A Phase II, Randomized, Controlled Trial of Nivolumab in Combination With BMS-986253 in Advanced Hepatocellular Carcinoma (HCC) Patients
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: NYU Langone Health

Official Title: 
A PHASE II, RANDOMIZED, CONTROLLED TRIAL OF NIVOLUMAB 
IN COMBINATION WITH BMS-986253 IN ADVANCED 
HEPATOCELLULAR CARCINOMA (HCC) PATIENTS
NCT Number: 
NCT04050462
Study Number: 
s18-01028
Document Type: 
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
•
January 17, 2025

Study number: S18-01028 
 
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A PHASE II, RANDOMIZED, CONTROLLED TRIAL OF NIVOLUMAB IN 
COMBINATION WITH BMS-986253 IN ADVANCED HEPATOCELLULAR 
CARCINOMA (HCC) PATIENTS 
 
Principal Investigator: 
 
Nina Beri, MD 
Laura & Isaac Perlmutter Cancer Center 
NYU Langone Health 
240 East 38th Street, New York, NY 10016 
Nina.Beri@nyulangone.org 
212-731-5770 
Additional Investigators: 
 
Thomas Karasic, MD 
Perelman Center for Advanced Medicine, 10-102 
Division of Hematology-Oncology 
University of Pennsylvania 
3400 Civic Center Blvd., Philadelphia, PA 19104 
Thomas.karasic@uphs.upenn.edu 
215-360-0414 
 
Paul Oberstein, MD 
Perlmutter Cancer Center, NYU Langone Health 
160 East 34th St., 9th floor, New York, NY 10016   
Paul.Oberstein@nyulangone.org 
212-731-6110 
NYULHStudy Number: 
s18-01028 
Funding Support:  
Bristol-Myers Squibb (BMS study #CA025-013) 
Princeton, NJ 08543 
609-302-4510 
IND/IDE Number:  
143069  
Regulatory Supporter:  
Perlmutter Cancer Center at NYU Langone Health 
160 East 34th Street, New York, NY 10016 
Nina.Beri@nyulangone.org 
212-731-5770 
Biostatistician: 
Benjamin Levinson, PhD 
NYU Grossman School of Medicine 
Department of Population Health 
Division of Biostatistics 
180 Madison Avenue, Suite 4-42C 
New York, NY 10016 
Benjamin.Levinson@nyulangone.org   
646-501-3419 
Medical Monitor: 
Nina D’Abreo, MD 
Nina.D'Abreo@nyulangone.org 
Study Product: 
Nivolumab (Opdivo), BMS-986253 
Study Product Provider:  
Bristol-Myers Squibb 
Coordinating Center: 
NYU Langone Health 
Clinical Research Protocol 
Perlmutter Cancer Center 

Study number: S18-01028 
 
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[If applicable] 
Perlmutter Cancer Center 
Clinical Trials Office 
PCC-QAU@nyulangone.org 
Participating sites: 
NYU Langone Health and University of Pennsylvania  
ClinicalTrials.gov 
Number                 
NCT04050462 
 
 
 
 
Initial version: 8/14/18 
Amended: 
9/17/18 
Amended: 
11/8/18 
Amended: 
1/14/19 
Amended:  
3/11/19 
Amended: 
6/13/19 
Amended:          6/28/19 
Amended:           7/25/19 
Amended:    
1/22/20 
Amended: 
3/9/20 
Amended: 
7/30/20 
Amended: 
12/7/20 
Amended: 
9/9/21 
Amended: 
5/28/24 
Amended:           1/17/25 
 
 

Study number: S18-01028 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the supporter and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 

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PROTOCOL APPROVAL SIGNATURES 
 
 
Protocol Title: A PHASE II, RANDOMIZED, CONTROLLED TRIAL OF NIVOLUMAB IN COMBINATION 
WITH BMS-986253 IN ADVANCED HEPATOCELLULAR CARCINOMA (HCC) PATIENTS 
 
 
Protocol Number: s18-01028 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use guidelines for current Good Clinical Practice, and applicable 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
Date 
 
 

Study number: S18-01028 
 
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Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................................ III 
LIST OF ABBREVIATIONS ....................................................................................................................... VIII 
PROTOCOL SUMMARY .............................................................................................................................. 1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................... 3 
1 
KEY ROLES ......................................................................................................................................... 4 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 4 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 4 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT .............................................................. 7 
2.2.1 
Preclinical Data........................................................................................................................ 8 
2.2.2 
Clinical Data to Date ................................................................................................................ 8 
2.2.3 
Dose Rationale (if applicable) ................................................................................................. 8 
2.3 
RATIONALE .................................................................................................................................... 8 
2.4 
POTENTIAL RISKS & BENEFITS ........................................................................................................ 9 
2.4.1 
Known Potential Risks ............................................................................................................. 9 
2.4.2 
Known Potential Benefits ...................................................................................................... 12 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 12 
3.1 
PRIMARY OBJECTIVE .................................................................................................................... 12 
3.2 
SECONDARY OBJECTIVES (IF APPLICABLE) .................................................................................... 12 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 13 
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 13 
4.2 
STUDY ENDPOINTS....................................................................................................................... 13 
4.2.1 
Primary Study Endpoints ....................................................................................................... 13 
4.2.2 
Secondary Study Endpoints .................................................................................................. 13 
4.2.3 
Exploratory Endpoints ........................................................................................................... 13 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 13 
5.1 
INCLUSION CRITERIA .................................................................................................................... 14 
5.2 
EXCLUSION CRITERIA ................................................................................................................... 15 
5.3 
INCLUSION OF WOMEN AND MINORITIES ........................................................................................ 16 
5.4 
VULNERABLE SUBJECTS ............................................................................................................... 16 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 16 
5.6 
REGISTRATION PROCEDURES ....................................................................................................... 17 
5.6.1 
General Guidelines ................................................................................................................ 17 
5.6.2 
Multi-Site Surveillance ........................................................................................................... 17 
5.6.3 
Patient Registration at Additional Sites ................................................................................. 17 
5.7 
DURATION OF STUDY PARTICIPATION ............................................................................................ 18 
5.8 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 18 
5.9 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 18 
5.9.1 
Reasons for Withdrawal or Termination ................................................................................ 18 
5.9.2 
Handling of Participant Withdrawals or Termination ............................................................. 19 
5.10 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 19 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 20 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 20 
6.1.1 
Acquisition ............................................................................................................................. 20 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................ 20 
6.1.3 
Product Storage and Stability ................................................................................................ 21 

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6.1.4 
Preparation ............................................................................................................................ 21 
6.1.5 
Dosing and Administration .................................................................................................... 21 
6.1.6 
Route of Administration ......................................................................................................... 21 
6.1.7 
Dose Adjustments/Modifications/Delays ............................................................................... 21 
6.1.8 
Duration of Therapy ............................................................................................................... 23 
6.1.9 
Tracking of Dose ................................................................................................................... 23 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 23 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 23 
7.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 23 
7.1.1 
Study Specific Procedures .................................................................................................... 23 
7.1.2 
Standard of Care Study Procedures ..................................................................................... 24 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 24 
7.2.1 
Clinical Laboratory Evaluations ............................................................................................. 24 
7.2.2 
Other Assays or Procedures ................................................................................................. 24 
7.2.3 
Specimen Preparation, Handling, and Storage ..................................................................... 25 
7.2.4 
Specimen Shipment .............................................................................................................. 25 
7.3 
STUDY SCHEDULE ........................................................................................................................ 25 
7.3.1 
Screening .............................................................................................................................. 25 
7.3.2 
Enrollment/Baseline .............................................................................................................. 25 
7.3.3 
Intermediate Visits ................................................................................................................. 26 
7.3.4 
Final Study Visit ..................................................................................................................... 27 
7.3.5 
Withdrawal/Early Termination Visit........................................................................................ 28 
7.3.6 
Unscheduled Visit .................................................................................................................. 28 
7.3.7 
Follow-up Visit ....................................................................................................................... 28 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 29 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 29 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................... 29 
7.7 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................................. 29 
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........................................................ 29 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 29 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 29 
8.1.1 
Definition of Adverse Events (AE) ......................................................................................... 29 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 29 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 30 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 30 
8.2.1 
Severity of Event ................................................................................................................... 30 
8.2.2 
Relationship to Study Agent .................................................................................................. 30 
8.2.3 
Expectedness ........................................................................................................................ 31 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 31 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 31 
8.4.1 
Adverse Event Reporting ...................................................................................................... 32 
8.4.2 
Serious Adverse Event Reporting ......................................................................................... 33 
8.4.3 
Unanticipated Problem Reporting ......................................................................................... 34 
8.4.4 
Reporting of Pregnancy ......................................................................................................... 35 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SUPPORTER ................................................... 35 
8.6 
REPORTING PROCEDURES – NOTIFYING THE STUDY SUPPORTER ................................................... 36 
8.7 
REPORTING PROCEDURES – NOTIFYING THE FDA ......................................................................... 37 
8.8 
REPORTING PROCEDURES – PARTICIPATING INVESTIGATORS ......................................................... 37 
8.9 
STUDY HALTING RULES ................................................................................................................ 37 
8.10 
SAFETY OVERSIGHT ..................................................................................................................... 37 
9 
CLINICAL MONITORING .................................................................................................................. 39 
9.1 
DATA MONITORING COMMITTEE .................................................................................................... 39 
10 
STATISTICAL CONSIDERATIONS .................................................................................................. 40 

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10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 40 
10.2 
STATISTICAL HYPOTHESES ........................................................................................................... 40 
10.3 
ANALYSIS DATASETS .................................................................................................................... 40 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 40 
10.4.1 General Approach ................................................................................................................. 40 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) ........................................................................ 40 
10.4.3 Analysis of the Secondary Endpoint(s) ................................................................................. 40 
10.4.4 Safety Analyses ..................................................................................................................... 41 
10.5 
SAMPLE SIZE ............................................................................................................................... 41 
10.6 
RANDOMIZATION .......................................................................................................................... 41 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 41 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 42 
12.1 
SUB-SITE QC MONITORING ........................................................................................................... 43 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 43 
13.1 
ETHICAL STANDARD ..................................................................................................................... 43 
13.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 43 
13.3 
INFORMED CONSENT PROCESS .................................................................................................... 43 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ................... 43 
13.3.2 Consent Procedures and Documentation ............................................................................. 43 
13.3.3 Informed Consent .................................................................................................................. 44 
13.3.4 Documentation of Consent .................................................................................................... 45 
13.3.5 Patient Informed Consent at Additional Sites ........................................................................ 45 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 45 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data .......................................... 46 
13.5 
FUTURE USE OF STORED SPECIMENS ........................................................................................... 46 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 47 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 47 
14.2 
STUDY RECORDS RETENTION ....................................................................................................... 47 
14.3 
PROTOCOL DEVIATIONS ............................................................................................................... 48 
14.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 48 
15 
STUDY FINANCES ............................................................................................................................ 49 
15.1 
FUNDING SOURCE ........................................................................................................................ 49 
15.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 49 
15.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................ 49 
16 
STUDY ADMINISTRATION ............................................................................................................... 49 
16.1 
STUDY LEADERSHIP ..................................................................................................................... 49 
17 
CONFLICT OF INTEREST POLICY .................................................................................................. 49 
18 
REFERENCES ................................................................................................................................... 50 
19 
ATTACHMENTS ................................................................................................................................ 50 
20 
SCHEDULE OF EVENTS .................................................................................................................. 52 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
Cl 
Confidence Interval 
CrCl 
Creatinine Clearance 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSC 
Cancer Stem Cell 
CTO 
Clinical Trials Office 
DCR 
Disease Control Rate 
DHHS 
Department of Health and Human Services 
DOR 
Duration of Response 
DSMC 
Data Safety Monitoring Committee 
ECI 
Event of Clinical Interest 
EMT 
Epithelial Mesenchymal Transition 
FACS 
Fluorescence Activated Cell Sorting 
GCP 
Good Clinical Practice 
HCC 
Hepatocellular Carcinoma 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LR 
Local-regional 
MOP 
Manual of Procedures 

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N 
Number (typically refers to participants) 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 5.0 
NIH 
National Institutes of Health 
NYULH 
New York University Langone Health 
OHRP 
Office for Human Research Protections 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCC 
Perlmutter Cancer Center 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PR 
Partial Response 
QA 
Quality Assurance 
QC 
Quality Control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
mRECIST 
Modified RECIST 
SAE 
Serious Adverse Event/Serious Adverse Experience 
TAM 
Tumor Associated Macrophage 
TME 
Tumor Microenvironment 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
US 
United States 
WB 
Whole Blood 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 

Study number:  s18-01028  
 
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Protocol Summary 
Title 
A Phase II, Randomized, Controlled Trial of Nivolumab in Combination with 
BMS-986253 in Advanced Hepatocellular Carcinoma (HCC) Patients 
Short Title 
Nivolumab Combined with BMS-986253 in HCC Patients 
Brief Summary 
A phase II clinical trial is utilized to examine whether BMS-986253 (25 
subjects) when combined with Nivolumab offers improved radiographic 
objective response rates (ORR) over Nivolumab monotherapy (25 subjects) 
in advanced HCC patients.  Primary endpoint, ORRs, will be assessed at 2 
month increments while on treatment.  Safety will be verified for the 
Nivolumab/BMS-986253 combination.  Secondary endpoints of time to 
response (TTR), duration of response (DOR), progression free survival 
(PFS), and overall survival (OS) will also be assessed. Pre- and on-treatment 
tumor biopsies will be utilized for translational/correlative research. 
Phase 
Phase 2 
Objectives 
1. Determine the ORR of BMS-986253 in combination with Nivolumab. 
2. Determine the safety of BMS-986253 in combination with Nivolumab. 
3. Determine the TTR, DOR, PFS, and OS for subjects receiving BMS-
986253 in combination with Nivo. 
4. Exploratory study of the tumor microenvironment (TME) using novel 
NYU technologies of 30-parameter flow cytometry and single cell 
RNAseq on pre- and on-treatment fresh core biopsies. 
 
Methodology 
Randomized, controlled, single blind trial 
Endpoint 
Primary Endpoints:  ORR of BMS-986253 in combination with Nivolumab in 
comparison to Nivolumab monotherapy and safety of BMS-986253 in 
combination with Nivolumab. 
 
Secondary Endpoints:  TTR, DOR, PFS, OS, and exploratory analysis of the 
HCC TME in subjects receiving either BMS-986253 in combination with 
Nivolumab in comparison to Nivolumab monotherapy 
Study Duration 
The duration of this study from enrollment until completion of data analysis is 
up to 6 years 
Participant Duration 
2-5 years  
Enrollment Period 
2 years 
Duration of IP 
administration 
2-5 years 
Population 
50 total male and female participants: 25 participants Nivolumab 
monotherapy group, 25 participants Nivolumab/BMS-986253 combination, 
Age ≥ 18, Two U.S. sites 
Study Centers/Sites 
Multicenter (Two):  NYU Langone Health and Univ. of Pennsylvania 
Number of participants 
50 participants across 2 sites 
Description of Study 
Agent/Procedure 
Nivolumab 240 mg IV every 2 weeks + BMS-986253 2400 mg IV every 2 
weeks 
Reference Therapy 
Nivolumab 240 mg IV every 2 weeks 
Key Procedures 
Key procedures include pre- and on-treatment biopsies, peripheral blood for 
IL-8 determination 

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Statistical Analysis 
With the recent results of the CheckMate-040 study in HCC patients, we 
would expect a primary endpoint, ORR of 15%, for the Nivolumab 
monotherapy group (n=25 participants).  For the combination group 
(Nivolumab + BMS-986253) with n=25 participants each, a change in ORR of 
34% would be able to be detected at 80% power.  Thus an absolute ORR for 
the combination group of 49% would be able to be detected at 80% power, 
assuming the 15% ORR for the Nivolumab monotherapy group, utilizing the 
two-sided Z-Test with unpooled variance and significance level of 0.05.  
Secondary endpoint outcomes (TTR, DOR, PFS, OS) will be analyzed using 
the Kaplan-Meier method.  Exploratory endpoints for translational and 
correlative research will be assessed using logistic regression analysis. 
 
 
 

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Schematic of Study Design 
 
 
 
 
 
 
 

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1 Key Roles 
 
Principal Investigator 
Nina Beri, MD 
Laura & Isaac Perlmutter Cancer Center,  
NYU Langone Health 
240 East 38th Street, New York, NY 10016   
212-731-5770 
Nina.Beri@nyulangone.org 
 
Site Investigator 
Thomas Karasic, MD, Assistant Professor of Medicine 
Perelman Center for Advanced Medicine, 10-102 
Division of Hematology-Oncology, University of Pennsylvania 
3400 Civic Center Blvd., Philadelphia, PA 19104 
215-360-0414 
Thomas.karasic@uphs.upenn.edu 
 
Co-Investigator 
Paul Oberstein, MD, Assistant Professor of Medicine 
Perlmutter Cancer Center, NYU Langone Health 
160 East 34th St., 9th floor, New York, NY 10016   
212-731-6110 
Paul.Oberstein@nyulangone.org 
 
Biostatistician 
Judy Zhong, PhD, Associate Professor of Population Health 
Division of Biostatistics, Department of Population Health 
650 First Ave., 5th floor, Rm 540, New York, NY 10016 
212-263-7270 
Judy.Zhong@nyulangone.org 
 
2 Introduction, Background Information and Scientific Rationale 
 
2.1 Background Information and Relevant Literature 
 
HCC has the 2nd highest incidence and mortality rate worldwide among solid organ malignancies and has 
the highest rate of increasing incidence and mortality among all cancers in the U.S.(1, 2).  Despite 
surveillance of high risk populations, many patients present with advanced disease or progress despite 
initial therapies such as surgical resection or local-regional (LR) treatments (3, 4).  While recently tyrosine 
kinase inhibitors such as sorafenib and regorafenib have had some efficacy in advanced HCC patients (5, 
6), the immune oncology agent, Nivolumab (Nivo) (Opdivo®) has demonstrated safety and efficacy in HCC 
patients (CheckMate-040) resulting in its recent FDA approval for 2nd line in HCC patients (7).  Radiographic 
objective response rates (ORR) are reported to be 15% with 3% having a CR and 42% having stable 
disease.  Given HCC’s known prognostic link to the balance of immunosuppression versus immune 
activation within the tumor microenvironment (TME), ongoing studies of Nivo as possible 1st line therapy 
(Checkmate-459) are underway. 
 

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In order to maximize the potential response to immunotherapeutics, other targeting strategies in the TME 
should be investigated.  TAMs and myeloid-derived suppressive cells (MDSCs) are the dominant immune 
suppressive cells within the TME (8).  In HCC, TAMs have been directly linked to a worse prognosis (9, 10) 
and TAMs often reside at the invasive front of malignancies (11).  We and others have shown that TAMs 
and their secreted factors, particularly IL-6 and IL-8, contribute to HCC CSC and EMT phenotype (12, 13) 
(Fig. 1-2).  Additionally, IL-6 and M-CSF are both known to contribute to monocyte differentiation  
 
into TAMs (14, 15).  IL-8 has been independently linked to poor prognosis, being important for tumor 
angiogenesis.  Indeed, we have shown that serum levels of IL-8 independently predicted worse survival in 

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a cohort of HCC patients (16) (Fig. 3).  Furthermore, we have shown that IL-6 and IL-8 are dominant 
cytokines released from TAMs in HCC (Fig. 4).  These cytokines are responsible for stimulating 
 
 
 
 
cancer stem cell (CSC) function as well as epithelial-mesenchymal transition (EMT) behavior (Fig. 5-6).  
Therefore, our overall hypothesis is that therapeutic agents directed at targeting the function of TAMs may 
provide additive or synergistic benefits to known checkpoint inhibitor drugs such as Nivolumab. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.2 Name and Description of the Investigational Agent  
 
Nivolumab (Opdivo®) is a programmed death receptor-1 (PD-1) blocking, fully humanized, IgG4 antibody.  
It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, releasing PD-1-mediated 
inhibition of the immune response. Nivolumab is FDA approved for treatment of patients with melanoma, 
non-small cell and small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck 
squamous cell carcinoma, urothelial carcinoma, MSI-H or mismatch repair deficient colorectal cancer, and 
hepatocellular carcinoma. 
 
BMS-986253 is a blocking, humanized, IgG1k antibody to IL-8.  BMS-986253 binds soluble IL-8, thus 
disrupting IL-8’s ability to bind to its receptors, CXCR1 and CXCR2.  Disruption of IL-8 signaling through 
these receptors diminishes myeloid derived suppressor cell (MDSC) and TAM recruitment to the TME, 

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reduce CSC renewal, reverse EMT, and inhibit tumor angiogenesis.  Phase I studies in advanced solid 
tumors have demonstrated safety at a dose range from 4 mg/kg up to and including 32 mg/kg IV every 2 
weeks with no evidence of drug related toxicity (BMS Investigator Brochure).  Recently a phase 1/2a 
study with Nivolumab (480 mg every 4 weeks) in combination with BMS-986253 (varying doses every 4 
weeks) in cancer patients was shown to be tolerable (BMS Investigator Brochure).   
 
 
2.2.1 
Preclinical Data 
All study drugs have initiated clinical studies.  See sections 2.1, 2.2.2, 2.3, and 2.4. 
2.2.2 
Clinical Data to Date 
While recently tyrosine kinase inhibitors such as sorafenib and regorafenib have had some efficacy in 
advanced HCC patients (5, 6), the immune oncology agent, Nivolumab (Nivo) (Opdivo®) has 
demonstrated safety and efficacy in HCC patients (CheckMate-040) resulting in its recent FDA 
approval for 2nd line in HCC patients (7).  Radiographic objective response rates (ORR) are reported to 
be 15% with 3% having a CR and 42% having stable disease.  Most recent updates on this trial 
(N=154) have shown that the median time to response was 2.8 months.  The median DOR has not 
been reached after 48 months of follow up.  Of those patients responding, 59% had a DOR of greater 
than 12 months.  Median OS based on best overall response (RECIST v.1.1) and stratified as 
complete/partial response, stable disease, and progressive disease was not reached, 16.7 months, 
and 8.9 months, respectively (El-Khoueiry et al, ASCO-GI, 2018). 
 
In the phase I study of BMS-986253 in solid tumor malignancy patients (CA027-001, Investigatory 
Brochure), there were no observed objective radiographic responses in the 15 participants.  There 
were no dose limiting toxicities noted.  AEs that were attributable to treatment were grade 1-2 in 
severity.  There were no SAEs considered to be treatment related.  There were no immune related 
AEs observed.  The ongoing phase 1/2a study (CA027-002) with Nivolumab (480 mg every 4 weeks) 
in combination with BMS-986253 (variant doses every 4 weeks) in advanced cancer patients has 
shown tolerability with the combination.  
2.2.3 
Dose Rationale (if applicable)  
 
BMS-986253 monotherapy in 15 advanced cancer patients has been performed with no dose limiting 
toxicities observed (CA027-001, Investigator Brochure).  A dose range of 4-32 mg/kg every 2 weeks 
was evaluated.  Only 5 of 15 participants were considered to have experienced an AE related to 
treatment with BMS-986253 and were grade 1-2 with no correlation to dose level.  An ongoing phase 
1/2a study (CA027-002) with Nivolumab (480 mg every 4 weeks) in combination with BMS-986253 in 
advanced cancer patients receiving BMS-986253 at 2400 mg every 4 weeks along with Nivolumab at 
480 mg every 4 weeks has shown tolerability, therefore in order to ensure the maximum potential 
reduction in serum IL-8, the highest tolerated dose of BMS-986253 at 2400 mg is chosen for the present 
study along with Nivolumab at 240 mg every 2 weeks.    
2.3  Rationale 
Despite surveillance of high risk populations, many HCC patients present with advanced disease or 
progress despite initial therapies such as surgical resection or local-regional (LR) treatments (3, 4).  While 
recently tyrosine kinase inhibitors such as sorafenib and regorafenib have had some efficacy in advanced 
HCC patients (5, 6), survival has only been extended for a median of 2.7-2.8 months.  The immune oncology 
agent, Nivolumab (Nivo) (Opdivo®) has demonstrated safety and efficacy in HCC patients (CheckMate-
040) resulting in its recent FDA approval for 2nd line in HCC patients (7).  Radiographic objective response 
rates (ORR) using RECIST criteria are reported to be 15% with 3% having a CR and 42% having stable 
disease.  Responding patients are still being followed and have an as yet “non-reached” median survival 
after greater than 45 months of follow up.  Given HCC’s known prognostic link to the balance of 
immunosuppression versus immune activation within the tumor microenvironment (TME), ongoing studies 
of Nivolumab as possible 1st line therapy (Checkmate-459) are underway.  Dosing of Nivolumab, 240 mg 

Study number: S18-01028 
 
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IV, every 2 weeks has been shown to be well tolerated, particularly in patients with underlying liver disease, 
the main risk factor for HCC. 
 
In order to maximize the potential response to immunotherapeutics, other targeting strategies in the TME 
should be investigated.  TAMs and myeloid-derived suppressive cells (MDSCs) are the dominant immune 
suppressive cells within the TME (8).  In HCC, TAMs have been directly linked to a worse prognosis (9, 10) 
and TAMs often reside at the invasive front of malignancies (11).  We and others have shown that TAMs 
and their secreted factors, particularly IL-6 and IL-8, contribute to HCC CSC and EMT phenotype (12, 13) 
(Fig. 1-2, Appendix).  Additionally, IL-6 and M-CSF are both known to contribute to monocyte differentiation 
into TAMs (14, 15).  IL-8 has been independently linked to poor prognosis, being important for tumor 
angiogenesis.  Indeed, we have shown that serum levels of IL-8  independently predicted worse survival in 
a cohort of HCC patients (16) (Fig. 3, Appendix).  Additionally, a recent pan-tumor study in patients 
receiving nivolumab based therapy showed that patients with increased baseline IL-8 had worse overall 
survival and less responsiveness to nivolumab therapy (ASCO Meeting, 2018).   Furthermore, we have 
shown that IL-6 and IL-8 are dominant cytokines released from TAMs in HCC (Fig. 4, Appendix).  These 
cytokines are responsible for stimulating cancer stem cell (CSC) function as well as epithelial-mesenchymal 
transition (EMT) behavior (Fig. 5-6, Appendix).  Therefore, our overall hypothesis is that therapeutic agents 
directed at targeting the function of TAMs may provide additive or synergistic benefits to known checkpoint 
inhibitor drugs such as Nivolumab. 
 
With these aims toward disrupting TAM function in cancer for therapeutic effect, recent studies to verify 
dose and safety have been utilized for BMS-986253, an antibody to IL-8.  A dose of BMS-986253 at 4 
mg/kg up to 32 mg/kg IV every two weeks as monotherapy was found to be safe.  Additionally, the 
combination of BMS-986253 (variant doses every 2-4 weeks) and Nivolumab (480 mg IV every 4 weeks) 
was found to be tolerable.  Therefore in order to target TAM function in HCC more effectively, we will 
compare combination therapy of Nivolumab and BMS-986253 to Nivolumab monotherapy and evaluated 
for improved ORR along with other biologic correlates. 
 
2.4 Potential Risks & Benefits 
2.4.1 
Known Potential Risks 
    
The AEs reported for Nivolumab in HCC patients based upon the recent Checkmate 040 study 
(154 patients) and the package insert included the following:  AST increase (5.8%, Grade 3-4 3.2%), ALT 
increase (7.8%, Grade 3-4 2.6%), ALP increase (5.6%, Grade 3-4 0%), bilirubin increase (1.9%, Grade 3-
4 0%), hepatitis (0.6%, Grade 3-4 0.6%), other GI (25%, Grade 3-4 1.3%), endocrine AEs (8.4%, Grade 
3-4 0%), pulmonary AE (1.3%, Grade 3-4 0.6%), renal AE (0.6%, Grade 3-4 0%), skin AE (31.8%, Gr 3-4 
1.3%), and infusion reaction AE (3.9%, Grade 3-4 0%).  All AEs were reversible with holding of dose.  
Thirteen patients discontinued treatment due to drug toxicity.  The AEs observed and incidence in HCC 
patients were immune related and similar to that observed for use of Nivolumab in treatment of patients 
with other cancer types (7)(AASLD Annual Meeting, 2017) (Nivolumab package insert).   
 
 
 
A phase I, dose escalation study (CA027-001, Investigator Brochure) of BMS-986253 
monotherapy in 15 advanced cancer patients has been performed with no dose limiting toxicities 
observed.  A dose range of 4-32 mg/kg was evaluated.  Drug was given every 2 weeks.  Only 5 of 15 
participants were considered to have experienced an AE related to treatment with BMS-986253 and were 
grade 1-2.  There was no correlation to dose level.  The most frequent AEs (regardless of causality) were 
constipation, nausea and anemia.  Six SAEs were reported, but none were attributable to study drug.  
There is an ongoing phase 1/2a study (CA027-002) with Nivolumab (480 mg every 4 weeks) in 
combination with BMS-986253 (variant doses every 2-4 weeks) in advanced cancer patients (n=92) with 
31 patients receiving BMS-986253 2400 mg IV every 2 weeks and nivolumab 480 mg IV every 4 weeks 
which has shown tolerability with the combination.  AEs that were attributable to treatment were grade 1-2 
in severity.  There was only one participant who discontinued treatment due to a grade 4 infusion 
reaction.  In three other phase I studies involving either patients with progressive plaque psoriasis, 

Study number: S18-01028 
 
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palmar-plantar pustulosis, or induced follicular rash in healthy volunteers, no dose limiting toxicities were 
observed and therefore no maximal tolerated dose was reached.   
 
2.4.1.2  Other Risks of Study Participation 
 
Additional risks associated with participation in this study, include the risk of phlebotomy, risks 
associated with CT/MRI scans, and breach of confidentiality. Risks associated with phlebotomy 
include weaknesses, redness, pain, bruising, bleeding, or infection at the needle site. Privacy 
protection procedures are in place and good clinical practice guidelines are followed for the 
study to minimize risks associated with research procedures and participation.  
 
Risks associated with MRI  
MRI uses strong magnetic fields and radiowaves to make images of the inside of your body. MRI does 
NOT involve high-energy radiation (like x-rays). For most people MRI is very safe. However, if you have 
anything made of metal on your skin or inside your body, MRI may not be safe for you, and you must tell 
study personnel before your scan.  
 
Also, if you have any electronic devices on the outside or inside of your body, you must tell study 
personnel about those too. Some things, like tattoos, may have metal materials in them even though you 
might not realize it. For this reason, study personnel will give you a checklist of things that have metal or 
electronic parts in them. You must read the list carefully before your scan and put a checkmark next to 
everything that applies to you.  
 
The following paragraphs will describe the possible risks of MRI. To reduce many of these risks, you will 
be given an emergency squeeze ball to hold in your hand during the scan. If you feel any discomfort you 
should squeeze the ball. This sets off an alarm that the technologist can hear. The technologist will then 
talk to you, and will stop the scan if you want. There is a microphone in the scanner so that you can 
communicate with the technologist. However, the scanner makes a lot of noise when it is running and the 
technologist may not always hear what you say. If you need to get the technologist’s attention, you should 
squeeze the ball.  
 
Remember, if at any point you feel uncomfortable and want to stop the scan, just squeeze the ball and tell 
the technologist. 
 
Risks from metal 
The strong magnetic field in the scanner will pull on things that contain certain types of metal. If someone 
takes a metal object into the scan room, it might fly towards the scanner and hurt you. For this reason, 
everyone (including you) must remove everything metal from their clothes and pockets before going into 
the scan room. Also, the door to the scan room will be kept closed during the scan to prevent 
unauthorized people from walking in. 
If you have something metal inside your body, the scanner might pull on it and make it move. You must 
tell study personnel before your scan if you have anything metal inside your body. 
Some types of metal might heat up when the scanner is running. If you feel any burning sensation during 
the scan, you should squeeze the emergency ball and the technologist will stop the scan. 
 
Risks from electronic devices 
If you have any electronic devices on the inside or outside of your body, the scanner might make them 
stop working properly. For this reason, you must tell study personnel before your scan if you have 
anything electronic on or in your body. 
 
Burns  
Metal is not the only thing that can cause burns in MRI. It’s possible (although very rare) to get burned by 
touching the inside walls of the scanner or by making skin-to-skin contact. The technologist will give you a 
blanket or cushions so that you don’t touch the inside walls of the scanner. You should also avoid letting 
your hands or legs touch each other. Remember, if you feel any burning sensation during the scan, you 
should squeeze the emergency ball and the technologist will stop the scan. 

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Tinnitus (ringing in the ears) and hearing loss 
The scanner makes very loud sounds while it is running. You will be given earplugs or headphones to 
wear during the scan. Make sure you roll the earplugs tightly and let them expand in your ears so that 
they work properly. If the sound of the scanner is still so loud that it causes you discomfort, squeeze the 
emergency ball and tell the technologist. This is important because very loud sounds can cause ringing in 
the ears or even hearing loss. 
 
Feeling warm or hot 
The radiowaves used in MRI are like those your cellphone uses, but much stronger. Sometimes they are 
strong enough to make you feel warm (just like standing in bright sunshine makes you feel warm). MRI 
scanners are designed to try to avoid you getting too hot. However, if you start to feel uncomfortable, 
squeeze the emergency ball and tell the technologist. 
 
Peripheral nerve stimulation (tingling or twitching) 
The magnetic field inside the scanner changes very quickly while the scanner is running. If it changes too 
quickly, it can give you tingling sensations or make you twitch. MRI scanners are designed to try to avoid 
this. However, if you experience tingling or twitching, squeeze the emergency ball and tell the 
technologist. 
 
Claustrophobia (discomfort in enclosed spaces) 
Some people get panic attacks inside enclosed spaces. This is called ‘claustrophobia’, which means ‘fear 
of confined spaces’. If you know that you are claustrophobic, tell study personnel before your scan. Some 
people only find out they are claustrophobic when they have an MRI for the first time. If you feel anxious 
or panicky inside the scanner, squeeze the emergency ball and the technologist will get you out. 
 
Quench  
In very rare circumstances, the scanner can lose its magnetic field. This happens very suddenly and is 
known as a ‘quench’. The helium that helps keep the magnetic field strong will then escape from the 
scanner. The scanner is connected to a vent so that the helium will go outside the building. However, if 
for some reason the vent doesn’t work properly, helium might fill the scan room, making it difficult to 
breathe. In the very unlikely event of a quench, the technologists will get you out of the scanner 
immediately.  
 
Gadolinium contrast (MRI dye)  
You might need to have an injection of gadolinium contrast (a dye that lights up on the images). 
Sometimes the dye can cause side effects like headache, dizziness, or nausea (feeling slightly sick) for a 
short time after the injection. Some people might get an itchy skin rash, although this is uncommon (about 
1 in 1000 people). It is also possible to have a serious allergic reaction called ‘anaphylactic shock’, which 
can cause swelling of the mouth and make it difficult to breathe. However, this is very rare (about 1 in 
10,000 people). The technologist will tell you ahead of time when the dye is about to be injected, and will 
keep in contact with you to make sure that you’re OK. If you feel any discomfort, squeeze the emergency 
ball and the technologist will come into the room to check on you. 
 
The dye leaves your body in your pee. Provided your kidneys are healthy, it should be almost all gone in 
about 24 hours. However, if you have kidney problems, you should tell study personnel before your scan. 
In rare situations, people with severe kidney problems have developed a serious condition called 
‘nephrogenic systemic fibrosis’ from certain types of dye.  
 
Fairly recently (in 2014) scientists discovered that if people get many injections of certain types of dye, 
some of the dye seems to stay in their brain for a long time afterwards. Doctors don’t know yet whether 
this is bad for you or not. However, if you have already had dye many times before, you should tell study 
personnel before your scan.  
 
 
CT Scan risks (if unable to undergo MRI): 

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Radiation Exposure: During this study, you will have exposure to radiation from liver CT scans if you are 
unable to undergo MRI, as well as CT-guided biopsy. This radiation exposure is not necessary for your 
medical care and is for research purposes only. This means that you will be exposed to small doses or 
amounts of radiation. The risk from this amount of radiation is less than the risk from everyday exposure 
to the sun. The risks of receiving very small doses of radiation are thought to be low. These risks are not 
actually known.  
 
Pregnant women cannot be exposed to radiation. Women must have a negative pregnancy test before 
they can have a CT scan.  
 
 
2.4.2 
Known Potential Benefits 
Nivolumab has been evaluated in a phase II study in HCC patients (Checkmate 040 study) and was 
recently FDA approved for use in HCC patients.  The ORR was noted to be 15% with 3% having a CR 
and 12% having a PR (7).  Most recent updates on this trial (N=154) have shown that the median time to 
response was 2.8 months.  The median DOR has not been reached after 48 months of follow up.  Of 
those patients responding, 59% had a DOR of greater than 12 months.  Median OS based on best overall 
response (RECIST v.1.1) and stratified as complete/partial response, stable disease, and progressive 
disease was not reached, 16.7 months, and 8.9 months, respectively (El-Khoueiry et al, ASCO-GI, 2018). 
 
 
 
In the phase I study of BMS-986253 in solid tumor malignancy patients (CA027-001, Investigator 
Brochure), there were no observed objective radiographic responses in the 15 participants.  In the phase 
1/2a study evaluating the combination of BMS-986253 and Nivolumab (CA027-002) in advanced cancer 
patients there is no efficacy data available at the present time. 
 
It is possible that some study subjects who receive the study therapies may experience an improvement 
in their cancer during the study.  Others with HCC may benefit in the future from what is learned in this 
study. 
 
3 Objectives and Purpose 
3.1 Primary Objective 
 
The primary objective is to determine the ORR of BMS-986253 in combination with Nivolumab in 
comparison to Nivolumab monotherapy using RECISTv.1.1 criteria.  Additionally, the safety of the BMS-
986253 in combination with Nivolumab will be determined. 
 
3.2 Secondary Objectives 
 
The secondary objectives are to determine the TTR, DOR, PFS, and OS for subjects receiving BMS-
986253 in combination with Nivolumab in comparison to Nivolumab monotherapy.  An additional 
secondary objective is to evaluate the tumor microenvironment (TME) using novel NYU technologies of 
30-parameter flow cytometry and single cell RNAseq on pre- and on-treatment fresh core tumor biopsies. 
 

Study number: S18-01028 
 
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4 Study Design and Endpoints 
4.1 Description of Study Design 
The trial is a phase II, randomized controlled, single blinded study evaluating 2 study arms:  Arm 1 
(control) Nivolumab 240mg IV every 2 weeks monotherapy; Arm 2 Nivolumab 240 mg IV plus BMS-
986253 2400 mg IV every 2 weeks(see Study Schema).  Six patients will be observed for toxicity in each 
arm   The trial will be performed at two sites.  Holding of dose will occur if a dose limiting toxicity occurs 
on any arm. 
4.2 Study Endpoints 
4.2.1 
Primary Study Endpoints 
 
The primary endpoint will be the ORR of the Nivolumab and BMS-986253 combination, and the ORR of the 
Nivolumab monotherapy.  ORR will be determined based upon RECIST v. 1.1 criteria.  The safety of BMS-
986253 in combination with Nivolumab will be determined. 
4.2.2 
Secondary Study Endpoints 
The secondary endpoints will include determining the TTR, DOR, PFS, OS, and safety for both treatment 
arms.  These endpoints will allow achievement of the secondary objectives for the study.  Thus, these 
determinations will provide greater insight toward expected clinical response of BMS-986253 when 
combined with Nivolumab for use in HCC patients.  Additionally, potential new insights into the 
management of side effects and increased safety is possible. 
4.2.3 
Exploratory Endpoints 
Exploratory/translational endpoints will include detailed analysis of fresh pre-treatment and on-treatment 
(protocol at three months and at time of progression) core biopsies.  Our collaboration team at NYU 
includes the ability to interrogate the TME in a novel, rigorous manner using 30-parameter platforms for 
single cell flow cytometry.  This novel technology also has the ability to “tag” cell subsets/markers and 
perform single cell RNAseq.  Using these techniques, we will aim to discover novel biomarkers predictive 
of response along with the ability to identify additional novel targets in patients who may “escape” or 
relapse to known immune oncology therapies. 
5 Study Enrollment and Withdrawal 
Advanced HCC patients who are not eligible for resection or other local-regional therapy, and are eligible 
for systemic treatment will be considered.  Patients must be naïve to other systemic therapies.  The study 
is a phase II design with 50 patients to be randomized 1:1 into the following arms (see Study Schema): 
Arm 1 (control) Nivolumab 240mg IV every 2 weeks monotherapy; Arm 2 Nivolumab 240 mg IV plus 
BMS-986253 2400mg IV every 2 weeks.The first six patients will be monitored for Dose Limiting Toxicity 
in each arm. Dose Limiting Toxicities will be defined by toxicity occurring during the first 4 weeks of 
treatment on this study.  If no drug related AE meeting DLT criteria is observed in any arm in >=4 of 6 
patients, the study arms will continue as planned.  If >2 out of 6 patients are observed to have related AE 
(i.e., AE with no clear alternative explanation) meeting DLT criteria that has not been observed in the use 
of nivolumab monotherapy as described in the package insert, then a lower dose strategy for BMS-
986253 (1200 mg IV q 2 weeks) vs. discontinuation of the arm  will be implemented in coordination with 
the DSMC and the study supporter. Should a lower dose strategy be chosen, DLTs will be observed in 
the first 6 subjects will be observed as above prior to expansion to 25 subjects. 
The following will be considered DLTs: 
• Any grade 4 toxicity 

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• Any grade 3 toxicity, with the exceptions of fatigue; rash that improves to grade 2 with medical 
management within 3 day; elevations of amylase and lipase in the absence of clinical pancreatitis; 
elevations in AST, ALT or alkaline phosphatase; nausea, vomiting or diarrhea that improves to grade 2 or 
lower, with maximal medical management within 3 days; and any grade 3 electrolyte abnormality that is 
corrected to grade 2 or lower within 48 hours; hypothyroidism that improves to grade 2 with medical 
management. 
Asymptomatic lymphopenia or leukopenia of any grade will NOT be considered a DLT. 
Any toxicity fitting the above criteria for the definition of a DLT and with an attribution of “related” to study 
treatment is required to be considered a DLT.  
   
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. 
Have histologically confirmed evidence of HCC, Childs-Pugh score of ≤7. 
a. Participants must be willing to provide specimen from fresh, pre- and on-treatment tumor 
core biopsies for histologic diagnosis and translational studies. 
2. 
Radiographically measurable disease by RECIST1.1 in at least one site. 
3. 
Deemed to not be a candidate for resection or other local-regional therapy. 
4. 
Must not be receiving treatment with other investigational agents and must not have received 
any other systemic therapy prior to registration. 
a. Prior radioembolization, local ablative therapies (radiofrequency, microwave or 
cryoablation), radiation (external beam or stereotactic), or hepatic resection permitted if 
completed ≥ 4 weeks prior to study enrollment and if patient has recovered with ≤ grade 1 
toxicity and if untreated measurable disease is present. 
5. 
Be willing and able to provide written informed consent/assent for the trial. 
6. 
Participants must be ≥ 18 years  
7. 
Have a Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 
8. 
If hepatitis B is present, participants must be on anti-viral HBV therapy. 
9. 
All women of childbearing potential (not surgically sterilized and between menarche and 1 
year post menopause) must have a blood test to rule out pregnancy within 24 hours prior to 
start of study treatment 
10. 
All women of childbearing potential must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study treatment (s) and for 4 months following 
discontinuation of study treatment. 
11. 
Male participants must not donate sperm during this period. 
12. 
Demonstrate adequate organ function as defined by the following required lab and 
acceptable range criteria: 
Adequate bone marrow function: 
Absolute neutrophil count 
> 1000/mcL 
Platelet count 
 
 
> 50,000/mcL 
Hemoglobin 
 
 
> 8.5 g/dL 
Adequate hepatic function: 
Total bilirubin 
 
 
< 2 mg/dL or < 1.5 times upper limit of normal 
(ULN) 
AST and ALT 
 
 
< 5 times ULN 
INR 
 
 
 
< 1.5 times ULN 
Albumin 
 
 
> 2.8 g/dL 
Adequate renal function: 
Creatinine 
 
 
< 2.0 mg/Dl 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 

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1. Women who are pregnant or breastfeeding. 
2. Presence of other malignancies. Participants with active second malignancy other than non-
melanoma skin cancer or cervical carcinoma in situ. NOTE: Patients with history of malignancy 
are not considered to have a “currently active” malignancy if they have completed therapy and 
are now considered by their physician to be at less than 30% risk for relapse. 
3. Have active or history of Tuberculosis 
4. Participants with known HIV positive status 
5. Participants with known CNS metastases 
6. Uncontrolled ascites 
7. Uncontrolled encephalopathy 
8. Uncontrolled gastro-esophageal varices. Prior organ allograft or allogeneic bone marrow 
transplantation 
9. Participants with active, known, or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, euthyroid participants with a history of Grave’s disease (participants with suspected 
autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies 
and thyroid stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll. 
 
10. Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of study 
treatment administration except for adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent in the absence of active autoimmune disease.  Note: Treatment with a short course of 
steroids (< 5 days) up to 7 days prior to initiating study treatment is permitted. 
 
11. Interstitial lung disease that is symptomatic or may interfere with the detection or management of 
suspected treatment-related pulmonary toxicity. 
 
12. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following: 
-Myocardial infarction or stroke/transient ischemic attack within the past 6 months 
-Uncontrolled angina within the past 3 months 
-Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes) 
-History of other clinically significant heart disease (eg, cardiomyopathy,               
congestive heart failure with New York Heart Association functional classification 
III to IV, pericarditis, significant pericardial effusion, or myocarditis) 
-Cardiovascular disease-related requirement for daily supplemental oxygen 
therapy.  
13.  Participants with ongoing or active, uncontrolled infections (afebrile for ≥ 48 hours off antibiotics).  
If hepatitis B is present, must be on anti-viral HBV therapy. 
14. Must not have a psychiatric illness, other significant medical illness, or social situation, which, in 
the investigator’s opinion, would limit compliance or ability to comply with study requirements. 
15. Any major surgery within 4 weeks of study treatment. Participants must have recovered from the 
effects of major surgery or significant traumatic injury at least 14 days before 
16. Any uncontrolled inflammatory disease including Crohn’s disease and ulcerative colitis 
17. Treatment with botanical preparations (eg, herbal supplements, including potential drugs of 
abuse, or traditional Chinese medicines) intended for general health support or to treat the 
disease under study within 2 weeks prior to randomization/treatment. 
18. Concomitant use of statins while on study. 
19. Current or history of clinically significant muscle disorders (eg, myositis), recent unresolved 
muscle injury, or any condition known to elevate serum CK levels. 
20. Known history of sensitivity to infusions containing Tween 20 (polysorbate 20) and Tween 80 
(polysorbate 80). 
21. Participants who have received a live / attenuated vaccine within 30 days of first treatment. 

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22. Concomitant use of any live / attenuated vaccine during treatment and until 100 days following 
last dose. 
5.3 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
5.4 Vulnerable Subjects 
Vulnerable subjects will not be eligible for enrollment into the study. 
5.5 Strategies for Recruitment and Retention 
Potential patients with advanced HCC will be identified in the multidisciplinary liver cancer programs at 
the participating sites.  This may include review during multidisciplinary tumor boards to identify potential 
participating patients.  Potential participating patients will be referred in to the site cancer center 
ambulatory clinics for formal screening and consent.  It is anticipated that 90 patients total may need to be 
screened anticipating potential screening failures.  The study title will be included on cancer center web 
content listing available clinical trials at individual study site.  The study will also be listed on 
https://clinicaltrials.gov website. 
 
The inclusion and exclusion criteria in this study should not have a negative effect on the enrollment of 
the desired populations. 
Target enrollment for this study is 50 patients over 2 years.  The target accrual goal is 25 patients per 
year.  Patients will be recruited from physicians participating in this study.  Consenting, screening, and 
treatment will take place at the NYU Langone Health PCC or participating sub-sites under the supervision 
of the Site PI.  Prospective subjects will receive detailed information regarding this study; its 
investigational nature, required study procedures, alternative treatments, risks and potential benefits of 
the study.  They will also receive the informed consent document to read.  All questions are answered by 
the PI and qualified research personnel. 
The Principal Investigator will: 
1.  Obtain signed and dated informed consent from the potential subject before any study specific 
procedures are performed. 
 
2.  Determine patient eligibility; see Section 5.1 and 5.2  
 
3.  Submit registration to NYU Langone Health Perlmutter Cancer Center CTO 
4.  Receive registration confirmation from the NYU Langone Health Perlmutter Cancer Center 
CTO, including a unique study identification number assigned to the patient that will be distributed 
to the study team upon registration of the patient. 
The informed consent process and documentation follows established institutional guidelines. 
 
5.6 Registration Procedures 
5.6.1 
General Guidelines 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedure unless a procedure is being performed as part of the patient’s standard of care. 

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Enrollment in the study requires that all inclusion and exclusion criteria have been met.  Enrollment 
occurs upon confirmation of registration from the NYULH PCC Clinical Trials Office.  The following 
materials must be submitted to the CTO for subject registration: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the above documents.  A 
written confirmation of enrollment including a unique study identification number assigned by the research 
coordinator will be disbursed to the study team upon registration. 
 
A unique patient study number will be issued once consent is received, due to serum IL-8 samples 
collected prior to eligibility confirmation.  The patient will not be identified by name.  Once remaining 
registration material is verified, the patient is considered accrued on study.  
 
5.6.2 
Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Principal Investigator is responsible for organizing and 
conducting monthly teleconferences with all participating sites. The PI will also be responsible for 
including data from all of the participating sites within the overall trial’s quarterly Data and Safety 
Monitoring report to the DSMC. Each participating site will be responsible for submitting the results 
and recommendations from the DSMC’s quarterly reviews to their IRB of record at the time of 
continuing review. Additionally, the NYU Langone Health PCC Clinical Trial Office, Quality 
Assurance Unit will provide remote extensive monitoring including real-time review of all eCRFs to 
ensure completeness and compliance with the protocol (100% source documentation verification).  
Additionally, a first subject audit is to be completed within four weeks of enrollment. 
 
5.6.3 
Patient Registration at Additional Sites 
Enrollment at addition sites can begin once each site’s IRB has approved this protocol, a copy of 
each site’s IRB approval, Citi training certificates, Medical Licenses and signed CVs are 
provided to NYU Langone Health Perlmutter Cancer Center (PCC) Clinical Trials Office. Once, all 
required documents are provided to NYU Clinical Trials Office an activation notification will be 
sent to the PI and research coordinator of that site. Central registration for this study will take 
place at NYU Langone Health PCC Quality Assurance Unit (PCC-QAU@nyulangone.org). 
 
Each patient must sign and date an informed consent form before undergoing any study 
specific procedures unless a procedure is being performed as part of the patient’s standard of 
care. Once a patient has signed consent, each site must notify the NYU Langone Health PCC 
Quality Assurance Unit and forward a copy of the signed consent to NYU Langone Health PCC 
Clinical Trials Office within 24 hours. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. 
Enrollment occurs upon confirmation of registration from the NYU Langone Health PCC Clinical 
Trials Office. The following materials must be submitted to the Quality Assurance Unit at NYU 
Langone Health via email (PCC-QAU@nyulangone.org): 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met. 
 
Registration will occur once the Senior Research Nurse for Quality Assurance conducts a central 
review of the submitted materials. A unique patient study number will be issued once consent is 
received, due to serum IL-8 samples collected prior to eligibility confirmation.  The NYU Langone Health 

Study number: S18-01028 
 
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PCC CTO will provide the subject’s unique study number via email.  Once remaining registration 
material is verified a signed eligibility conformation worksheet email is sent. This number is unique to 
the participant and must be written on all data and correspondence for the participant.  
 
The subject will not be identified by name. This is the point, at which, the patient is considered 
accrued on study. Protocol treatment should  begin within  designated timeframe; issues  that 
would cause treatment delays should be discussed with the overall PI, Dr. N i n a  B e r i .  All 
screen failures/ineligible subjects, as well as subject’s who withdraw consent prior to initiation 
of protocol therapy must be submitted to the CTO in a manner analogous to the procedures 
noted above. Applicable source documentation will be required within the corresponding 
submissions. 
 
Subjects must not start any protocol procedures prior to registration; each participating 
institution will order the study agent directly from the supplier, Bristol-Myers Squibb (Nivolumab, 
BMS-986253). 
 
Each site is responsible for reporting all unexpected problems involving risks to participants or 
others to NYU Langone H e a l t h  PCC Clinical Trials Office and to their IRB as per site 
institutional policy. 
 
Please email all SAEs to NYUPCCsafetyreports@nyulangone.org, Dr. Beri, PCC Assigned 
Medical Monitor, and the NYU Langone Health CTO Quality Assurance specialist. 
 
 
5.7 Duration of Study Participation 
Study participants will receive study drug until events such as (outlined in Section 5.9.1) a) disease 
progression, b) treatment related toxicity or other adverse event preventing continued participation, or c) 
withdrawal of consent.  It is estimated that of the 50 enrolled, evaluable patients, that 50% will complete 
17 cycles and 50% will complete an additional 17 cycles.  Thus, the screening period and intervention 
period for 50% of participants will have a duration of 17.5 months and for 50% a duration of 34.5 months.  
The follow up period will occur for at least every 3 months for 1 year after last study treatment dosage, 
even in patients who discontinue the study drug.  Thus the total study duration is estimated to be 20.5-
23.5 months for 50% of participants and 34.5-37.5 months for 50% of participants. 
5.8 Total Number of Participants and Sites  
 
Recruitment will end when approximately 50 participants are randomized over 2 years. It is expected that 
approximately 70 participants will be screened in order to enroll and produce 50 randomized participants.  
There will be no international sites.  Other U.S. sites may be considered to facilitate enrollment. 
5.9 Participant Withdrawal or Termination 
5.9.1 
Reasons for Withdrawal or Termination 
 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
 

Study number: S18-01028 
 
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A subject has the right to voluntarily discontinue study treatment or withdraw from the study at any time, 
for any reason, and without repercussion.  The investigator and supporter have the right to discontinue a 
patient from study treatment or withdraw a patient from the study at any time. 
 
Reasons for subject withdrawal from the study may include, but are not limited to: 
 
• 
Subject withdrawal of consent at any time. 
• 
Disease progression (if applicable) 
• 
Intolerable toxicity (If applicable) 
• 
Any medical condition that the investigator or supporter determines may jeopardize the 
patient’s safety if s/he continues in the study or continues treatment with study drug. 
• 
The investigator or supporter determines it is in the best interest of the patient. 
• 
Failure of the subject to adhere to protocol procedure requirements 
• 
Pregnancy (if applicable) 
• 
Study termination by Supporter 
 
The reason for taking a participant off study, and the date the participant was removed, must 
be documented in the case report form (CRF). All patients who withdraw from study drug 
prematurely will undergo end-of-treatment assessments within 30 days after the last dose, if 
possible. Regardless of the reason for withdrawal, effort shall be made to follow safety events 
from the time of withdrawal through resolution or until the event stabilizes.  Subjects who 
discontinue study drugs will continue to be followed for adverse events for up to 100 days and for 
survival every 3 months (+/- 2 weeks) from the date of last dose of study drug(s) for up to 12 
months. 
5.9.2 
Handling of Participant Withdrawals or Termination 
 
Significant efforts will be made to continue follow-up of withdrawn or terminated participants or 
participants who discontinue study agent but remain in the study for follow-up, especially for safety and 
efficacy of secondary study endpoints. Every effort will be made to undertake protocol-specified safety 
follow-up procedures to capture AEs, serious adverse events (SAEs), and unanticipated problems (UPs). 
The PI and site PIs will attempt to obtain at a minimum survival data on all participants lost to follow-up. 
Methods that will be used prior to stating that a participant is lost to follow up will include at least three 
phone calls to participant or next-of-kin if possible.  A certified letter will be mailed if the phone calls fail to 
secure follow up information.  
 
Withdrawal from the study can be made in writing to the Principal Investigator, Dr. Nina Beri. Any 
samples/specimens remaining after formal withdrawal, will be destroyed/discarded per Institutional 
guidelines. 
5.10 Premature Termination or Suspension of Study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to Dr. Nina Beri, BMS, and any regulatory authorities. If the study 
is prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) 
for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 

Study number: S18-01028 
 
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• 
Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the supporter, IRB and/or FDA. 
 
6 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
6.1 Study Agent(s) and Control Description 
6.1.1 
Acquisition 
 
The study drugs will be shipped from Bristol-Myers Squibb at 2-8oC (36-46oF) and be stored in the study 
site cancer center pharmacy of each participating institution until use at the same temperature. 
6.1.2 
Formulation, Appearance, Packaging, and Labeling 
 
Product 
Description / Class 
and Dosage Form 
Potency/Route of 
Administration 
Blinded or 
Open Label 
Packaging / 
Appearance 
Storage Conditions 
(Per Label) 
Nivolumab 
(BMS-936558-01) 
Solution for Injection 
100 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label on 
container 
Nivolumab  
(BMS-936558-01) 
Solution for Injection 
40 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label on 
container 
BMS-986253 
(BMS-986253) 
Solution for Injection 
200 mg 
(20 mg/mL) 
Open Label 
Vial 
Refer to the label on 
container 
BMS-986253 
(BMS-986253) 
Solution for Injection 
1000 mg 
(100 mg/mL) 
Open Label 
Vial 
Refer to the label on 
container 
BMS-986253 
(BMS-986253) 
Solution for Injection 
1200 mg 
(100 mg/mL) 
Open Label 
Vial 
Refer to the label on 
container 
Please refer to the current version of the Investigator Brochures for complete preparation, storage, and 
handling information. 
 
Nivolumab:  Nivolumab is and IgG4 monoclonal antibody in a clear to opalescent, colorless to pale-yellow 
solution available for injection in a single dose 100 mg or 40 mg vial.  See Package Insert (Appendix). 
 
 
 
BMS-986253:  BMS-986253 is a IgG1k monoclonal antibody in a clear to opalescent, colorless to pale-
yellow solution available for injection in a single dose vial.  Some particulates may be present.  See 
Investigator Brochure (Appendix).  Each vial contains 200 mg/vial (20 mg/mL), 1000 mg/vial (100mg/mL) 
or 1200 mg/vial (100 mg/mL) 
 
All 2 trial drugs are manufactured and packaged by Bristol-Myers Squibb. 
 

Study number: S18-01028 
 
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6.1.3 
Product Storage and Stability 
 
All three study drugs should be stored at 2-8oC (36-46oF) protected from light, and protected from 
freezing.  BMS-986253 should be stored in original container. 
6.1.4 
Preparation 
 
Nivolumab (Opdivo®):  See Package Insert (Appendix).  Withdraw the required volume of OPDIVO and 
transfer into an intravenous container. 
• Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to prepare an infusion with a final concentration ranging from 
1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of OPDIVO. 
 
After preparation, store the OPDIVO infusion either: 
• at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container and 
time for administration of the infusion or 
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from 
the time of infusion preparation. 
Do not freeze. 
 
 
 
BMS-986253:  See Investigator Brochure (Appendix).  Vials are single use.  Dilute drug into 0.9% sodium 
choloride injection.  Administration of diluted BMS-986253 injection must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored for up to 24 hours 
refrigerated at 2° to 8°C (36° to 46°F) protected from light; 4 hours of the 24 hours can be at room 
temperature (15° to 25°C, 59° to 77°F) ambient light. The diluted solution in IV bag should not 
be shaken or frozen. Equilibration to room temperature is recommended for the infusion bag, drug 
product, or their combination prior to administration. 
6.1.5 
Dosing and Administration 
Nivolumab will be administered by infusion over 30 minutes through an intravenous line containing 
asterile, non-pyrogenic, low protein binding in-line filter. BMS-986253 will be administered by infusion 
over 120 minutes through an intravenous line containing asterile, non-pyrogenic, low protein binding in-
line filter. If the patient’s weight is < 35 kg, the infusion will be administered over 180 minutes.  Pore size 
of 0.2 micrometer to 1.2 micrometer is acceptable for Nivolumab and BMS-986253 (see package insert 
and IB, respectively).Do not co-administer other drugs through the same intravenous line.  Flush the 
intravenous line at end of infusion.  When administering BMS-986253 with Nivolumab, infuse Nivolumab 
first followed by a 30 minute period of observation followed by infusion BMS-986253 over 120 minutes on 
the same day. Use separate infusion bags and filters for each infusion. 
6.1.6 
Route of Administration 
 
Intravenous (IV) 
6.1.7 
Dose Adjustments/Modifications/Delays 
Recommendations for study drug modifications are provided in the tables below. The recommendations 
for Nivolumab monotherapy are from the Package Insert.  Since no dose limiting toxicity has been 
observed for BMS-986253 monotherapy in phase I (Investigator Brochure) and the combination of 
Nivolumab and BMS-986253 is currently being evaluated in CA027-002 with no new safety signals noted, 

Study number: S18-01028 
 
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the management plan for toxicity will be the same as for Nivolumab monotherapy however both agents 
will be withheld or discontinued based on the described AEs below. 
 
There are no recommended dose modifications for hypothyroidism or hyperthyroidism. 
 
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. 
Discontinue the study drug in patients with severe or life-threatening infusion reactions. 
 
ADVERSE EVENT MANAGEMENT FOR NIVOLUMAB MONOTHERAPY OR FOR NIVOLUMAB IN 
COMBINATION WITH BMS-986253 
Adverse Reaction 
Severity* 
Dose Modification 
 
Grade 2 diarrhea or colitis 
Withhold dosea 
Colitis 
Grade 3 diarrhea or colitis 
Withhold dose when single 
agent (Nivolumab 
monotherapy), Permanently 
discontinue when administered 
with additional study drug 
 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold dosea 
 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
 
If AST/ALT is within normal 
limits at baseline and increases 
to more than 3 and up to 5 times 
ULN 
 
Hepatitis 
If AST/ALT is more than 1 and 
up to 3 times ULN at baseline 
and increases to more than 5 
and up to 10 times ULN 
Withhold doseb 
 
If AST/ALT is more than 3 and 
up to 5 times ULN at baseline 
and increases to more than 8 
and up to 10 times ULN 
 
 
If AST or ALT increase to more 
than 10 times the ULN or total 
bilirubin increases to more than 
3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold dosea 
 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal Insufficiency 
Grade 2 adrenal insufficiency 
Withhold dosea 
 
Grade 3 or 4 adrenal 
insufficiency 
Permanently discontinue 
Type I Diabetes Mellitus 
Grade 3 hyperglycemia 
Withhold dosea 
 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and Renal Dysfunction 
Serum Cr more than 1.5 and up 
to 6 times the ULN 
Withhold dosea 
 
Serum Cr more than 6 times the 
ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold dosea 
 
Grade 4 rash or confirmed SJS 
or TEN 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe 
neurologic signs or symptoms 
Withhold dosea 

Study number: S18-01028 
 
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Immune-mediated encephalitis 
Permanently discontinue 
 
Other Grade 3 adverse reaction 
   First Occurrence 
Withhold dosea 
 
   Recurrence of same Grade 3  
   Adverse reactions 
Permanently discontinue 
 
Life threatening or Grade 4 
adverse reaction 
Permanently discontinue 
Other 
Grade 3 myocarditis 
Permanently discontinue 
 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks 
Permanently discontinue 
 
Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
* Toxicity is graded per National Cancer Institute Common Terminology Criteria for Adverse Events. 
Version 5.0 (NCI CTCAE v5). 
a Withhold all study drugs, resume treatment when adverse reaction improves to Grade 0 or 1. 
b Withhold all study drugs, resume treatment when AST/ALT returns to baseline. 
 
 
6.1.8 
Duration of Therapy 
Duration of therapy will be at least three cycles, unless AE requiring dose modification is required (6.1.7), 
at which point first radiographic imaging is performed.  From a statistical standpoint, this will be an 
evaluable participant for objective response based on RECISTv1.1 criteria.  One cycle is defined as 4 
weeks. 
6.1.9 
Tracking of Dose 
Dosing of drugs will occur under supervision in the infusion center at the study sites. 
6.2 Study Agent Accountability Procedures 
 
The study agents will be distributed to the pharmacy at their request to ensure dosing of all study 
participants with additional 2 doses surplus in case there is damage.  Shipping requires 5-7 days with no 
deliveries on Mondays.  Drug request forms will be provided to sites at study start.  Receiving and 
documentation of adequate and safe handling will be performed by the pharmacy and records maintained 
by the study coordinator.  Unused product will be returned to the supporter (Bristol-Myers Squibb). 
 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated by the 
study team. 
 
Any unused drug and also at the final reconciliation of the site’s drug supply at the end of the study will be 
shipped back to the supporter (Bristol-Myers Squibb, Princeton, NJ 08543). 
7 Study Procedures and Schedule 
7.1 Study Procedures/Evaluations 
7.1.1 
Study Specific Procedures 
 
• 
Informed Consent 
• 
Peripheral serum IL-8 determination (Pre- and On-treatment) 

Study number: S18-01028 
 
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• 
Assessment of eligibility should include a review of permitted and prohibited medications. 
• 
Toxicity Evaluation 
• 
Study Drug Administration 
• 
On-treatment biopsy 
 
 
7.1.2 
Standard of Care Study Procedures 
• 
Medical history (by interview and from medical records, social history, past medical and surgical 
history) 
• 
Symptom Assessment (complete review of systems) 
• 
Medication history (complete medication history is needed, prescription and over-the-counter 
medications). Assessment of eligibility will include a review of permitted and prohibited 
medications. 
• 
Physical examination (vital signs including height and weight, head and neck, respiratory, 
lymphatic, abdomen, cardiovascular, neurologic, musculoskeletal). 
• 
Performance Status (ECOG) 
• 
Radiographic or other imaging assessments. MRI or CT (3 phase liver protocol with IV contrast), 
CT chest 
• 
Biological specimen collection and laboratory evaluations.  See Section 7.2 Laboratory 
Procedures/Evaluations below. 
• 
A discussion of if the results of any study specific procedures (e.g., radiographic or other imaging 
or laboratory evaluations) will be provided to participant. 
 
7.2 Laboratory Procedures/Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
 
Screening Laboratory Tests 
 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. 
• 
Biochemistry: creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), albumin, alkaline phosphatase, sodium, glucose 
• 
Coagulation:  Prothrombin Time (International Normalized Ratio/INR) 
• 
Tumor Marker: alpha fetoprotein (AFP) 
• 
Pregnancy test, usually to be done within 24 hours prior to study intervention and results must 
be available prior to administration of study product. 
 
Post-enrollment Laboratory Tests 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. 
• 
Biochemistry: creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), albumin, alkaline phosphatase, sodium, glucose 
• 
Coagulation:  Prothrombin Time (International Normalized Ratio/INR) 
• 
Tumor Marker: alpha fetoprotein (AFP) 
7.2.2 
Other Assays or Procedures 
Serum IL-8 determination:  Venipuncture for blood into yellow top tube (2-3 mL) to collect blood/serum for 
IL-8 at screening and at beginning of cycle 4.  Serum will be collected on site, frozen, and sent on dry ice 
for screening IL-8 assay at Rules Based Medicine.  IL-8 assay will be performed using the Luminex 

Study number: S18-01028 
 
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ELISA so that screening IL-8 level can be determined.  Serum obtained may be saved frozen (-20oC) in 
aliquots for later exploratory analysis. 
 
Pre- (Standard of Care) and On-treatment (Translational/Correlative Study) Tumor Core Biopsies:  
Ultrasound guided or CT guided percutaneous core needle biopsies will be performed by Interventional 
Radiology.  Core needle biopsies (6 cores) will be obtained using 14-18G needles as per Standard of 
Care techniques for both pre-treatment and on-treatment biopsies.  Fresh cores (4 pre-treatment and 6 
on-treatment) will be placed immediately in Miltenyi Tissue Storage Buffer on ice.  Two cores (pre-
treatment only) will go to pathology for SOC evaluation.  Research samples will then be processed and 
analyzed at NYU (Welling Lab). 
7.2.3 
Specimen Preparation, Handling, and Storage 
 
See sections 7.2.2 and 7.2.4 
7.2.4 
Specimen Shipment 
Serum IL-8 determination:  All serum samples for IL-8 determination will be sent frozen on dry ice via 
FedEx overnight shipping to Rules Based Medicine for analysis. Sera obtained at screening or cycle 4 
may be stored frozen (-20oC) and sent in batches on dry ice for analysis in batches at Rules Based 
Medicine.  Serum specimens will only be sent on Mondays-Thursdays. 
 
Pre-(Standard of Care) and On-treatment (Translational/Correlative Study) Tumor Core Biopsies:  Core 
biopsies will be obtained at screening and 2 cores will be provided for clinical pathologic evaluation as 
part of standard of care practice.  An additional 4 cores will be immediately placed in Miltenyi Tissue 
Storage Buffer on ice and sent to the Theodore H. Welling Liver Cancer Lab (Dr. Shanshan Wan and Dr. 
Theodore Welling, NYU Langone Health, Science Building, 4th floor, 435 E. 30th St., New York, NY 
10016).  Study sites separate from NYU will schedule and send core biopsy specimens on Mondays-
Thursdays only, via Fed Ex, overnight.  Cycle 3 tumor core biopsies will be processed in the same 
manner except that all 6 cores will go to Welling lab and no cores will go to SOC pathology. 
 
As of February 2024, specimen analysis is complete, and no samples will be collected or stored for future 
analysis.  
7.3 Study Schedule 
7.3.1 
Screening  
 
Screening Visit (Day -20 to -1)  
• 
Obtain informed consent of potential participant verified by signature on written informed consent 
for screening form. 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Perform medical examinations needed to determine eligibility based on inclusion/exclusion criteria. 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1), AFP, IL-8 levels. 
• 
MRI abdomen (or CT if not eligible), 3 phase IV contrast, liver protocol. 
• 
CT chest (with or without IV contrast). 
• 
Ultrasound or CT guided core tumor biopsy. 
• 
Schedule study visits for participants who are eligible and available for the duration of the study. 
• 
Provide participants with instructions needed to prepare for first study visit. 
• 
Randomize participant to either Arm 1or Arm 2 of study treatment (see Study Schema). 
 

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7.3.2 
Enrollment/Baseline 
 
Enrollment/Baseline Visit (Visit 1, Day 1, Cycle 1) 
• 
Verify inclusion/exclusion criteria. 
• 
Record vital signs, results of physical examinations, and medical history. 
• 
Collect blood for hematology, biochemistry, coagulation, and pregnancy test (Section 7.2.1). 
• 
Administer the study treatment (Arm 1 (control) Nivolumab 240mg IV every 2 weeks 
monotherapy; Arm 2 Nivolumab 240 mg IV plus BMS-986253 2400mg every 2 weeks.. 
• 
Observe for infusion reactions and treat if needed (see Package Insert for Nivolumab and 
Investigator Brochures for BMS-986253). 
 
7.3.3 
Intermediate Visits 
7.3.3.1 
Visit 2 
 
Visit 2, Cycle 1 (Day 15 +/- 3)  
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1). 
• 
Administer the study treatment (Arm 1 (control) Nivolumab 240mg IV every 2 weeks 
monotherapy; Arm 2 Nivolumab 240 mg IV plus BMS-986253 2400 mg IV every 2 weeks. 
 
 
7.3.3.2 
Visit 3 
Visit 3, Cycle 2 (Day 29 +/- 3)  
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1). 
Administer the study treatment (Arm 1 (control) Nivolumab 240mg IV every 2 weeks monotherapy; Arm 2 
Nivolumab 240 mg IV plus BMS-986253 2400 mg IV every 2 weeks. 
7.3.3.3 
Visit 4 
Visit 4, Cycle 2 (Day 45 +/- 3)  
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1). 
Administer the study treatment (Arm 1 (control) Nivolumab 240mg IV every 2 weeks monotherapy; Arm 2 
Nivolumab 240 mg IV plus BMS-986253 2400 mg IV every 2 weeks. 
 
7.3.3.4 
Visit 5 
 
Visit 5, Cycle 3 (Day 59 +/- 3) 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1).  AFP to be determined 
every 8 weeks for 12 months then every 12 weeks thereafter 

Study number: S18-01028 
 
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• 
Collect blood for IL-8 level (Cycle 3 only) 
• 
Administer the study treatment (Arm 1 (control) Nivolumab 240mg IV every 2 weeks 
monotherapy; Arm 2 Nivolumab 240 mg IV plus BMS-986253 2400 mg IV every 2 weeks. 
• 
MRI abdomen (or CT if not eligible), 3 phase IV contrast, liver protocol.  To be performed every 8 
weeks for 12 months, then every 12 weeks thereafter 
• 
CT chest (with or without IV contrast).  To be performed every 8 weeks for 12 months, then every 
12 weeks thereafter 
• 
Tumor objective response determination (RECIST v. 1.1).  To be performed every 8 weeks for 12 
months, then every 12 weeks thereafter 
• 
Ultrasound or CT guided core tumor biopsy (Cycle 3 only). 
 
7.3.3.5 
Visit 6 
Visit 6, Cycle 3 (Day 74 +/- 3) 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1). 
• 
Administer the study treatment. 
 
 
 
7.3.4 
Final Study Visit 
A final study visit will be scheduled if a treatment related or non-treatment related AE occurs such that 
further treatment is not advised, disease progression has occurred, or participant wishes to withdraw from 
the study (or other reasons as listed in Section 5.9). 
 
For participants having suspected disease progression, consideration will be made for ultrasound or CT 
guided tumor biopsy as part of standard of care.  For participants deemed to be deriving a clinical benefit 
despite evidence of disease progression, consideration will be made for continuation of study drug 
treatment.  For example, appearance of new tumors if index tumors have had a response/stable disease 
will be one type of consideration.  If tissue biopsy is obtained, clinical and translational core biopsy tissue 
will be obtained and processed as described (Section 7.2).  Study participants will be informed regarding 
all results of diagnostic imaging studies and clinical pathology biopsy results. 
 
• 
In order to allow continued administration of study treatment despite progression of disease, e.g. 
based on appearance of a new lesion, patients must have absence of symptoms and signs of 
clinically important morbidity due to disease progression (e.g. requirement for additional medical 
management to control symptoms or irradiations to prevent morbidity), absence of symptomatic 
rapid disease progression requiring urgent medical intervention (e.g. spinal cord compression), 
and no decline in ECOG or Karnofsky performance status 
• 
If a patient is treated past disease progression, the patient will be re-consented using a written 
informed consent document at that time. 
• 
Patients treated past disease progression will then be re-evaluated at 3 month intervals with CT 
or MRI to determine if progression is confirmed. 
 
If there are any ongoing AEs or SAEs, participants will continue to receive treatment and follow up as per 
standard of care.  Documentation of resolution or continued progression of AEs/SAEs will be provided.   
 
Final Study Visit (Visit Z, Day Z+/-3)  
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 

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• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1), AFP 
• 
Ultrasound or CT guided biopsy if applicable 
• 
Provide final instructions to participant with regard to management of AEs. 
7.3.5 
Withdrawal/Early Termination Visit 
Significant efforts will be made to continue follow-up of withdrawn or terminated participants or participants 
who discontinue study agent but remain in the study for follow-up, especially for safety and efficacy of 
secondary study endpoints. Every effort will be made to undertake protocol-specified safety follow-up 
procedures to capture AEs, serious adverse events (SAEs), and unanticipated problems (UPs). Subjects 
whom do not wish to continue further follow-up can formally withdraw consent, having the below 
assessments obtained.  The PI and site PIs will attempt to obtain at a minimum survival data on all 
participants lost to follow-up. Methods that will be used prior to stating that a participant is lost to follow up 
will include at least three phone calls to participant or next-of-kin if possible.  A certified letter will be mailed 
if the phone calls fail to secure follow up information. 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1), AFP 
• 
MRI abdomen (or CT if not eligible), 3 phase IV contrast, liver protocol if greater than 6 weeks since 
most recent evaluation radiographic evaluation 
• 
Tumor objective response determination (RECIST v. 1.1). 
• 
Provide final instructions to participant with regard to management of AEs. 
7.3.6 
Unscheduled Visit 
Unscheduled visits may be required for example to evaluate a participant for a suspected AE or to 
evaluate for symptomatic possible disease progression requiring potential study termination and 
consideration of other treatments (e.g. symptomatic bony metastasis requiring radiation therapy).  The 
visit will be documented as “Unscheduled Visit”. 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1), AFP 
 
If clinically indicated: 
• 
MRI abdomen (or CT if not eligible), 3 phase IV contrast, liver 
• 
CT chest (with or without IV contrast). 
• 
Tumor objective response determination (RECIST v. 1.1). 
 
7.3.7 
Follow-Up Visits 
 
The follow-up period will occur for at least every 3 months for 1 year after last study treatment dosage, even 
in patients who discontinue the study drug. 
 
• 
Record survival status 
• 
Record adverse events and concomitant medications as reported by participant or observed by 
investigator. 
• 
Record vital signs, results of medical history, physical exam, height/weight, performance status 
(ECOG). 
• 
Collect blood for hematology, biochemistry, coagulation (Section 7.2.1), AFP 
• 
Record new anti-cancer treatment since last study visit, if applicable 
• 
MRI abdomen (or CT if not eligible), 3 phase IV contrast, liver protocol. 
• 
CT chest (with or without IV contrast). 

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• 
Tumor objective response determination (RECIST v. 1.1). 
 
7.4 Concomitant Medications, Treatments, and Procedures 
 
All concomitant prescription medications taken during study participation will be recorded on the case 
report forms (CRFs). For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in the CRF are 
concomitant prescription medications, over-the-counter medications and non-prescription medications. 
 
7.5 Prohibited Medications, Treatments, and Procedures 
 
Treatment with oral steroids, calcineurin inhibitors, immune suppressive, other immune stimulatory, or 
anti-proliferative agents will not be permitted.  Treatment with other chemotherapeutic agents will not be 
permitted.  If participants are found to be taking such medications after entering treatment in the trial, then 
the participant will be recorded as an AE and undergo early termination from the trial. 
 
7.6 Prophylactic Medications, Treatments, and Procedures 
Topical numbing medications such as Emla cream or lidocaine cream may be used at site of injection.  
Nivolumab can cause severe infusion reactions, which have been reported in less than 1.0% of patients 
in clinical trials. Nivolumab will be discontinued in patients with severe or life-threatening infusion 
reactions. The rate of infusion will be interrupted or slowed in participants with mild or moderate infusion 
reactions. 
 
7.7 Rescue Medications, Treatments, and Procedures 
Corticosteroids may be provided at the discretion of the site clinical investigators as rescue therapy for 
high grade treatment related AEs (e.g. pneumonitis), usually 1-2 mg prednisone equivalents/kg/day and 
then tapered to off as AE resolves. 
 
7.8 Participant Access to Study Agent at Study Closure 
If the study is for any reason terminated due to completed enrollment and follow up, unexpected toxicity, 
or demonstrated superiority of one of the arms, individual participants who are judged to be experiencing 
a clinical benefit will be considered for continued treatment with study drug after consultation with the 
medical monitor assigned by NYULH DSMC and the funding supporter (BMS). If there are patients that 
fall into this criteria, a protocol amendment will be submitted to provide the continued treatment with 
adequate justification in doing so. 
8 Assessment of Safety 
8.1 Specification of Safety Parameters  
8.1.1 
Definition of Adverse Events (AE) 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 

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8.1.2 
Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
8.1.3 
Definition of Unanticipated Problems (UP) 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
8.2 Classification of an Adverse Event 
8.2.1 
Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
8.2.2 
Relationship to Study Agent 
 
The clinician’s assessment of an AE's relationship to study agents (drug,) is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any doubt as 
to whether a clinical observation is an AE, the event should be reported. All AEs must have their 

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relationship to study agent assessed. In a clinical trial, the study product must always be suspect. To help 
assess, the following guidelines are used. 
 
• Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, or 
an alternate etiology has been established. 
 
 
8.2.3 
Expectedness 
 
The PI, Dr. Nina Beri, and the Medical Monitor will be responsible for determining whether an AE is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study agents. 
8.3 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate RF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization.  
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study supporter of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The supporter should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  

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8.4 Reporting Procedures – Notifying the IRB  
Federal regulations require timely reporting by investigators to their local IRB of unanticipated 
problems 
posing risks to subjects or others. The following describes the NYULH IRB reporting 
requirements, though Investigators at participating sites are responsible for meeting the specific 
requirements of their IRB of record. 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 
working days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document and other relevant sources of information, such 
as product labeling and package inserts. 
– Related to the research procedures: An event is related to the research procedures if 
in the opinion of the principal investigator or supporter, the event was more likely 
than not to be caused by the research procedures. 
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional 
deviations from the IRB approved protocol) for any of the following situations: 
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• New Information indicating a change to the risks or potential benefits of the 
research, in terms of severity or frequency. (e.g. analysis indicates lower-than-expected 
response rate or a more severe or frequent side effect; Other research finds arm of 
study has no therapeutic value; FDA labeling change or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event 
Form” or 
as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent 
form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file 

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8.4.1 
Adverse Event Reporting 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 100 days following the last administration of study treatment.  
 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
8.4.2 
Serious Adverse Event Reporting 
 
 
Investigators and the protocol supporter must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported within 5 days of PI notification are those that are: 
• related to study participation, 
• unexpected, and  
• Harmful or have the potential to cause harm (see definitions, section 8.1) 
   
Events should be reported using the NYU CTO Medical Events Form. 
 
Adverse events that do not fit the above immediately reportable criteria must still be reported to the IRB at 
each annual review, either in a summary or tabular format. 
 
Serious adverse event reporting will begin in conjunction with the date of participant’s written 
consent. Any SAEs occurring prior to study drug administration that the investigator believes may 
have been caused 
by a protocol procedure must be reported immediately to the principal 
investigator and PCC Assigned Medical Monitor, 
with 
a 
notification 
email sent to 
NYUPCCsafetyreports@nyulangone.org and recorded on the case report form. 
 
All fatal or life-threatening adverse events must be immediately reported to the Principal Investigator, 
via appropriate reporting mechanism and the NYU Langone Health IRB by telephone or e-mail. 
Within 24 
hours of the event, the Serious Adverse Event Form must be emailed to  
NYUPCCsafetyreports@nyulangone.org  and PCC Assigned Medical Monitor whether full 
information regarding the event is known or not.  
 
Additional follow-up by the investigator will be required if complete information is not known. De-
identified source documentation of all examinations, diagnostic procedures, etc. which were 
completed with respect to the event should be included with the SAE form. Care should be 
taken to ensure that the patient’s identity is protected and the patient’s identifiers (as assigned at 
the time of study enrollment) are properly mentioned on any copy of source document provided to 
the Supporter. For laboratory results, include the laboratory normal ranges. 

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All other serious adverse events must be reported to the supporter and DSMC’s appointed medical 
monitor 
within 24 hours by e-mail (NYUPCCsafetyreports@nyulangone.org) or fax (212-263-
0715). The Serious Adverse Event Form must also be emailed to the principal investigator and 
Clinical Trials Office (NYUPCCsafetyreports@nyulangone.org) or it can be faxed (212-263-0715), 
this documentation will be forwarded to the DSMC’s appointed medical monitor 
within 24 
hours of the event whether full information regarding the event is known or not. Additional follow-
up by the investigator will be required if complete information is not known.  All SAEs that occur 
following the subject’s written consent to participate in the study through 100 days of discontinuation 
of dosing must be reported to BMS Worldwide Safety, whether related or not related to study drug 
within 24 hours of becoming aware of the event. SAEs must be recorded on either MedWatch, or 
approved site SAE form.   
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to BMS Global 
Pharmacovigilance (Worldwide.Safety@bms.com).  
 
The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com the SAE 
reconciliation report and include the BMS protocol number every 3 months and prior to data base lock 
or final data summary 
 
GPV&E will send the investigator the report.  The investigator must verify and confirm all SAEs are 
captured in this report. 
The data elements listed on the GPV&E reconciliation report will be used for case identification purposes. 
If the Investigator determines a case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS (Worldwide.Safety@bms.com). 
 
Current contact information shall be maintained at the site within the regulatory binder. 
 
All serious adverse events (SAEs) will be evaluated by the DSMC if meeting the requirements 
for expedited reporting, the study Supporter will report the adverse event to all regulatory authorities 
with jurisdiction over ongoing trials with the study drug and to all other investigators involved in 
clinical trials with the study drug. The investigator is responsible for reporting all SAEs to the 
appropriate IRB, DSMC, and FDA. 
 
8.4.3 
Unanticipated Problem Reporting 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB and to the DSMC/study 
supporter. The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 

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• UPs that are SAEs will be reported to the IRB and to the DSMC/study supporter within 24 hours of 
the investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the DSMC/study supporter within 24 hours of the 
investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and OHRP within 5 days 
of the IR’s receipt of the report of the problem from the investigator. 
 
8.4.4 
Reporting of Pregnancy 
If a study participant develops a pregnancy, this represents a study exclusion criteria and study drugs will 
be discontinued and the participant will be withdrawn from the study.  The occurrence of the pregnancy 
will be reported the DSMC, BMS, the study PI and medical monitor, the IRB, and the FDA.  The 
pregnancy must be reported immediately to the principal investigator, and the Clinical Trials Office, 
by emailing: NYUPCCsafetyreports@nyulangone.org, and the s t u d y  supporter (NYU Langone 
Health PCC) will report to BMS in accordance with their outlined procedures.  A Final Study Visit 
will be scheduled, however the participant will continue to be followed until pregnancy outcome and 
continuing safety follow up will occur. 
 
8.5 Reporting Procedures – Notifying the Study Supporter 
 
The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to the DSMC/study supporter within 24 hours of site awareness. 
See Section 1, Key Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the DSMC/study supporter within 72 
hours of site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the DSMC/study supporter and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative.  This should include a copy of the completed Unanticipated Problem form, 
and any other diagnostic information that will assist the understanding of the event.  Significant new 
information on ongoing unanticipated adverse effects shall be provided promptly to the study supporter.  
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 
hours  of becoming aware of the event. SAEs must be recorded on either  MedWatch, or approved site 
SAE form.  
  
Pregnancies must be reported and submitted to BMS on either the MedWatch or approved site SAE form.  
In addition the Pregnancy Surveillance Form (3 Parts) must be completed and submitted to BMS.  BMS 
will perform due diligence follow-up using the BMS Pregnancy Form which the investigator must 
complete.  
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
 
Adverse Events that are routinely collected according to GCP shall be submitted to BMS every three (3) 
months by the last working day of the third month.   

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The Adverse Event information required to be sent to BMS is noted in an attached ‘Bristol-Myers Squibb 
Early Asset Investigator Sponsored Research (ISR) Import Plan’, which describes the method of 
collection and submission to BMS via the mailbox: 
MG-RD-GPVE-PHARMACOVIGILANCE@bms.com 
When the file is submitted to BMS, it must be noted  the file contains 
1) all Non Serious Adverse Events (only adverse events not previously submitted to BMS within 
the 3 months)  
 
 
 
 
8.6 Reporting Procedures – Notifying the Study Supporter  
Since multiple sites will be participating, the following describes events that must be reported to the 
study supporter (NYU Langone Health PCC) and the study supporter reports to BMS in an expedited 
fashion.  
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 
24 hours  of becoming aware of the event. SAEs must be recorded on either  MedWatch, or 
approved site SAE form.   
 
Pregnancies must be reported and submitted to BMS.  BMS will perform due diligence follow-up 
using the BMS Pregnancy Form which the investigator must complete.  
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
 
   
 
Initial Report: within 24 hours: 
The following events must be reported to the study supporter (NYULMC PCC) by email within 24 
hours of awareness of the event using the NYU CTO Medical Events Form: 
 
• Unanticipated problems related to study participation, 
• 
Serious adverse events, regardless of whether they are unexpected. 
The investigator shall maintain a copy of the Medical Events Form on file at the study site. All report 
forms must be signed and dated by the Principal Investigator. If the Principal Investigator is not 
available at the time of the initial report, then the form can be submitted by a Co-Investigator. This 
form should be reviewed by the Principal Investigator, whom sign/date initial report upon return. 
 
Report to: 
 
 
 
NYUPCCsafetyreports@nyulangone.org 
 
 
 
 
 
 
AND 
 
Nina Beri, MD 
Laura & Isaac Perlmutter Cancer Center 
NYU Langone Health 
240 East 38th Street, New York, NY 10016 

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Nina.Beri@nyulangonec.org 
Phone:  212-731-5770 
 
AND 
PCC Assigned Medical Monitor 
Events of Clinical Interest (any medical event that is deemed significant via Principal Investigator’s 
expertise, but does not apply to SAE categories) will be reported within 2-5 days, or as per study 
Supporter specifications 
 
 
8.7 Reporting Procedures – Notifying the FDA  
 
The study supporter is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated 
type of event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
 
Additional reporting requirements 
Supporters are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form; see Attachment1), or in a 
narrative format. If supplied as in a narrative format, the minimum information to be supplied is noted 
above at the beginning of section 8.3. The contact information for submitting IND safety reports is noted 
below: 
 
NYU Langone Health Contacts: 
 
NYUPCCsafetyreports@nyulangone.org 
 
AND 
 
Nina Beri, MD 
Laura & Isaac Perlmutter Cancer Center 
NYU Langone Health 
240 East 38th Street, New York, NY 10016 

Study number: S18-01028 
 
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Nina.Beri@nyulangone.org 
Phone:  212-731-5770 
 
AND 
 
PCC Assigned Medical Monitor 
8.8 Reporting Procedures – Participating Investigators  
 
In addition to reporting certain unanticipated problems and adverse events noted above to the FDA, it is 
the responsibility of the study supporter to report those same adverse events or findings to participating 
investigators at other study sites. The same materials and timeline used to report to the FDA are used 
for notifying participating investigators. 
8.9 Study Halting Rules 
 
Administration of study agent will be halted when four grade 4 AEs and/or AEs that would require 
permanent discontinuation of study drugs (See Section 6.1.8) determined to be “probably related” are 
reported to the PI and the Medical Monitor. The study supporter and PI will notify investigators 
immediately when the third grade 4 event is reported and enrollment screens will stop accepting new 
study participants. The study supporter will inform the DSMC members within 24 hours of this occurrence 
and will provide the DSMC with AE listing reports. The DSMC will convene an ad hoc meeting by 
teleconference or in writing as soon as possible. The DSMC will provide recommendations for proceeding 
with the study to the study supporter/NIH. The study supporter will inform the FDA of the temporary halt 
and the disposition of the study. 
8.10 Safety Oversight 
A Medical Monitor will be appointed to advise the study investigators and will monitor participant safety. 
The role of the Medical Monitor is to 1) Review all AEs on a regular basis throughout the trial; 2) be 
available to advise the investigators on trial-related medical questions or problems, and 3) evaluate 
cumulative participant safety data and make recommendations regarding the safe continuation of the 
study.  
 
 
All Internal SAEs reported by the CTO, occurring to patients on clinical trials that are not monitored 
by any other institution or agency, are reported via email: NYUPCCsafetyreports@nyulangone.org 
and reviewed within 48 hours by the medical monitor. Based on the review, one of three 
determinations will be made: 
 
• 
SAE report is considered to be adequate 
• 
Queries for clarification to PI regarding treatment attribution and/or resolution of 
SAE or 
completeness of other information. The committee may request a 
cumulative review of all SAEs on the study to date. 
• 
Request for full DSMC committee review of protocol at the next scheduled meeting. 
 
The DSMC Coordinator will record the committee’s decision and incorporate it into the study 
summary for the next scheduled study review. 
 
 
 
 

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Safety oversight will be under the direction of a DSMC composed of individuals with the appropriate 
expertise, including clinical investigators/oncologists, biostatisticians, nurses, and research administration 
staff knowledgeable of research methodology and design and in proper conduct of clinical trials. The 
DSMC will meet at least quarterly to assess safety and efficacy data on each arm of the study. The 
DSMC operates under the rules of an approved charter. The DSMC will provide its input to Bristol-Myers 
Squibb. 
 
 
9 Clinical Monitoring 
 
 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan. 
Serious adverse events are evaluated regularly by the principal investigator in conjugation with the 
research team, the DSMC is notified of serious adverse events via email initially, reviewed offline by 
the designated medical monitor, and presented at the next DSMC monthly meeting. The Data 
Safety and Monitoring Committee (DSMC) will review the study at least quarterly. Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
 
 
 
9.1 
Data Monitoring Committee 
 
 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee (DSMC) of the 
New York University (NYU) Perlmutter Cancer Center (PCC). The DSMC operates based on the National 
Cancer Institute approved Charter.  It is an existing and multidisciplinary committee (consisting of clinical 
investigators/oncologists, biostatisticians, nurses, and research administration staff knowledgeable of 
research methodology and design and in proper conduct of clinical trials) that is responsible for monitoring 
safety, conduct and compliance in accordance with protocol data monitoring plans for interventional clinical 
trials conducted in the NYULMC Perlmutter Cancer Center that are not monitored by another institution or 
agency. The DSMC reports to the Director of the NYULH PCC.   
 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this phase II trial will be monitored by 
DSMC quarterly (from the date the first patient is enrolled), at protocol-specified interim time points, 
and at the completion of the study prior to study closure. This review includes accrual data, subject 
demographics and adverse events. Principal Investigators are required to attend the review of 
their studies. Additional reviews can be scheduled based on SAE reports, investigator identified 
issues, external information, etc. The DSMC will review safety data every 3 months.  DSMC summary 
reports are available to facilitate the review and monitoring of this study.    These reports include the 
following:  patient listings and summary reports that describe study enrollment and accrual, eligibility, 
demographic characteristics, dose modifications, adverse experiences, subject’s death and additional 
external published data if applicable to the study.  Cumulative toxicities, SAEs, and AEs are reviewed, 
to identify possible adverse events with elevated frequency that is unexpected.  Once a 

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recommendation is made if further action is required, the Investigator’s must respond within of the time 
period specified in the DSMC letter.   
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
A formal SAP will be completed prior to database lock. 
 
10.2 Statistical Hypotheses 
The null hypothesis for the primary endpoint is that there is no difference in the ORR of the Nivolumab 
and BMS-986253 combinationand the ORR of the Nivolumab monotherapy. 
The null hypothesis for the secondary endpoint is that there is no difference in TTR, DOR, PFS, OS, and 
safety for the Nivolumab and BMS-986253 combination and the Nivolumab monotherapy arm. 
The alternative hypothesis for the primary endpoint is that there is a difference in the ORR of the 
Nivolumab and BMS-986253 combinationand the ORR of the Nivolumab monotherapy. 
The alternative hypothesis for the secondary endpoint is that there is a difference in TTR, DOR, PFS, OS, 
and safety for the Nivolumab and BMS-986253 combinationand the Nivolumab monotherapy arm. 
10.3 Analysis Datasets 
The analysis dataset will be the Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized 
participants). 
 
10.4 Description of Statistical Methods 
10.4.1 
General Approach 
Descriptive statistics will be provided for every covariate and outcome by the studied arms. Continuous 
data will be presented as means with standard deviations, and categorical data will be presented as 
numbers with percentages. All p-values will be two sided. Normality assumptions will be checked and log 
transformation will be considered if normality assumption is violated. 
 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
ORR will be defined as the best objective response using RECIST v.1.1 criteria based on MRI or CT scan 
evaluations following treatment.  ORR will be compared by two-sample proportion test between BMS-
986253 in combination with Nivolumab in comparison to Nivolumab monotherapy. P-values will be two-
sided and any p-values less than 0.05 will be significant.  No adjustment to significance determination for 
multiple comparisons will be made. 
10.4.3 
Analysis of the Secondary Endpoint(s) 
Secondary Endpoints, including TTR, DOR, PFS, OS, and exploratory analysis of the HCC TME, will be 
performed.  TTR and DOR will be described and PFS and OS will be compared between subjects 
receiving BMS-986253 in combination with Nivolumab in comparison to Nivolumab monotherapy.  
Kaplan-Meier method will be used to analyze the median TTR, DOR, PFS, and OS.  Categorical variables 
will be compared by two-sample proportion test, survival outcomes will be compared by log rank test, and 
continuous outcome will be compared by two-sample t-test. 

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10.4.4 
Safety Analyses 
Descriptive statistics will be provided for every safety endpoints by the studied arms. The occurence of 
safety endpoints will be compared between BMS-986253 in combination with Nivolumab in comparison to 
Nivolumab monotherapy.  
 
The first six patients assigned in each arm will be monitored for AEs meeting DLT criteria as specified in 
Section 5.  Dose Limiting Toxicities will be defined by toxicity occurring during the first 4 weeks of 
treatment on this study.  If no treatment related AE is observed in >=4 of 6 patients, the study will 
continue as planned. If >2 out of 6 patients are observed to have treatment  related AE (i.e., AE with no 
clear alternative explanation) meeting DLT criteria that has not been observed in the use of nivolumab 
monotherapy as described in the package insert, then a lower dose strategy for BMS-986253 (1200 mg 
IV q 2 weeks) vs. discontinuation of Arm 2 will be implemented in coordination with the DSMC and the 
study supporter.    
 
10.5 Sample Size 
Group sample sizes of 25 in Nivolumab combination group and 25 in Nivolumab-only monotherapy group 
achieve 80% power to detect a difference between the group ORRs of 34%. The ORR in Nivo-only group 
is assumed to be 15%. The ORR in Nivolumab combination group is assumed to be 49% under the 
alternative hypothesis. The test statistic used is the two-sided Z-Test with unpooled variance. The 
significance level of the test is 0.05. 
 
The powered sample size and expected ORR is based upon results from the phase II study of nivolumab 
in HCC as well as other checkpoint inhibitors (e.g. pembrolizumab) in HCC. If the results do not show 
significant efficacy, the HRs and 95% CIs will be estimated to quantify the magnitude of the efficacy in each 
treatment arm. If results are sufficiently promising, then the protocol may be amended to expand the cohort 
to allow comparison between treatments with higher confidence. 
 
10.6 Randomization 
  The randomization list will be generated by the biostatistics department according to the proposed 
sample size and study design and uploaded into the REDCap randomization module.  All centers will 
receive randomization assignment from NYU as the coordinating center.  If a patient is randomized, but 
not ultimately treated, then the coordinating center (NYU PCC) must be notified.  Randomization will be 
stratified within center.   
11 Source Documents and Access to Source Data/Documents 
 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 
documents. If this is the case, it should be stated in this section what data will be collected on CRFs and 
what data will be collected from other sources. 
 
Trialmaster, an electronic database capture system will be created to record the data for this trial.  Research 
coordinators will input clinical trial data into the database.  This database is password protected and only 
the PI, assigned study team members, and CTO staff will have access to the database.  DataCore, a core 
resource of the institution, will provide the primary data collection instrument for the study.  All data 

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requested in the system must be reported.  All missing data must be explained.  The quality assurance 
specialists will monitor this trial every 4-6 weeks for data entry accuracy. 
 
Source documentation should be consistent with data entered into any electronic medical record or 
Trial 
master.  Relevant source documentation to be reviewed by the assigned QA specialist 
throughout the study includes: 
 
1.  Baseline measures to assess pre-protocol disease status 
2.  Concurrent medications 
3.  Treatment records 
4.  Adverse events 
 
12 Quality Assurance and Quality Control 
This study will be monitored according to the monitoring plan detailed below.  Sub-site monitoring will 
follow parameters detailed in Section 12.1.  The Investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given access to all the above noted study-related documents.  
If an on-site monitoring visit is necessary, the Investigator will provide access to all study related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.), and ensure there is adequate space to conduct the 
monitoring visit. A risk-based, data-driven monitoring approach will be used to verify data for this trial 
which will also include a centralized review of data for quality, trends, consistency and general safety 
review.  At each visit, the monitor will review various aspects of the trial including, but not limited to:  
screening and enrollment logs; compliance with the protocol and study manual and with the principles of 
Good Clinical Practice; completion of case report forms; source data verification; study drug accountability 
and storage; facilities and staff. 
 
At any time during the course of the study, representatives of the FDA and/or local regulatory 
agencies may review the conduct or results of the study at the investigational site. The investigator 
must promptly inform NYU PCC CTO and BMS of any audit requests by health authorities, and will 
provide BMS with the results of any such audits and with copies of any regulatory documents related 
to such audits. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use 
personal identifiable health information may be required from each patient before commencement 
of research 
activities. This authorization document must clearly specify what parties will have 
access to a patient’s personal health information, for what purpose and for what duration. 
 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a 
standardized   data and safety monitoring, which includes scientific peer review, IRB review and 
DSMC review as well as internal auditing. 
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal 
investigator in conjunction with the research nurses, data manager and research team. 
 
(2) DSMC, quarterly 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the trial PI 
for continuation of the protocol. It includes a summary of all AEs, total enrollment with 
demographics, protocol violations, and current status of subjects as well as available 
research data. 

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In addition, the quality assurance unit will monitor this trial every 4-6 weeks; this includes real- time 
review of all eCRFs to ensure completeness and to verify adherence to the protocol; the completeness, 
accuracy and consistency of the data; and adherence to ICH Good Clinical 
Practice guidelines. 
Additionally, a first subject audit is to be conducted within four weeks of enrollment. 
 
 
 
12.1 Monitoring of Other Participating Institutions 
Monitoring visits are done remotely unless otherwise specified, via remote EMR access. If not possible, 
secure email exchange will be utilized. The quality assurance specialist will confirm an upcoming 
monitoring visit with a Site Investigator and staff. If remote EMR access is not available, then the Site 
Coordinator will ensure that all source documents for subjects are de-identified and labeled only with 
the subject ID number(s), before emailing all requested documents to the quality assurance specialist 
within 5 business days from  the date of the visit. Any outstanding documents will be listed in the report 
as a high- priority request for the next monitoring visit. It is expected that response to data clarification 
requests and other trial-related inquiries will occur throughout the course of the study through regular 
communication with the site monitor, the Supporter or representatives, and review/entry of data into 
the electronic study database. Continued non-compliance and failure to submit documentation will 
result in the suspension of subject enrollment at the site, until the documents have been received. 
 
 
13 Ethics/Protection of Human Subjects 
13.1 Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
13.2 Institutional Review Board 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
13.3 Informed Consent Process 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The following consent materials are submitted with this protocol: 
Informed Consent. 
 
13.3.2 
Consent Procedures and Documentation 
 

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Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB-
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants should have 
the opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. 
The participant will sign the informed consent document prior to any procedures being done specifically 
for the study. The participants may withdraw consent at any time throughout the course of the trial. A 
copy of the signed informed consent document will be given to the participants for their records. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The 
consent process, including the name of the individual obtaining consent, will be thoroughly documented in 
the subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, 
consent from a legally authorized representative, consent document presented orally, etc.) and the 
justification for such alteration will likewise be documented.  
 
The informed consent process and documentation will follow established institutional guidelines. 
 
13.3.3 
Informed Consent 
Consent will be obtained only by a participating investigator who has completed requisite training 
for human subject research and has been instructed by the Principal Investigator about the 
research study 
and consent process. Investigators will review the informed consent form with 
patients and address any questions or concerns prior to obtaining written informed consent for 
participation and HIPAA authorization. 
 
Patients will be given adequate time to read the consent form. They will be given time to ask 
questions about the study in private exam rooms. Questions will be answered by a participating 
physician, or qualified research study team member all of whom have completed requisite training 
for human subject research. Investigators will review the informed consent form with patients and 
address any questions or concerns prior to obtaining written informed consent for participation. 
Investigators will stress that participation in the study is completely voluntary and will not affect 
the care patients receive or result in any loss of benefits to which patients are otherwise entitled. 
 
For non-English speaking patients, institutional translation services will be utilized. All procedures 
for consenting non-English speaking patients will be in accordance with NYU Langone Health 
PCC CTO guidelines and policies. 
 
For patients who cannot read; a witness, not related to the research study will be present. The 
consent will be read to the patient. The patient will also be allowed to ask any questions s/he 
may have. The investigator will ask the patient questions to ensure s/he understands the study. 
If the investigator determines the subject understands the study, the patient will mark an X where 
his/her name would go and the witness will sign the consent form. 
  

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13.3.4 
Documentation of Consent 
The Principal Investigator or IRB approved sub-investigator will be responsible for documentation in the 
medical record that consent has been obtained from all participants. A signed copy of the consent form will 
be given to each participant. Original consent forms will be stored in the subject’s medical chart. 
 
13.3.5 
Patient Informed Consent at Additional Sites 
The Principal Investigator (PI) at each participating site will identify the physician members of the study 
team who will be obtaining consent and signing the consent form for therapeutic protocols. It is NYULH 
policy that Nurses and Fellows cannot obtain consent to greater than minimal risk trials, unless Fellows are 
listed as co-investigators.  
 
The Investigator must ensure that each participant is fully informed about the nature and objectives of the 
study and possible risks associated with participation. All participants must be provided a consent form 
describing this study and providing sufficient information for participants to make an informed decision about 
their participation in this study. The formal consent of a participant, using the IRB approved consent form, 
must be obtained before the participant is involved in any study-related procedure. The consent form must 
be signed and dated by the participant and by the person obtaining the consent. The participant must be 
given a copy of the signed and dated consent document. The original signed copy of the consent document 
must be retained in the medical record or research file. 
 
All parties will ensure protection of participant personal data and will not include participant names on any 
sponsor forms, reports, publications, or in any other disclosures, except where required by laws.  In case 
of data transfer, NYULH Perlmutter Cancer Center (PCC) will maintain high standards of confidentiality and 
protection of participant personal data. 
 
The informed consent form must be in compliance with ICH/GCP, local regulatory requirements, and legal 
requirements. 
 
The informed consent form used in this study, and any changes made during the course of the study, 
must be prospectively approved by both the IRB and NYULH before use. 
 
 
13.4 Participant and Data Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
supporter(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No information 

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concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the supporter. 
 
The study monitor, other authorized representatives of the supporter, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at NYU Langone Health. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical sites 
and by NYU Langone Health research staff will be secured and password protected. At the end of the 
study, all study databases will be de-identified and archived at the NYU Langone Health. 
 
13.4.1 
Research Use of Stored Human Samples, Specimens, or Data 
As of February 2024, specimen analysis is complete, and no samples are left in storage.  
• Intended Use: Samples and data collected under this protocol may be used to study 
hepatocellular carcinoma and its tumor microenvironment. No genetic testing will be performed 
other than tumor mutational analysis. 
• Storage: Access to stored samples will be limited using the PI, Dr. Theodore Welling. Samples 
and data will be stored using codes assigned by the investigators. Data will be kept in password-
protected computers. Only investigators will have access to the samples and data. 
• Tracking: Data will be tracked using Trialmaster. 
Disposition at the completion of the study: All stored samples will be sent to the study primary 
investigator, Dr. Welling. Study participants who request destruction of samples will be notified of 
compliance with such request and all supporting details will be maintained for tracking.  However, 
withdrawal of consent with regards to specimens storage will not be possible after the study is completed.  
13.5 Future Use of Stored Specimens  
 
Data collected for this study will be analyzed and stored at NYU Langone Health. After the study is 
completed, the coded and de-identified, archived data will be archived at the Perlmutter Cancer Center 
Clinical Trials Office. Permission to transmit data to the Clinical Trials Office will be included in the 
informed consent. Storage of samples, specimens, and data are required in order for subjects to 
participate in the study.   
 
Any leftover materials from the biological samples collected per protocol will be stored and used for future 
research. The storage of samples and data for future research will be used to research into the causes of 
hepatocellular carcinoma, its complications, and other conditions for which individuals of hepatocellular 
carcinoma are at increased risk, and to improve treatment. There can also be other research aims that 
are unknown at this time. Data and samples will be kept for 15 years, or until samples are completely 
used and/or data is no longer needed, whichever comes first.  With the participant’s approval and as 
approved by local IRs, de-identified biological samples will be stored at the Theodore H. Welling Liver 
Cancer Laboratory. The Theodore H. Welling Liver Cancer Laboratory will also be provided with a code-
link that will allow linking the biological specimens with the phenotypic data from each participant, 
maintaining the masking of the identity of the participant. Samples will be labeled with freezer viable 

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labels and stored in freezers that are temperature monitored with emergency back-up generators. The 
linking key will remain with the PI, Theodore H. Welling. As of February 2024, specimen analysis is 
complete, and no samples are left in storage. 
 
True genetic testing will not be done on the samples stored for future research, and no results will be 
shared with the study participants,   
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to biological 
sample storage will not be possible after the study is completed. Subjects will be able to withdraw their 
consent by writing to the Principal Investigator of the study. Upon receipt of the subject’s written 
statement, the Principal Investigator and affiliated laboratory members will ensure the stored samples are 
discarded.  
 
When the study is completed, access to study data will be provided through the Perlmutter Cancer Center 
Clinical Trials Office by the permission of Dr. Beri.   
 
14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be maintained for recording data for each participant enrolled in 
the study. Data reported in the eCRF derived from source documents should be consistent with the 
source documents or the discrepancies should be explained and captured in a progress note and 
maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into Trialmaster, a 21 CFR Part 11-compliant data capture system 
provided by Data Core. The data system includes password protection and internal quality checks, such 
as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
 
14.2 Study Records Retention 
 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for the drug 
for the indication for which it is being investigated or 2 years after the investigation is discontinued and 
FDA is notified if no application is to be filed or if the application has not been approved for such 
indication. No records will be destroyed without the written consent of the supporter, if applicable. It is the 
responsibility of the supporter to inform the investigator when these documents no longer need to be 
retained. 
 
 

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14.3 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
 
All protocol deviations must be addressed in study source documents, reported to NYULH PCC CTO and  
BMS Program Official. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. All protocol deviations must be 
addressed in study source documents and reported to IRB Program Official at the time of annual 
continuing review.  If a protocol deviation is determined to be reportable new information, the IRB will 
be notified immediately.   
14.4 Publication and Data Sharing Policy 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is supportered by the 
National Library of Medicine. Other biomedical journals are considering adopting similar policies. For 
interventional clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s 
responsibility to register the trial in an acceptable registry, so the research results may be considered for 
publication in ICMJE member journals. The ICMJE does not review specific studies to determine whether 
registration is necessary; instead, the committee recommends that researchers who have questions 
about the need to register err on the side of registration or consult the editorial office of the journal in 
which they wish to publish. 
 
FDAAA mandates that a "responsible party" (i.e., the supporter or designated principal investigator) 
register and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 

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• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
 
15 Study Finances 
15.1 Funding Source 
 
This study is financed through funding from Bristol-Myers Squibb. 
15.2 Costs to the Participant 
There are no additional costs to the study participants. 
15.3 Participant Reimbursements or Payments 
No subjects will receive payments or stipends for participation in this research study.  BMS will provide 
coverage of tests and procedures that are not covered by the participant’s insurance/standard of care 
(e.g. IL-8 serum measurements and on-treatment biopsy). 
 
16 Study Administration 
16.1 Study Leadership 
 
The Steering Committee will govern the conduct of the study. The Steering Committee will be composed 
of the PI, Dr. Nina Beri, representatives of the PCC CTO, and the PI of the clinical sites. The Steering 
Committee will meet in person or via teleconference at least monthly, these meetings are facilitated by 
CTO’s quality assurance specialists. 
17 Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership in conjunction with the NYU 
PCC CTO has established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study supporter prior to participation in this study. All 
NYULH investigators will follow the applicable conflict of interest policies. 
 

Study number: S18-01028 
 
Page 50 
Version: 11.0 
 
 
18 References 
 
1. 
El-Serag HB. Hepatocellular carcinoma. The New England journal of medicine. 
2011;365(12):1118-27. 
2. 
Sawyers CL, Abate-Shen C, Anderson KC, Barker A, Baselga J, Berger NA, et al. AACR Cancer 
Progress Report 2013. Clin Cancer Res. 2013;19(20 Suppl):S4-98. 
3. 
Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical 
patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective 
study. Hepatology (Baltimore, Md. 2016;63(3):827-38. 
4. 
Bruix J, Reig M, and Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients 
With Hepatocellular Carcinoma. Gastroenterology. 2016;150(4):835-53. 
5. 
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced 
hepatocellular carcinoma. The New England journal of medicine. 2008;359(4):378-90. 
6. 
Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with 
hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. 
7. 
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with 
advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 
1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-502. 
8. 
Wan S, Kuo N, Kryczek I, Zou W, and Welling TH. Myeloid cells in hepatocellular carcinoma. 
Hepatology. 2015. 
9. 
Wu K, Kryczek I, Chen L, Zou W, and Welling TH. Kupffer cell suppression of CD8+ T cells in 
human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer 
research. 2009;69(20):8067-75. 
10. 
Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, et al. Activated monocytes in peritumoral 
stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-
L1. The Journal of experimental medicine. 2009;206(6):1327-37. 
11. 
Ruffell B, and Coussens Lisa M. Macrophages and Therapeutic Resistance in Cancer. Cancer 
Cell.27(4):462-72. 
12. 
Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, et al. Tumor-associated 
macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human 
hepatocellular carcinoma stem cells. Gastroenterology. 2014;147(6):1393-404. 
13. 
Fernando RI, Castillo MD, Litzinger M, Hamilton DH, and Palena C. IL-8 signaling plays a critical 
role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res. 
2011;71(15):5296-306. 
14. 
Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, et al. Tumor-associated leukemia 
inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like 
cells. Blood. 2007;110(13):4319-30. 
15. 
Grugan KD, McCabe FL, Kinder M, Greenplate AR, Harman BC, Ekert JE, et al. Tumor-
Associated Macrophages Promote Invasion while Retaining Fc-Dependent Anti-Tumor Function. 
The Journal of Immunology. 2012;189(11):5457-66. 
16. 
Welling TH, Fu S, Wan S, Zou W, and Marrero JA. Elevated serum IL-8 is associated with the 
presence of hepatocellular carcinoma and independently predicts survival. Cancer Invest. 
2012;30(10):689-97. 
19 Attachments 
These documents are relevant to the protocol, but they are not considered part of the protocol.  They are 
stored and modified separately. As such, modifications to these documents do not require protocol 
amendments. 
 
• Investigator Agreement (for any investigator, other than supporter-investigator, who participates in 
the study) 
• Sample Consent Form 
• Study Procedures Flowchart/Table 

Study number: S18-01028 
 
Page 51 
Version: 11.0 
 
 
• Study Monitoring Plan 
• Core Lab Instructions To Investigators 
• Specimen Preparation And Handling (e.g. for any specialized procedures that study team must 
follow to process a study specimen, and/or prepare it for shipment) 
• Nivolumab Package Insert 
• BMS-986253 Investigator Brochure 
• Women of Childbearing Potential Definitions and Methods of Contraception 
 

Study number:  s18-01028  
 
Page 52 
Version:  1.0 
 
 
20 Schedule of Events 
 
STUDY DAY 
► 
Pre-
study, 
screening 
C1D1 
C1D15  
C2D1 (Day 
29+/- 3 days) 
C2D15 
(Day 45+/- 
3 days) 
C3D1 (Day 
59+/- 3 
days) 
C3D15 
(Day 74+/- 
3 days) 
Subsequent 
Visits* 
(Estimate  
24 visits 
average) 
Follow 
UpF 
(Day -20 
to -1) 
  
(+/- 3 
days) 
 
 
 
  
  
  
  
  
  
 
  
 
Study Team 
Procedures 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
  
  
  
  
  
 
  
 
Medical 
History 
X 
  
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
  
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
 
 
 
 
 
X 
Weight 
X 
  
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
X 
ECOG 
Performance 
Status 
X 
  
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Evaluations 
(AE reporting) 
  
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RECIST v. 
1.1A  
X 
  
  
  
X 
 
X 
XF 
Study DrugsB  
  
X 
X 
X 
X 
X 
X 
X 
 
Venipuncture 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
CBC, CMP, 
INR 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Study number: S18-01028 
 
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Version: 11.0 
 
 
AFPC  
X 
  
  
  
X 
 
X 
XF 
TSH Testing 
X 
 X 
 
X 
 
X 
 
X 
 
Venipuncture 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
Pregnancy 
Test 
X 
  
  
  
  
  
  
 
Translational 
Peripheral 
Blood SampleD  
X 
  
  
  
X 
 
  
 
Tumor Biopsy  
X 
  
  
  
 
X 
 
  
 
Fresh frozen 
tissue from 
core biopsy 
(Processing) 
X 
  
  
  
X 
 
  
 
Imaging 
Assessments 
 
 
 
 
 
 
 
 
 
ImagingE  
 
X 
  
  
  
X 
 
X 
XF 
A every 8 weeks for 12 months, see Schema 
B Arm 1: Nivolumab 240 mg IV every 2 weeks; Arm 2:  BMS-986253 2400mg IV + Nivolumab 240mg IV every 2 weeks;    
C AFP to be checked pre-study and at every 8 weeks for 12 months, see Schema 
D IL-8 level and other, cycle 3 only 
E 3-phase liver CT, or MR abdomen with contrast every 8 weeks for 12 months, see Schema 
F every 3 months for 1 year, See Schema 
*Scheduled treatment visits occurring after Cycle3