required for registration:
•
Date of birth
•
Gender
•
Diagnosis
•
Tumor Type
•
Date of Informed Consent
•
Planned date of 1st dose
Enrolled subjects meeting all eligibility criteria will be assigned to a dose cohort. Specific 
instructions regarding enrollment and dose cohort assignment will be provided to the study sites 
in their training materials.
The SCCHN Randomized Cohorts (Part 3)
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS for the SCCHN Randomized Cohorts (Part 3). Once enrolled in 
IVRS, enrolled subjects who have met all eligibility criteria and have been assigned to the SCCHN 
Randomized Cohorts (Part 3) will be ready to be randomized through the IVRS in a 2:1 ratio of 
Arm A to Arm B:
•
Arm A: flat dose of lirilumab 240 mg Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg 
Q2W (Days 1, 15, 29, and 43) until PD
•
Arm B: placebo for lirilumab Q4W (Days 1 and 29) and flat dose of nivolumab 240 mg 
monotherapy Q2W (Days 1, 15, 29, and 43) until PD
The following information is required for subject randomization:
•
Subject number
•
Date of birth
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•
Prior cetuximab treatment (yes/no)
•
PD-L1 status
The stratification factor includes:
•
PD-L1 ≥ 50% expression (yes/no)
•
Prior cetuximab treatment (yes/no)
The first dose of study drug is to be administered within 3 days following randomization. 
Specific instructions for using IVRS will be provided to the study sites in a separate document.
Details regarding the selection and timing of dose for each subject can be found in Section 4.3 of 
the protocol.
2.3
Blinding and Unblinding
This is only applicable for the single-blinded SCCHN Randomized Cohorts (Part 3). All other 
parts are open label and non-randomized, thus do not require blinding and unblinding.
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the
event of a medical emergency or pregnancy in an individual subject in which knowledge of the
investigational product is critical to the subject's management, the blind for that subject may be
broken by the investigator. The subject’s safety takes priority over any other considerations in
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine
that the unblinded information is necessary, ie, that it will alter the subject's immediate
management. In many cases, particularly when the emergency is clearly not related to the
investigational product, the problem may be properly managed by assuming that the subject is
receiving active product. It is highly desirable that the decision to unblind treatment assignment
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the
decision to unblind. The Principal Investigator should only call in for emergency unblinding
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is the Interactive Response
Technology (IRT). In cases of accidental unblinding, contact the Medical Monitor and ensure
every attempt is made to preserve the blind. Any request to unblind a subject for non-emergency
purposes should be discussed
with the Medical Monitor. In case of an emergency, the
investigator(s) has unrestricted access to randomization information via the IRT and is capable of
breaking the blind through the IRT system without prior approval from the Sponsor. Following
the unblinding, the investigator shall notify the Medical Monitor and/or study director.
For information on how to unblind for emergency, please consult the IRT manual.
The subjects, investigator, and site staff will be blinded to the study drug administered (lirilumab
in combination with nivolumab or nivolumab monotherapy). For all subjects in the SCCHN
Randomized Cohorts (Part 3), and the Signal Detection in SCCHN with Lirilumab, Nivolumab, 
and Ipilimumab Combination (Part 5), each investigative site must assign an unblinded
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pharmacist/designee and an unblinded site monitor will be assigned by sponsor to provide
oversight of drug supply and other unblinded study documentation.
2.4
Protocol Amendments
This analysis plan reflects all protocol amendments through Amendment 12, dated 08-May-2018.
2.5
Data Monitoring Committee 
For all parts of the study, a blinded independent review committee will review all available tumor 
assessment scans to determine response using RECIST v1.1 criteria. When required, adjudicated 
events will be submitted to health authorities for review on a specified timeframe in accordance 
with the adjudication documentation.
3
OBJECTIVES
3.1
Primary Objective
3.1.1
Primary Objective for the Dose Escalation and Cohort Expansion 
(Part 1; Completed) and the SCCHN Cohort Expansion (Part 2; 
Completed)
The Dose Escalation and Cohort Expansion (Part 1): To assess the safety and tolerability of 
lirilumab given in combination with nivolumab and to identify DLTs and the MTD of the 
combination in subjects with advanced (metastatic and/or unresectable) solid tumors.
The SCCHN Cohort Expansion (Part 2): To assess the safety and preliminary anti-tumor activity 
of the combination of lirilumab and nivolumab in subjects with advanced solid tumors.
3.1.2
Primary Objective for the SCCHN Randomized Cohorts (Part 3 - closed 
to enrollment)
To estimate the ORR of lirilumab given in combination with nivolumab in subjects with recurrent 
or metastatic SCCHN that has relapsed or progressed within 6 months of the last dose of a 
platinum-containing therapy and whose tumors express PD-L1. 
3.1.3
Primary Objective for the Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
3.1.4
Primary Objective for the Signal Detection in SCCHN with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 5 - closed to enrollment)
To assess the safety and preliminary anti-tumor activity of the combination of lirilumab with 
nivolumab and ipilimumab in subjects with platinum-refractory recurrent or metastatic SCCHN.
3.1.5
Primary Objective for the Signal Detection in Previously Untreated MEL 
with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
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3.2
Secondary Objectives
3.2.1
Secondary Objectives for the Dose Escalation and Cohort Expansion 
(Part 1; Completed) and the SCCHN Cohort Expansion (Part 2; 
Completed)
The secondary objectives are as follows:
•
To characterize the PK of lirilumab and nivolumab when co-administered.
•
To monitor immunogenicity of lirilumab and nivolumab when administered as combination 
therapy.
•
To assess the pharmacodynamic effect in tumor tissue on TIL subsets from MEL and SCCHN 
subjects treated with lirilumab given in combination with nivolumab.
3.2.2
Secondary Objectives for the SCCHN Randomized Cohorts (Part 3 -
closed to enrollment)
The secondary objectives are as follows:
•
To estimate disease control rate (DCR), DOR, and time to response of lirilumab given in 
combination with nivolumab.
•
To assess depth of response of lirilumab given in combination with nivolumab and of 
nivolumab monotherapy.
•
To assess the OS of lirilumab given in combination with nivolumab and nivolumab 
monotherapy. 
•
To assess the PFS of lirilumab given in combination with nivolumab and nivolumab 
monotherapy.
•
To estimate the ORR by investigator assessment of lirilumab given in combination with 
nivolumab and nivolumab monotherapy.
•
To assess the safety of lirilumab given in combination with nivolumab in subjects with 
SCCHN.
3.2.3
Secondary Objectives for the Signal Detection Cohort Expansion 
(Part 4)
Removed with Revised Protocol 12.
3.2.4
Secondary Objectives for the Signal Detection in SCCHN with 
Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5 - closed to 
enrollment)
The secondary objective is as follows:
•
To estimate DOR of lirilumab given in combination with nivolumab and ipilimumab.
•
To assess depth of response of lirilumab given in combination with nivolumab and ipilimumab.
•
To characterize the PK and immunogenicity of lirilumab in combination with nivolumab and 
ipilimumab.
•
To investigate the immunomodulatory properties of lirilumab in combination with nivolumab 
and ipilimumab, and to evaluate potential baseline and on-treatment biomarkers in peripheral 
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blood and tumor for association with efficacy in subjects with platinum-refractory recurrent or 
metastatic SCCHN.
•
To explore biomarkers of lirilumab in combination with nivolumab and ipilimumab as therapy 
in all subjects with platinum-refractory recurrent or metastatic SCCHN.
3.2.5
Secondary Objectives for the Signal Detection in Previously Untreated 
MEL with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
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4
ENDPOINTS
4.1
Primary Endpoints
Safety and preliminary anti-tumor activity are the primary objective for all parts (i.e. Parts 1, 2, 3, 
and 5) except Part 1, where the primary objective is to assess the safety and tolerability of lirilumab 
given in combination with nivolumab, and Part 3, where the primary objective is to assess estimate 
the objective response rate of lirilumab given in combination with nivolumab. 
For safety objective, all subjects who receive at least 1 dose of study drug will be evaluated for 
safety as measured by the incidence of AEs, SAEs, AEs leading to discontinuation, and deaths
assessed during treatment and for 150 days in follow-up. In addition, clinical laboratory test 
abnormalities will be examined.
All non-serious AEs will be collected from Day 1 until 150 days after the subject’s last dose of 
study drug or until they discontinue the study as per study protocol Section 3.5 and all SAEs must 
be collected from the date of the subject’s written consent until 150 days after discontinuation of 
dosing or until they discontinue the study as per study protocol Section 3.5. AEs will be categorized 
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using the most current version of MedDRA. AEs and laboratory values will be graded according 
to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
For preliminary-antitumor activity, the primary endpoint will be to estimate ORR by derived BORs 
per RECIST v1.1 using investigator-provided tumor assessments for all Parts. The BORs for 
investigator-assessed responses per RECIST v1.1 for Parts 3 and 5 will be listed. Details regarding 
the definition of ORR will be given in the upcoming Secondary endpoint section for preliminary 
antitumor activity.
4.2
Secondary Endpoints
4.2.1
Preliminary Antitumor Activity
The following set of study-level efficacy endpoints will be used for comprehensive assessment of 
antitumor activity.
4.2.1.1
Objective Response Rate (ORR)
ORR is defined as the total number of participants whose best overall response (BOR) is either a 
complete response (CR) or partial response (PR) divided by the total number of participants in the 
population of interest. BOR for a participant will be derived using investigator-provided tumor 
measurements per RECIST v1.1 for all Parts. BOR for a participant will also be assessed by the 
investigator per RECIST v1.1 for Parts 3 and Part 5. All summaries or listings of BOR will be 
using derived BOR per RECIST v1.1 for all Parts.
BOR for a participant is defined as the best response designation recorded between the date of first 
dose (or date of randomization) and the date of first objectively documented progression per 
RECIST v1.1 or the date of subsequent 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 participants without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR assessment. For 
participants who continue treatment beyond progression or begin subsequent therapy, the BOR 
should be determined based on response designations recorded up to the time of the initial 
RECIST v1.1 defined progression or subsequent therapy, whichever occurs first.
4.2.1.2
Median Time to Response (mTTR)
The objective response will be further characterized by the time to response. TTR for a participant
with a confirmed BOR of CR or PR is defined as the time from the first dosing date to the date of 
the first documented objective response (CR or PR). TTR will only be evaluated in participants 
with a BOR of CR or PR.
4.2.1.3
Median Duration of Response (mDOR)
The significance of ORR is assessed by its magnitude and duration of response. DOR for a 
participant with confirmed response is defined as the time from the date of first response (CR or 
PR) to the date of first objectively documented tumor progression as determined using 
RECIST v1.1 or death due to any cause, whichever occurs first. Participant who remain alive and 
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have not progressed will be censored on the date of their last evaluable tumor assessment. 
Participants who started subsequent anticancer therapy without a prior reported progression will 
be censored at the last evaluable tumor assessment prior to initiation of the subsequent anticancer 
therapy. Response duration will only be evaluated in participants with a confirmed BOR of CR or 
PR.
4.2.1.4
Progression Free Survival Rate (PFSR)
The PFSR is defined as the proportion of treated participants remaining progression free and
surviving at time T (eg, 24 weeks) since the first dosing date. The proportion will be calculated by 
the K-M estimate which takes into account censored data.
PFS for a participant is defined as the time from the first dosing date to the date of first objectively 
documented disease progression or death due to any cause, whichever occurs first. Clinical 
deterioration in the absence of radiographic evidence is not considered progression for the purpose 
of determining PFS. Participants who died without a reported prior progression will be considered 
to have progressed on the date of their death. Participants who remained alive and have not 
progressed will be censored on the last evaluable tumor assessment date. Participants who started
subsequent therapy without a prior reported progression will be censored at the last evaluable 
tumor assessment prior to initiation of the subsequent anticancer therapy. Participants who did not 
have any post-baseline tumor assessment and did not die will be censored on the date of first dose 
of study medication.
Table 4.2.1.4-1:
Censoring Scheme for PFS
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessment
First dosing date
Censored
No on-study tumor assessments and 
no death
First dosing date
Censored
Documented progression
Date of first documented 
progression per RECIST v1.1
(excludes clinical progression)
Progressed
No progression and no death
Date of last evaluable tumor 
assessment
Censored
New anticancer therapy, tumor-
directed radiotherapy, or tumor-
directed surgery received without 
progression reported prior or on the 
same day
Date of last evaluable tumor 
assessment prior to the date of 
initiation of subsequent anticancer 
therapy
Censored
Death without progression
Date of death
Progressed
General Efficacy Endpoints Definitions:
Best overall response (BOR) for a subject is the best response designation over the study as a 
whole, recorded between the date of first dose of study medication and the date of objectively 
documented progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever 
occurs first, in the study. For subjects without documented progression per RECIST 1.1 or 
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subsequent anti-cancer therapy, all available response designations will contribute to the BOR 
determination. 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. Additionally, the following will be applicable for BOR evaluation:
−
For a BOR of complete response (CR) or partial response (PR), the response assessment 
must have been confirmed by a consecutive assessment no less than 4 weeks (28 days) 
later. 
−
For a BOR of stable disease (SD), the minimum criteria for SD duration (e.g, 6-8 weeks) 
must have been satisfied (42 days will be used to derive SD). This time minimum criteria 
only applies to derived BOR of SD, not to per timepoint evaluation.
Duration of response (DOR) for a subject with confirmed response is defined as the time from first 
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. Subjects who remain alive 
and have not progressed will be censored on the date of their last tumor assessment (prior to 
subsequent cancer therapy). Response duration will only be evaluated in subjects with objective 
response of CR or PR.
Time to response (TTR) for a subject is defined as the time from date of first dose of study 
medication to the date of the first documented objective response (CR or PR). Time to response 
will only be evaluated in subjects with objective response of CR or PR.
Progression-free survival (PFS) for a subject is defined as the time from the date of first dose of 
study medication to the date of first documented disease progression or death due to any cause, if 
death occurred within 100 days after last lirilumab or nivolumab dose of study drug. Clinical 
deterioration in the absence of radiographic evidence is not considered progression for the purpose 
of determining PFS. Subjects who remain alive and have not progressed will be censored on the 
last tumor assessment date (prior to subsequent cancer therapy). Subjects who did not have any on 
study tumor assessment and did not die will be censored on the date of first dose of study 
medication.
Overall survival (OS) for a subject is defined as the time from date of first dose of study medication 
to the date of death for any cause. A subject who has not died will be censored at last known date 
alive. OS for a subject who initiated new cancer treatment, will also be censored at the date of the 
new treatment initiation.
The efficacy endpoints that will used to evaluate BOR, PFS, and OS include:
•
Objective response rate (ORR): The proportion of subjects with BOR of either a CR or PR 
in the population of interest (all treated patients or response evaluable patients).
•
Disease control rate (DCR): The proportion of subjects with BOR of either a CR, PR, or SD 
in the population of interest (all treated patients or response evaluable patients).
•
Median duration of response (mDOR) 
•
Median time to response (mTTR)
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•
Median overall survival (mOS)
•
Median progression-free survival (mPFS)
•
Progression-free survival rate (PFSR) at Month 3, 6, and 12: The proportion of subjects 
remaining progression free and surviving at 3, 6, 9, and 12 months (conditional on 
availability of a minimum number of subjects with sufficient follow-up) calculated by the 
product-limit method (Kaplan-Meier estimate) 
•
Overall survival rate (OSR) at Month 6, 12, 18, 24, and 36: The proportion of subjects 
surviving at month 6, 12, 18, 24, and 36 (conditional on availability of a minimum number 
of subjects with sufficient follow-up) calculated by the product-limit method (Kaplan-Meier 
estimate) 
Disease assessment with CT and/or MRI, as appropriate, will be performed at baseline and every 
8 weeks (Q8W and Q12W for subjects in the Signal Detection in Previously Untreated MEL with 
Lirilumab, Nivolumab, and Ipilimumab Combination [Part 6]) until confirmed disease 
progression, at the completion of follow-up, or until subjects withdraw from the study. Disease 
assessments at other timepoints may be performed if the investigator is concerned about tumor 
progression. Tumor responses will be derived for appropriate populations of subjects as defined 
by RECIST v1.122 (see Appendix 3 of the protocol) from tumor measurements. For the Dose 
Escalation and Cohort Expansion (Part 1; completed) and the SCCHN Cohort Expansion (Part 2; 
completed), investigator-assessed responses and treatment decisions related to subject 
management will be based on irRECIST9 (see Appendix 2 of the protocol); all other study parts 
will use only RECIST v1.1. All radiographic assessments performed for study purposes will be 
submitted to the third-party radiology vendor for central review. Tumor assessments should be 
submitted to the third-party radiology vendor as they are performed on an ongoing basis. At the 
time of investigator-assessed disease progression, the site must request a BICR from the third-
party radiology vendor. For details on the timelines and associated process requirements refer to 
the imaging manual.
Changes in tumor measurements and tumor responses will be assessed by the investigator using 
irRECIST criteria. Investigators will also report the number and size of new lesions that appear 
while on-study. The timepoint tumor assessments will be reported on the CRF based on 
investigators’ assessment using irRECIST criteria. The SCCHN Randomized Cohorts (Part 3), the 
Signal Detection Cohort Expansion (Part 4),
 
however, will use only 
RECIST v1.1 for all assessments. Please refer to Appendix 3 of the protocol for specifics of 
RECIST v1.1 and Appendix 2 of the protocol for specifics of irRECIST criteria to be utilized in 
this study.
The SCCHN Randomized Cohorts (Part 3) 
The primary endpoint is ORR based on assessment in all subjects randomized to lirilumab plus
nivolumab.
The secondary efficacy endpoints of the SCCHN Randomized Cohorts (Part 3) are DCR, DOR,
time to response, depth of response, OS, PFS, ORR by investigator (in subjects randomized to
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nivolumab monotherapy), and ORR according to investigator-assessed response. All randomized
subjects will be monitored by radiographic assessment Q8W (± 7 days) beginning from the first
dose date until Week 48 and Q12W (± 7 days) thereafter until PD or treatment discontinuation
(whichever occurs later), to determine changes in tumor size. Tumor progression or response
endpoints will be assessed by investigator using RECIST v1.1 criteria.
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and 
Ipilimumab Combination (Part 6) 
Removed with Revised Protocol 12.
4.2.2
Pharmacokinetic Endpoints
PK endpoints (Cmax [μg/mL], Tmax [hr], AUC[0-T] [μg.hr/mL], Ctrough [μg/mL], AUC[TAU] 
[μg.hr/mL], AUC[INF] [μg.hr/mL], CL [L/day], T-HALF, Vz, and Cmin [μg/mL]) will be 
evaluated using non-compartmental analysis, where feasible. In addition, nivolumab end of 
infusion and trough (Cmin) concentrations will be calculated at specified visits for certain study 
parts.
Table 4.2.2-1:
PK Parameters, Naming Conventions and Definitions
Parameter
Definition
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(TAU)
Area under the concentration time curve in one dosing interval
Ceoinf
End of infusion concentration
Cmin
Trough observed concentration
T-HALFeff
Effective serum half-life
CL
Total body clearance
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4.2.3
Biomarker Endpoints
Due to limited numbers of tumor samples collected and limited amount of tumor tissue, PD-L1 
IHC is the only biomarker analyzed and reported on for this study.
PD-L1 expression is defined as the percent of tumor cells demonstrating plasma membrane PD-
L1 staining of any intensity. PD-L1 expression at baseline (+ or -) will be a key endpoint for 
assessing associations with efficacy, due to the need to better understand its utility as a potential 
marker of associations with response in the combination setting. It will be measured in all patients 
with available archival tumor sample, and in patients with paired pre- and on-treatment biopsies 
in the expansion cohorts. 
4.2.4
Immunogenicity
Endpoints for the study are incidence rates of persistent positive ADA as well as neutralizing 
positive ADA from initiation of each drug treatment and up to and including the follow-up period 
of the last study drug dosing. Based on recommendation from BMS Immunogenicity Council, 
Harmonization of Clinical Immunogenicity Reporting by an Initiative of the Therapeutic Protein 
Immunogenicity Focus Group of the American Association Pharmaceutical Scientists, and the 
FDA Guidance for Industry Immunogenicity Assessment for Therapeutic Protein Products, the 
following definitions will be applied.
ADA Status of a Sample:
•
Baseline ADA-Positive Sample: ADA is detected in the last sample before initiation of 
treatment
•
ADA-Positive Sample: After initiation of treatment, (1) an ADA-positive sample in a subject 
who is baseline ADA-negative, or (2) an ADA-positive sample with ADA titer to be 
significantly increased (at least 9-fold for lirilumab and at least 4-fold for nivolumab) relative 
to baseline according to the corresponding analyte assay.
•
ADA-Negative Sample: After initiation of treatment, ADA not-positive sample relative to 
baseline
ADA Status of a Subject:
•
Baseline ADA-Positive Subject: A subject with baseline ADA-positive sample 
•
ADA-Positive Subject: A subject with at least one ADA-positive sample relative to baseline 
at any time after initiation of treatment during the defined observation time period, such as:
−
Persistent Positive: ADA-positive sample at 2 or more sequential timepoints, where there 
is an adequate elapse of time between the first and last ADA-positive samples (16 weeks 
for both BMS-986015 and nivolumab)
−
Only the Last Sample Positive: Not persistent but ADA-positive sample in the last 
sampling timepoint 
−
Other Positive: Not persistent but some ADA-positive samples with the last sample being 
negative
−
Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies 
detected.
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•
ADA-Negative Subject: A subject with no ADA-positive sample after the initiation of 
treatment
5
SAMPLE SIZE AND POWER
5.1
Dose Escalation (Part 1; Completed)
As this is a Phase 1/2 dose escalation cohort, the sample size at each dose cannot be determined 
exactly, as it depends on the number of observed toxicities. Between 3 and 12 subjects 
approximately are expected to be treated during dose escalation in each Dose Level, and up to 
15 subjects may be dosed at selected Dose Levels. 
5.2
Cohort Expansion (Part 1; Completed)
During cohort expansion, approximately 18 subjects are expected to be enrolled in each of the 
3 unknown or low historic response cohort expansions and 35 subjects in the 2 cohorts with higher 
historic ORR and treated at the previously determined MTD, MAD, or at an alternative dose that 
is not to exceed the MAD. 
CRC, SCCHN, and HCC cohorts: The sample size for each tumor cohort will be guided by a 
2-stage Gehan design.21 In order to determine whether a target ORR is likely in a tumor cohort, 
9 subjects will be treated at Stage 1 in each tumor type, as outlined in Table 2.1.1.2-1.  For a tumor 
type in which no responses are observed, it will be concluded that the true ORR is unlikely to be 
greater than or equal to the target ORR and no more subjects will be enrolled in these tumor 
cohorts. Otherwise, for the tumor cohort(s) in which at least 1 response among the first 9 subjects 
is observed, up to an additional 9 subjects will be enrolled as guided by Table 2.1.1.2-2.  With 
9 subjects in Stage 1, per tumor there is no more than a 10% chance of declaring that there is no 
therapeutic effect when actually there is an effect. A total of up to 18 subjects across the 2 stages 
per tumor will guarantee an estimate of the true ORR with 12% precision. 
NSCLC and MEL cohorts: Thirty-five subjects will be enrolled in each of these tumor cohorts 
based on achieving a higher precision with a reasonable control on the type I error. In a cohort of 
35 subjects, if 12, 14, or 16 responses are observed, then the lower limit of the 1-sided 90% CI for 
the ORR is 24%, 29%, or 34%, respectively. In addition, 19 responses would need to be observed 
in 35 subjects so that the 90% 1-sided CI for the ORR is entirely above 20%. These calculations 
are based on the lower limit of the Clopper-Pearson method for exact CIs. If the true ORR in a 
tumor type is 45%, then with 35 subjects in a cohort there is 96% chance of observing at least 10 
responses, and 93% chance of observing at least 11 responses, and there is 7% chance of observing 
10 or fewer responses (false negative rate). If the true ORR for a tumor is only 30% rather than 
45%, then there is a 35% and 14% chance, respectively, that there will be at least 12 or at least 14 
responses in 35 subjects (false positive rate).
The above numbers are approximate, as subjects treated during dose escalation with a tumor under 
the same setting (eg, dose and population) as in cohort expansion may be included in the total n 
per tumor.
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5.3
The SCCHN Cohort Expansion (Part 2; Completed)
More than 35 subjects will be enrolled in the SCCHN Cohort Expansion (Part 2). The null
hypothesis that the true ORR is 25% will be tested against a 1-sided alternative: ORR = 40%. The 
null hypothesis will be rejected if 12 or more responses are observed in 35 subjects. This design 
gives a 1-sided type 1 error rate of 0.15 and a power of 0.81. 
5.4
The SCCHN Randomized Cohorts (Part 3)
The SCCHN Randomized Cohorts (Part 3) has a primary endpoint of ORR. A total of 225 subjects 
will be randomized in a 2:1 ratio to the 2 treatment arms, nivolumab combined with lirilumab 
(Arm A) and nivolumab monotherapy (Arm B), stratified by PD-L1 ≥50% expression (yes/no) 
and prior treatment with cetuximab (yes/no).
Objective Response Rate:
The sample size is calculated to assess the ORR of lirilumab in combination with nivolumab. The 
type 1 error is set to 0.10 (2-sided) with no planned interim analysis. The final analysis for ORR 
will take place approximately 6 months after the last subject is randomized and treated. With 
150 subjects in Arm A, if 50 responses are observed, the estimated ORR will be 33% and the 90% 
CI will be [26%, 41%]. In Study CA209041, the 90% CI for the nivolumab arm in PD-L1+ (> 1%) 
subjects was [9%, 25%].
The above sample size calculation was performed using EAST® 6 and SAS 9.2.
5.5
The Signal Detection Cohort Expansion (Part 4)
Removed with Revised Protocol 12.
5.7
The Signal Detection in Previously Untreated MEL with Lirilumab, 
Nivolumab, and Ipilimumab Combination (Part 6)
Removed with Revised Protocol 12.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
This study consists of 3 periods: pre-treatment, on-treatment, and post-treatment/follow-up period.
The pre-treatment period covers from the time of signing of the informed consent form to prior to 
the first dose of study medication.
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The on-treatment period starts at the time of the first dose of study medication and extends to the 
time of decision to discontinue a subject from study therapy or when the subject completes therapy 
per protocol.
The post-treatment clinical follow-up period begins the day after the on-treatment period ends and 
extends to up to 150 days after the last dose of lirilumab or nivolumab or ipilimumab, as long as 
the patients are still enrolled in the study. 
Additional follow-up for survival outcomes may extend to up to 3 years after initiation of study 
drug.
6.2
Treatment Regimens
The treatment group “as randomized/assigned” will be retrieved from the IRT system, if 
applicable. The treatment group “as treated” will be the same as the arm as randomized/assigned 
by IRT. However, if a participant received an incorrect treatment for the entire period of treatment, 
the participant’s treatment group will be defined as the incorrect treatment the participant actually 
received.
6.3
Populations for Analyses
•
All Enrolled Subjects: All subjects who signed an informed consent and were registered into 
IRT;
•
All Treated Subjects: All subjects who have received at least one dose of study medication; 
•
Response-Evaluable Subjects: All treated participants with measurable disease at baseline and 
one of the following: 1) at least one post-baseline tumor assessment, 2) clinical progression, 
or 3) death 
•
All Randomized Subjects: all subjects who were randomized in Part 3. This population will be 
used for listing of randomization schedule for Part 3 only.
•
Lirilumab PK: all subjects who receive at least 1 dose of lirilumab and have adequate serum 
concentration data for lirilumab PK.
•
Nivolumab PK: all subjects who receive at least 1 dose of nivolumab and have adequate 
nivolumab PK.
•
Lirilumab Immunogenicity: all subjects who receive at least 1 dose of lirilumab and have at 
least 1 ADA sample available.
•
Nivolumab Immunogenicity: all subjects who receive at least 1 dose of nivolumab and have at 
least 1 ADA sample available. 
•
Biomarker: all treated subjects who have biomarker data available.
7
STATISTICAL ANALYSES
SAS® version 9.2 or higher will be used for statistical analyses, tabulations and graphical 
presentations. S-Plus®, may also be used for graphical presentations. 
7.1
General Methods
Continuous variables will be summarized using descriptive statistics, i.e., medians, minimums, 
maximums, and means with standard deviations/(or standard errors of the mean). Categorical 
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variables will be summarized by frequencies and percentages. Percentages will be rounded and 
may not always add up to 100. Confidence intervals for binomial proportions will be derived using 
the Clopper-Pearson method.23
Unless otherwise specified, the following general rules will be applied:
•
Data from Part 1 and Part 2 will be combined, with safety and tolerability data summarized by 
treatment group, and efficacy data summarized by tumor types.
•
All results from Part 3 and Part 5 will be included in listing only.
•
Additional outputs may be provided for SCCHN participants as appropriate.
7.2
Study Conduct
7.2.1
Study Information
A listing of batch number and randomization code (Part 3 only) will be provided.
Listing:
•
Batch number 
•
Randomization code by site (include randomization codes, participant ID, treatment assigned) 
- Part 3 only.
7.2.2
Accrual
The number (%) of participants accrued by country and investigational site will be summarized 
and listed, using All Enrolled population.
Summary:
•
Number (%) of participants accrued by country and investigational site: Include country, site 
number, (Principal Investigator’s name), number of participants enrolled, and number of 
participants treated
Listing:
•
Participants accrued by country and investigational site.
7.2.3
Relevant Protocol Deviations
Non-programmable relevant eligibility and on-treatment protocol deviations, as well as significant 
(both programmable and non-programmable) will be reported through ClinSIGHT listings. The 
following programmable deviations from inclusion and exclusion criteria will be considered as 
relevant protocol deviations and a listing will be provided. The following programmable deviations 
from inclusion and exclusion criteria will be considered as relevant (i.e., protocol deviations that 
could potentially affect the interpretability of the study results).
At Entrance: 
Subjects without measurable disease at baseline
Subject who received study medication less than 28 days from the last dose of the prior therapy
Subjects that have received greater than 5 prior treatment regimens 
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At Entrance for Expansion Cohorts:
Subjects with deviations on baseline or prior therapy related inclusion/exclusion criteria such as:
•
NSCLC subjects: 
−
who have not received prior platinum chemotherapy 
−
with ALK translocation that have not received an ALK inhibitor 
−
with an activating EGFR mutation that have not received an EGFR inhibitor
•
Melanoma subjects: 
−
who have not received prior therapy with ipilimumab 
−
with BRAF mutation (V600E or V600K) present who have not received a RAF or MEK 
inhibitor.
•
Colorectal Cancer (CRC) subjects: 
−
without Microsatellite instability stable (no alterations) or microsatellite instability low 
(only one alteration) 
−
without DNA mismatch repair gene proficient on tumor immunohistochemistry (IHC)
•
Head and Neck Squamous Cell Carcinoma (SCCHN) (oral cavity, pharynx, larynx) subjects:
−
without evidence of progression or recurrence within six months of last dose of platinum 
therapy 
−
with radiation therapy not completed at least 4 weeks prior to study drug administration
•
Hepatocellular carcinoma (HCC) subjects 
−
without Child-Pugh score of B 
−
with hepatitis B infection with hepatitis B DNA viral load greater than 100 IU/mL and not 
on antiviral therapy 
−
with hepatitis B infection with coinfection with hepatitis C or hepatitis D
On-treatment:
•
Subjects receiving anti-cancer therapy while on study therapy 
•
Subjects treated differently than as assigned (subjects who received the wrong treatment for 
the entire study period, excluding the never treated)
•
Subjects receiving greater than 10mg/day of prednisone or equivalent at the time of study drug 
administration.
7.3
Study Population
All study population related summary tables described in this section will include combined data 
from Part 1 and Part 2 only. Listings will include all available data from Parts 1, 2, 3, and 5.
7.3.1
Subject Disposition
Status of participants at the end of pre-treatment period will be summarized and listed by including 
all enrolled participants. Status of participants at the end of treatment period will be summarized 
by treatment and overall, based on All Treated population. In addition, status of participants at the 
end of each study period will be summarized as appropriate. A listing will be provided for those 
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participants who were treated and reason for discontinuation of treatment or not being followed 
will be described.
7.3.2
Demographic and Other Baseline Characteristics
Summary:
Descriptive statistics will be provided the following baseline characteristics for all treated 
participants by treatment and overall.
•
Age at Consent (in years) ; Age  Category (<65, ≥65)
•
Gender at Birth
•
Race
•
Ethnicity (if applicable)
•
Height
•
Weight
•
ECOG PS
•
Disease characteristics such as stage and severity of disease, mutation status, cell types, tumor 
locations (for SCCHN participants only), HPV status (for SCCHN participants only), prior 
cetuximab use (for SCCHN participants only), and prior therapy.
Listing:
All relevant data, generally variables listed above by treatment.
7.4
Extent of Exposure
The extent of exposure will be characterized according to the number of participants exposed, the 
duration of exposure, and the dose to which they were exposed. Analyses in this section will be 
performed on the All Treated Participants “as treated”.
7.4.1
Study Therapy
Summary:
•
Duration of therapy summary tables by treatment and total for each study drug: summarize by  
appropriate numbers of weeks intervals
•
Dose information summary tables for each study drug: summary (mean, median, standard 
deviation, and min and max) of drug dosage, number of doses, duration of therapy, cumulative 
dose, dose intensity, and relative dose intensity.
−
Duration of therapy (weeks) is (last dose date - first dose date +28)/7 for lirilumab, (last 
dose date - first dose date +14)/7 for nivolumab, and (last dose date - first dose date +42)/7 
for ipilimumab (for Part 5 listing only).
−
Cumulative dose is the sum of all actual doses that a subject received. 
−
Dose intensity is defined as the cumulative dose divided by the duration of treatment. 
−
Relative dose intensity is defined as dose intensity divided by planned dose. 
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Listing:
•
By patient listing of drug administered for each study drug by visit
•
By patient listing of dosing information for each study drug: Duration of therapy, cumulative 
dose, dose intensity, and relative dose intensity by study drug.
7.4.2
Modification of Study Therapy
Summary:
The following will be provided by treatment for each study drug.
•
Number (%) of subjects with dose delay, omission and discontinuation with reason
•
Infusion interruptions
−
Number (%) of subjects with at least one infusion interruption along with the reason
−
Number of infusion interruptions per subject
−
Number (%) of subjects with at least one IV infusion rate reduction along with the reason
Listing: All relevant information on dose modification listed above
7.4.3
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the WHO Drug Dictionary. Concomitant 
medications are defined as medications other than study medications which are taken at any time 
on-treatment.
Summary:
The number (%) of treated subjects for the following will be provided by treatment:
•
Summary table of prior therapy by tumor type and treatment group: include the settings of 
prior systemic cancer therapy, best responses, and number of prior regimens (0, 1, 2, and 
>=3), prior ipilimumab therapy and prior nivolumab therapy; 
•
Summary of non-study medication including prior and concomitant medications
•
Concomitant immune-modulating medications for management of AE by medication class 
and generic term - if applicable
Listing:
•
All prior and concomitant medications.
7.5
Efficacy
Efficacy analyses based on Response-evaluable Participants may be performed as supportive 
analyses. If majority of All Treated Participants is included in Response-evaluable Participants, 
limited efficacy analyses will be performed on Response-evaluable Participants (eg, ORR). For 
interim analyses when the minimum follow-up period is less than sufficient to warrant adequate 
interpretation of the result, efficacy analyses may be performed on Response-evaluable 
Participants. 
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Time to event distribution (e.g. progression free survival, overall survival, and duration of 
response) will be estimated using Kaplan-Meier (K-M) method. When appropriate, the median 
along with 95% CI will be provided using Brookmeyer and Crowley methodology24 (using log-
log transformation for constructing the confidence intervals). Rates at fixed timepoints (e.g. PFSR 
at 6 months or OS at 12 months) will be derived from the K-M estimate and corresponding 
confidence interval will be derived based on the Greenwood formula using log-log 
transformation25. Confidence intervals for binomial proportions will be derived using the Clopper-
Pearson method.
In general, efficacy summaries will be provided by tumor type and treatment group.
Summary:
•
ORR and DCR with corresponding 2-sided 95% CI, together with breakdown of BOR
•
Duration of response, OS, and PFS with median (95% CI) and range (min, max) by K-M
method. The number of subjects still in response at the time of data lock will be indicated
•
Time to response with median (95% CI) and range (min, max) by K-M method
Figure:
•
Maximum reduction in baseline target lesions (aka waterfall plot)
•
Kaplan-Meier (K-M) plot of duration of response for responders only
•
Swimmer plot of time to response and duration of response, including time on therapy for 
responders only
•
K-M plot of PFS
•
K-M plot of OS
Listing:
The following will be listed by tumor type and treatment group.
•
By patient listing of all tumor lesion measurements by visit
•
By patient listing of tumor evaluation at each visit
•
Subject level efficacy for all treated subjects: tumor best overall response (BOR), maximum 
reduction in tumor burden from baseline, time to response, duration of response, time to 
progression, and death indicator
7.6
Safety
Analysis of safety will be based on All Treated Subjects and presented by treatment (“as assigned”) 
and overall (if appropriate).
Adverse events (AEs) will be coded and grouped into Preferred Terms (PT) by System Organ 
Class (SOC) according to the most current version of MedDRA and be graded using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4. Drug-related AEs are 
those events with relationship to study drug “Related” as recorded on the CRF. If the relationship 
to study drug is missing, the AE will be considered as drug-related. All AEs will be summarized 
and listed by SOCs and PTs.
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Listing of adverse events will include all enrolled subjects as SAEs and deaths are collected 
pretreatment. Summaries of adverse events will include (1) events occurring from the first dose 
date to 150 days (inclusive) after the last dose of study drug for subjects who are off study treatment 
and (2) all events occurring from first dose date for subjects who are still on study medication.
When reporting adverse events by CTC grade, summary tables will be provided based on the event 
with worst CTC grade (independent of relationship to study medication). Subjects will only be 
counted (1) once at the preferred term (PT) level, (2) once at the system organ class (SOC) level, 
and (3) once in the ‘Total subject’ row at their worst CTC grade, regardless of SOC or PT.
The analysis of laboratory results will be based on All Treated Subjects. Laboratory results will be 
categorized according to NCI CTCAE (version 4.0) grade. Baseline is defined as the last non-
missing measurement prior to the first dosing date and time. Summaries of laboratory results 
include baseline and (1) post-baseline results up to 150 days (inclusive) after the last dose of study 
drug for subjects who are off study treatment and (2) all available post-baseline results for subjects 
who are still on study medication.
Summary tables will be generated for Part 1 and 2 combined. Listings will include all available 
data from Parts 1, 2, 3, and 5.
7.6.1
Adverse Events
Summary:
•
Overall summary of any AEs by worst CTC grade (Grade 1, 2, 3, 4, 3-4, 5, unknown) presented 
by SOC/PT
•
Overall summary of treatment-related AEs by worst CTC grade (Grade 1, 2, 3, 4, 3-4, 5, 
unknown) presented by SOC/PT
Listing:
All recorded adverse events occurring in the pre-treatment, on-treatment, and post-treatment 
period will be listed.
7.6.2
Deaths
Summary:
All deaths during the study within 150 days after the last dose of study drug will be summarized 
for cause of deaths by treatment.
Listing:
All recorded deaths during the study (after a subject is enrolled and has signed the informed 
consent), including post-treatment follow-up period, and deaths that resulted from a process that 
began during the study, will be listed.
7.6.3
Serious Adverse Events
Summary:
•
Overall summary of SAEs by worst CTC grade (Grade 1, 2, 3, 4, 3-4, 5, unknown) presented 
by SOC/PT
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•
Overall summary of treatment-related SAEs by worst CTC grade (Grade 1, 2, 3, 4, 3-4, 5, 
unknown) presented by SOC/PT
Listing:
A by-subject SAE listing will be provided for the All Enrolled Subjects.
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy
Adverse events leading to study drug discontinuation are AEs with action taken = “Drug was 
discontinued”.
Summary:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (Grade 1, 2, 3, 4, 3-
4, 5, unknown)  presented by SOC/PT
•
Overall summary of treatment-related AEs leading to discontinuation by worst CTC grade 
(Grade 1, 2, 3, 4, 3-4, 5, unknown)  presented by SOC/PT
Listing:
By-subject AEs leading to discontinuation listing will be provided.
7.6.5
Select Adverse Events
Summary of Select Adverse Events of Hypersensitivity/Infusion Reaction will be provided by 
ADA Status (Positive, Negative) for all Immunogenicity Subjects by treatment group and overall.
7.6.6
Immune-Mediated Adverse Events
The following summary tables will be generated by treatment group and overall. If needed, by 
patient listing can be provided to support the summary tables.
Summary:
•
Summary of related immune-mediated AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by PT.
•
Summary of related immune-mediated AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by PT for SCCHN participants only.
7.6.7
Multiple Events
Analyses that take into account the multiple occurrences of a given adverse event will be 
conducted. In order to prepare these analyses, the CRF data will be processed according to standard 
BMS algorithms26 in order to collapse adverse event records into unique records based on the 
preferred term. This data will be presented as the rate per 100 patient-years of exposure
(observation period). This analysis will take into account all on-treatment events (allowing more 
than 1 event per subject) and the total duration of exposure. The patient-years exposure will be 
computed as the sum over the subjects’ exposure expressed in years where the duration of exposure 
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•
Date of last dose of study treatment - date of first dose of study treatment + 100+1 days, for 
subject who are off study treatment and were followed at least 100 days after last dose of study 
medication. For patients being followed for 150 days, please use 150 days in above calculation. 
•
Last known date alive- date of first dose of study medication +1, for subjects who are still on-
treatment or who are off study treatment and were followed less than 100 days after last dose 
of study medication.
When specified, the 95% CI of the rate per 100 patient years of exposure will be derived using 
normal approximation and variance estimation proposed in Cook and Lawless 27 (optional).
Summary tables will be generated for part 1 and 2 combined. 
Summary:
The following summary tables will be provided:
•
Summary of frequency of unique adverse events
•
Total number and rate (exposure adjusted) of occurrences for all AEs occurring in at least 5% 
of the subjects treated across treatments.
Listing:
Unique instances of all AEs, i.e., after duplicates have been eliminated and overlapping and 
contiguous occurrences of the same event (i.e., same PT) have been collapsed.
7.6.8
Clinical Laboratory Evaluations
The results of all protocol-specified clinical laboratory tests, as well as laboratory results outside 
of the normal range, will be listed. Scheduled laboratory measurements and corresponding change 
from baseline values will be summarized by treatment and nominal visit for each laboratory test.
The analysis will be based on All Treated Subjects with available laboratory test result on-
treatment and up to and including 100 (or 150) days of the last dose of study medication.
Laboratory results will be categorized according to NCI CTCAE (version 4) grade.
Summary tables will be generated for Part 1 and 2 combined. Listings will include all available 
data from Parts 1, 2, 3, and 5.
Summary:
The number (%) of subjects with the following will be summarized by treatment and overall, if 
appropriate, using the worst CTC grade on-treatment per subject.
•
Post-baseline grade
•
Grade change from baseline
•
Descriptive statistics of laboratory test result and their changes from baseline by treatment and 
study day
Listing:
A by-subject listing of these laboratory parameters will be provided.
7.6.8.1
Abnormal Thyroid Test
Summary:
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Elevated TSH value > ULN and 
−
with baseline TSH value ≤ ULN
−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
−
with F3/F4 missing within 2-week window after the abnormal TSH test
Low TSH < LLN and 
−
with baseline TSH value ≥ LLN 
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with F3/F4 missing within 2-week window after the abnormal TSH test
Listing:
A by participant listing of these specific abnormalities will be provided.
7.6.8.2
Vital Signs and Other Safety Evaluation
Summary:
•
Vital signs 
•
ECG measures
Listing:
•
Vital signs
•
ECG measures and ECG abnormalities
•
Diagnostic procedures
•
Medical treatment procedures
7.6.8.3
Physical Examination Findings
All physical examination results (e.g., with abnormal findings) will be listed.
7.7
Pharmacokinetics
Cmax (μg/mL), Tmax (hr), AUC(TAU) (μg.hr/mL), AUC(INF) (μg.hr/mL), CL (L/day), Vss, T-
HALF, and Cmin (μg/mL) will be evaluated using non-compartmental analysis in all study 
subjects by study drug for part 1 and 2 combined. In addition, end of infusion (Ceoinf) and trough 
(Cmin) concentrations will be calculated at specified visits. Ctough will be listed by doses and 
visit.
The Pharmacokinetic (PK) population will be used for all listings. Evaluable PK population will 
be used for summaries and statistical analyses. Analysis will include all evaluable PK data for each 
analyte (BMS-986015 and BMS-986558).
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BMS-986015 PK: All individual PK parameters will be listed for each subject including any 
exclusions and reasons for exclusion from summaries. Summary statistics will be provided for the 
following parameters by treatment and study day: Cmax, AUC(TAU), AUC(0-T), AUC(INF),
Tmax, Cmin, Ceoinf, CL, Vss and T-HALFeff.
Geometric means and coefficients of variation will be presented for Cmax AUC, Cmin, CL, Vss, 
and AICmax, AIAUC. Median, minimum, and maximum will be presented for Tmax. Means and 
standard deviations will be provided for THALFeff. 
Cmin values will be listed and summarized by treatment and study day, and will be displayed 
graphically.
Dose proportionality of BMS-986015 PK will be assessed for AUC(INF) after single doses and 
for Cmax and AUC(TAU) at steady state. The dose proportionality analysis will be conducted for 
participants from Part 1 and Part 2 only.
To assess the dose proportionality the power model described by Gough et al.28
PK Parameter = A*Doseβ
will be estimated by the simple linear regression of the natural log of the PK Parameter (Cmax, 
AUC) on the natural log of Dose:
E[log(PK Parameter)| Dose] = α + β*log(Dose).
A slope (β) equal to 1 would indicate perfect dose proportionality. For each PK parameters (Cmax, 
AUC), the point estimates and 90% CI of the slopes will be provided.
Scatter plots or geometric mean plots related to dose proportionality, assessment of steady state or 
accumulation by dose, vs. study cycle may also be presented.
BMS-986558 PK: All individual PK parameters (Cmin and Ceoinf) will be listed including any 
exclusions and reasons for exclusion from summaries. Summary statistics will be presented, in 
terms of geometric means and coefficients of variation for Cmin and Ceoinf.
Results of population PK and exposure-response analyses using sparse or serial PK data for either 
analyte from this study may be combined with data from other studies and reported separately.
7.8
Immunogenicity (ADA)
The analysis may include the following presentations; modifications may occur based on the 
evolving understanding of the regulatory or other BMS updates on standards for reporting ADA.
Summary tables will be generated for Part 1 and 2 combined. Listings will include all available 
data from Parts 1, 2, 3, and 5.
Summary:
•
The number (%) of subjects with the following anti-drug responses will be reported by dose, 
if applicable, and overall, for each analyte:
•
Baseline ADA-Positive
•
ADA-Positive
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•
Persistent Positive
•
Only the Last Sample Positive
•
ADA-Positive with Neutralizing Positive
•
ADA-Negative
Listing:
All collected immunogenicity will be listed with flags indicating baseline-positive sample, 
ADA-positive sample or ADA-negative sample.
7.9
Biomarkers
All analysis of PD-L1 IHC data from archived tumor tissue will be based on All Treated Subjects 
population unless otherwise stated. Summary statistics will be provided for baseline PD-L1 status. 
In addition, best overall response summary by baseline PDL-1 status (< 1% vs >= 1%; <5% vs >= 
5%) will be provided for SCCHN participants from Part 1 and Part 2 combined.
8
CONVENTIONS
8.1
Pharmacokinetic Summaries
In-text Tables
For in-text pharmacokinetic tables, coefficient of variation (%CV) will be reported as integers. For 
other statistics except for standard deviations, values of 100 or higher will be presented as integers, 
values of 10 - <100 will be displayed to one decimal place, and values of 1 - < 10 will be displayed 
to two decimal places. Values less than 1 will be displayed to three decimal places.  Ratios will 
also be displayed to three decimal places. Standard deviations will be reported to a precision of 1 
decimal place more than the mean.
Handling of Non-Quantifiable Concentrations
For the summaries of concentration-time data, concentrations that are less than the lower limit of 
quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as missing 
in summary tables and plots. For the purpose of calculating PK parameters, other than Ctrough, 
pre-dose concentrations that are less than LLOQ and concentrations prior to the first quantifiable 
concentration that are less than LLOQ will be set to zero, and all other concentrations less than 
LLOQ will be set to missing.
Summary statistics for Ctrough concentrations, analyses of PD-concentrations and ECG-
concentrations relationships will be calculated by imputing values less than LLOQ as ½ * LLOQ. 
This imputation is done for Ctrough concentrations because it is treated like a PK parameter; the 
imputation is not done for Day 1 pre-dose concentrations.  Individual Ctrough listings will display 
these concentrations as “< LLOQ.”
All available concentration-time data and derived pharmacokinetic parameter values will be 
included in the PK data set and listed accordingly.
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9
CONTENT OF REPORTS
The complete list of analyses contributing to the clinical study report is given in the Data 
Presentation Plan.
10
CONVENTION FOR SELECT AES AND IMAES DATA ANALYSIS
Time-to onset definition
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment  and the onset date of the earliest AE (of any grade) in this category.
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE.
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category
or subcategory will be collapsed into what will be termed “clustered” AEs. For example, if a 
participant (without pre-treatment AE) experienced an AE from 1st to 5th January, another AE 
(with different PT but within same category) from 6th to 11th January and same AE from 10th to 
12th January, these will be collapsed into one clustered AE from 1st to 12th January. Table 10-1
is summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs in 
this category experienced by the participant. Events which worsened into grade 5 events (death) 
or have a resolution date equal to the date of death are considered unresolved. If a clustered AE is 
considered as unresolved, the resolution date will be censored to the last known date alive. 
Improvement to the grade at baseline implies that all different events in the clustered adverse event 
should at least have improved to the corresponding (i.e. with same preferred term) baseline grade. 
This measure is defined only for participants who experienced at least one AE in the specific 
category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly. For data presentation not restricted to 
IMAE, the additional condition that the participant started an immune modulating medication 
during the longest AE resolution period will be applied.
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Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 10-1:
Derivation of clustered AE
Type of clustered AE
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records  (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same 
category
Resolution will be based on the onset date of  the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event records is using the following conventions:
For each participant and specified category, the corresponding adverse event records will be 
collapsed when:
1) Multiple adverse event records have the same onset date.
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
The onset date of an event record is after the onset date and prior to or on the resolution date of a 
preceding event record (overlapping events).
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11
DOCUMENT HISTORY
Version Number
Author(s)
Description
0.1 to 0.4
Edits to schedule of analyses, added baseline 
characteristics, e.g., mutation data, 
 
 ADA updates. 
Efficacy: removed plot of TTR, clarified presentation 
of irRECIST results. Duration of therapy clarified. 
Cleaned up references and other details
0.5, 0.6
Replaced a ‘as treated’ with ‘as assigned’ language. 
Updated relevant protocol deviations. Clarified the 5% 
for AE summary applying too total, and made optional 
the CI and figure for multiple event reporting. Defined 
the BMS-986015 exposure duration by adding 4 
weeks to the dosing interval. Added text on handling 
relevant protocol deviations. 
1.0
Clarification of PD-L1 data collection in the first 
paragraph in Section 4.5.1. Named this vs. no 1 for 
consistent with CARA
2.0
Update the SAP based on the Revised Protocol 
Version 12.0
2.1
Minor update the SAP to remove BICR, to include 
derivation of RECIST v1.1 for all parts, and removal 
of stratification or summarizing by sub-population for 
ORR
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