Clinical trial NCT03656718
Conditions: Neoplasms by Site
Keywords: Subcutaneous Nivolumab rHuPH20
Sponsor: Bristol-Myers Squibb
Start date: 2018-10-29; Completion date: 2024-09-12
Enrollment: 139 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the effects of nivolumab when given under the skin with or without rHuPH20.

This study will include participants with 1 of the following advanced or metastatic tumors approved for treatment with nivolumab monotherapy:

* non-small cell lung cancer (NSCLC)
* renal cell carcinoma (RCC)
* unresectable or metastatic melanoma
* hepatocellular carcinoma (HCC)
* microsatellite instability-high or mismatch repair deficient colorectal cancer (MSI-H/dMMR CRC)
* in Part B, other solid tumors may be considered at the discretion of the Clinical Trial Physician
* In addition to the above tumors, Part E will also include participants with metastatic urothelial carcinoma (mUC).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None
Interventions: intervention 1: nivolumab intervention 2: rHuPH20 intervention 3: nivolumab
Intervention descriptions: intervention 1: (Subcutaneous) Specified dose on specified days intervention 2: Specified dose on specified days Permeation enhancer intervention 3: (IV) Specified Dose on Specified Days

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
Phase I/II Pharmacokinetic Multi-Tumor Study of Subcutaneous Formulation of Nivolumab 
Monotherapy 
 
NCT Number: NCT03656718 
Document Date (Date in which document was last revised): 08 September 2021 


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Phone 
ail: 
Page: 
Protocol Number: 
IND Number: 
EX-US 
1 
CA2098KX 
138,302 
Non-IND 
EUDRACT Number: 2018-001585-42 
Date: 13-Jun-2018 
Revised Date: 08-Sep-2021 
 
CLINICAL PROTOCOL CA2098KX 
Phase I/II pharmacokinetic multi-tumor study of subcutaneous formulation of nivolumab 
monotherapy 
Protocol Amendment 05 
Incorporates Administrative Letter 06 
 
Clinical Trial Physician - Medical 
Monitor 
Bristol-Myers Squibb Company 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Em 
Clinical Scientist 
Bristol-Myers Squibb Company 
86 Morris Ave. 
Summit, NJ 07901 
Em 
 
24-hr Emergency Telephone Number 
USA: 
International: 
 
Bristol-Myers Squibb Company 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Route 206 & Province Line Road 
Lawrenceville, NJ 08543 
Avenue de Finlande 4 
B-1420 Braine-l’Alleud, Belgium 
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
Phone 
ail: 


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be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO). 


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DOCUMENT HISTORY 
 
Document 
Date of Issue 
Summary of Change 
Protocol 
Amendment 05 
08-Sep-2021 
The primary purpose for the amendment is to 
collect additional pharmacokinetic 
(PK) samples of nivolumab at steady state in Part E of the study (600 mg 
subcutaneous (SC) Q2W coformulated with rHuPH20). 
Exclusion criteria were clarified 
. 
Updated study personnel. 
Administrative 
Letter 06 
26-May-2021 
Updated study personnel. 
Protocol 
Amendment 04 
02-Apr-2021 
Changes were made to the protocol to add a new cohort (Part E) with a 
600 mg Q2W regimen of subcutaneous (SC) nivolumab coformulated with 
recombinant human hyaluronidase PH20 (rHuPH20), administered manually 
by syringe. Approximately 36 participants with advanced/metastatic tumors, 
including approximately 10 participants with metastatic urothelial carcinoma 
(mUC), will be enrolled in Part E. 
Updated to incorporate modified background information and safety 
information (including contraceptive requirements) for nivolumab. 
Aligned dose modification criteria with Common Terminology Criteria for 
Adverse Events (CTCAE) v5. 
Included considerations in the context of the coronavirus disease 2019 
(COVID-19) pandemic. 
Updated study personnel. 
Revised 
Protocol 03 
25-Oct-2019 
Updated to increase participant number in Part D, and to identify the dose of 
SC nivolumab to be used for Parts C and D. 
Administrative 
Letter 05 
06-May-2019 
Updating study personnel 
Administrative 
Letter 04 
24-Apr-2019 
Confirming the Part B Cycle 1 dose of 960mg for Group 3 and Group 4 
Administrative 
Letter 03 
26-Feb-2019 
Updating study personnel 


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Document 
Date of Issue 
Summary of Change 
Revised 
Protocol 02 
11-Dec-2018 
Changes from Administrative Letter 02. 
Assignment (n = 10) / randomization (n = 20) of participants in Part B after 
dosing in Part A. 
Inclusion/Exclusion criteria only assessed during screening visit. 
Removed requirement for exclusion of participants based on positive urine 
screen for drugs of abuse. 
In Part B, other solid tumor types may be considered for enrollment at the 
discretion of the Medical Monitor. 
Updated frequency of scans for response/survival follow-up. 
Timing, method, and type of tumor tissue specimens from biopsy defined, 
including exceptions for participants who had a biopsy in the preceding 12 
months. 
Added criteria to the following sections takes into account anticipated 
compromise of baseline liver function in participants with HCC: 
• 
Inclusion/exclusion criteria 
• 
Criteria for dose delay, dose resumption, and dose discontinuation 
• 
Management of hepatic adverse events 
• 
Drug-induced liver injury 
Further characterized the Evaluable PK Participants population and defined 
what is considered an inadequate PK profile. 
Removed reference to number of interim analyses to allow for greater 
flexibility to add additional analyses if necessary. 
Updated required language for the Appendix 3. 
Added language for subcutaneous administration of nivolumab alone to 
Appendix 10. 
Minor formatting and typographical corrections. 
Minor clarifications throughout document for consistency across sections. 
Administrative 
Letter 02 
15-Oct-2018 
The purpose of this letter is to: 
a) Inclusion of the standard exclusion of any patient who tests positive for 
hepatitis B or hepatitis C virus indicating presence of virus. 
b) Notify of New Medical Monitor/Study Director 
Revised 
Protocol 01 
05-Jul-2018 
Removal of SC nivolumab Process D drug substance from the study. 
Participants in Part D will receive SC nivolumab + rHuPH20 manually by 
syringe beginning at Cycle 1. 
Procedures and inclusion criteria were updated to include assessment of 
tumor PD-L1 expression measured by IHC prior to treatment and to require 
results for participants in Part A to be available prior to opening Part B for 
enrollment. 
Each treatment group 
or prior documented MSI-H/dMMR status (for CRC). 
Additional biomarker and pharmacodynamic assessments added. 
Original 
Protocol 
13-Jun-2018 
Not applicable 


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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05: 
The primary purpose for the amendment is to 
collect additional pharmacokinetic (PK) samples of nivolumab 
at steady state in Part E of the study (600 mg subcutaneous [SC] Q2W coformulated with 
recombinant human hyaluronidase PH20 [rHuPH20]). Additionally, exclusion criteria were 
clarified 
, and study 
personnel were updated. 
This amendment incorporates the changes from the approved Administrative Letter 06, which are 
detailed in the Document History but not listed in the Summary of Key changes below. Other edits 
were made throughout the protocol to fix minor errors, to add clarity, and for consistency. 
Revisions apply to future participants enrolled in the study and, where applicable, to all 
participants currently enrolled. 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05 
Section Number & Title 
Description of Change 
Brief Rationale 
Title Page 
Updated study personnel. 
To provide current study personnel. 
5.1 Overall Design 
9.5.1 Pharmacokinetics 
and Anti-drug Antibody 
Sample Collection and 
Processing 
Added additional PK 
sampling for Part E. 
to include 
additional PK samples of 
nivolumab at steady state after 
multiple doses for adequate steady- 
state PK characterization of SC 
nivolumab at 600 mg Q2W. 
6.2 Exclusion Criteria 
Criterion 1) Medical 
Conditions, o) was clarified to 
indicate the criterion is only 
applicable to first-in-human 
(Parts A-D) and not 
applicable for Part E 
Originally included for first-in-man 
protocol requirement. However, 
treatment with nivolumab does not 
require baseline multigated 
acquisition (MUGA)/ transthoracic 
echocardiogram (TTE) based on the 
well characterized safety profile of 
nivolumab. Thus, no longer 
required for Part E. 
6.2 Exclusion Criteria 
Criterion 1) Medical 
Conditions, r) eligibility 
determination was clarified 
For clarification of decisions 
regarding eligibility for participants 
who received the COVID-19 
vaccine or who are in a COVID-19 
interventional trial. 


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
1 
DOCUMENT HISTORY.............................................................................................. 
3 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05: ............................ 
5 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05................ 
5 
TABLE OF CONTENTS.............................................................................................. 
6 
1 SYNOPSIS................................................................................................................. 
10 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
18 
3 INTRODUCTION ..................................................................................................... 
33 
3.1 Study Rationale ................................................................................................. 
34 
3.1.1 Research Hypothesis ................................................................................ 
35 
3.2 Background ....................................................................................................... 
35 
3.2.1 Nivolumab Mechanism of Action ............................................................. 
35 
3.2.2 Nivolumab Clinical Activity ..................................................................... 
36 
3.2.3 Clinical Pharmacology of Nivolumab ..................................................... 
36 
3.2.4 Recombinant Human Hyaluronidase PH20............................................. 
37 
3.2.4.1 
Nonclinical Toxicity of Recombinant Human Hyaluronidase PH20 
............................................................................................................... 
38 
3.2.4.2 
Clinical Pharmacology of Recombinant Human Hyaluronidase 
PH20 ..................................................................................................... 
38 
3.2.5 Nonclinical Toxicity of Subcutaneous Nivolumab ................................... 
39 
3.3 Benefit/Risk Assessment .................................................................................. 
40 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
43 
5 STUDY DESIGN....................................................................................................... 
44 
5.1 Overall Design .................................................................................................. 
44 
5.1.1 Screening Period...................................................................................... 
47 
5.1.2 Treatment Period ..................................................................................... 
48 
5.1.3 Safety Follow-up Period .......................................................................... 
48 
5.1.4 Data Monitoring Committee and Other External Committees ................ 
49 
5.2 Number of Participants ..................................................................................... 
49 
5.3 End of Study Definition .................................................................................... 
50 
5.4 Scientific Rationale for Study Design............................................................... 
50 
5.4.1 Rationale for Subcutaneous Administration ............................................ 
50 
5.4.2 Rationale for Selection of Tumor Types................................................... 
50 
5.4.3 Rationale for PK and Immunogenicity Sampling Plan............................ 
51 
5.4.4 Rationale for Two Year Duration of Treatment....................................... 
51 
5.5 Justification for Dose ........................................................................................ 
52 
5.5.1 Justification for 480 mg Q4W IV Dose .................................................... 
52 
5.5.2 Justification of Subcutaneous Doses of Nivolumab ................................. 
53 
5.5.3 Revised Protocol 03: Selection of SC Nivolumab Dose in Part C and D 
(1200 mg Q4W)........................................................................................... 
54 
5.5.4 Protocol Amendment 04: Rationale for SC Nivolumab Dose 
Coformulated with rHuPH20 in Part E (600 mg Q2W) ............................. 
56 
6 STUDY POPULATION ............................................................................................ 
56 
6.1 Inclusion Criteria .............................................................................................. 
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6.2 Exclusion Criteria ............................................................................................. 
60 
6.3 Lifestyle Restrictions ........................................................................................ 
63 
6.4 Screen Failures.................................................................................................. 
64 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
64 
7 TREATMENT ........................................................................................................... 
64 
7.1 Treatments Administered.................................................................................. 
67 
7.1.1 Intravenous Administration of Nivolumab Injection................................ 
68 
7.1.2 Subcutaneous Administration of Nivolumab............................................ 
68 
7.1.3 Subcutaneous Administration of Nivolumab with rHuPH20 ................... 
68 
7.1.3.1 
Subcutaneous Administration of Nivolumab without rHuPH20 ..... 
69 
7.2 Method of Treatment Assignment .................................................................... 
69 
7.3 Blinding............................................................................................................. 
70 
7.4 Dosage Modification......................................................................................... 
70 
7.4.1 Dose Modifications .................................................................................. 
70 
7.4.2 Dose Delay Criteria ................................................................................. 
78 
7.4.3 Criteria to Resume Treatment.................................................................. 
78 
7.4.4 Management Algorithms for Immuno-Oncology Agents ......................... 
79 
7.4.4.1 
Program Safety Management Algorithms....................................... 
79 
7.4.4.2  
Recommendations for Management of Hepatic Events in Nivolumab 
Participants with HCC.......................................................................... 
80 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
81 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
81 
7.6 Treatment Compliance...................................................................................... 
81 
7.7 Concomitant Therapy........................................................................................ 
82 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
82 
7.7.2 Other Restrictions and Precautions......................................................... 
83 
7.7.2.1 
Imaging Restriction and Precautions ............................................. 
83 
7.7.3 Permitted Therapy ................................................................................... 
83 
7.7.4 Treatment of Infusion-related Reactions ................................................. 
83 
7.8 Treatment After the End of the Study............................................................... 
85 
8 DISCONTINUATION CRITERIA ........................................................................... 
85 
8.1 Discontinuation from Study Treatment ............................................................ 
85 
8.1.1 Nivolumab Dose Discontinuation ............................................................ 
86 
8.1.2 Nivolumab Treatment Beyond Disease Progression ............................... 
87 
8.1.3 Criteria to Resume Treatment.................................................................. 
87 
8.1.4 Post Study Drug Follow-up ..................................................................... 
87 
8.2 Discontinuation from the Study ........................................................................ 
88 
8.3 Lost to Follow-Up............................................................................................. 
88 
9 STUDY ASSESSMENTS AND PROCEDURES..................................................... 
89 
9.1 Efficacy Assessments........................................................................................ 
89 
9.1.1 Imaging Assessment for the Study............................................................ 
89 
9.1.1.1 
Methods of Measurement ................................................................ 
90 
9.1.1.2 
Imaging and Clinical Assessment ................................................... 
91 
9.2 Adverse Events ................................................................................................. 
91 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
91 
9.2.2 Method of Detecting AEs and SAEs......................................................... 
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9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug-induced Liver Injury (DILI)............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Suicidal Risk Monitoring ......................................................................... 
9.4.6 Imaging Safety Assessment ...................................................................... 
9.4.7 Assessment of Subcutaneous Injection Site.............................................. 
9.5 Pharmacokinetics .............................................................................................. 
9.5.1 Pharmacokinetics and Anti-drug Antibody Sample Collection and 
Processing................................................................................................... 
9.5.2 Pharmacokinetics and Immunogenicity Sample Analyses ....................... 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8 Biomarkers ........................................................................................................ 
9.8.1 Tumor Tissue Specimens.......................................................................... 
9.8.2 Biomarker assessments in tumor ............................................................. 
9.8.3 Biomarker assessments in peripheral blood ............................................ 
 
9.8.4 Additional Research Collection ............................................................... 
9.8.5 Immunogenicity Assessments ................................................................... 
9.9 Medical Resource Utilization and Health Economics ...................................... 
9.10 Patient-reported Outcomes.............................................................................. 
9.10.1 Patient Experience and Preference Questionnaire................................ 
9.10.2 Qualitative Patient Interviews ............................................................... 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Pharmacokinetic Analyses ..................................................................... 
10.3.4 Immunogenicity Analyses....................................................................... 
10.3.5 Outcomes Research................................................................................ 
10.3.6 Biomarker Analyses ............................................................................... 
10.3.7 Other Analyses ....................................................................................... 
10.3.7.1 Population Pharmacokinetic Analysis of SC Nivolumab.............. 
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9.8.3.2 Exploratory Serum 
Biomarkers .................................. 


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10.3.8 Interim Analyses .................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION..................................................................... 
APPENDIX 5 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
APPENDIX 6 MANAGEMENT ALGORITHMS....................................................... 
APPENDIX 7 PERFORMANCE STATUS SCALES ................................................. 
APPENDIX 8 COUNTRY SPECIFIC AMENDMENTS ............................................ 
APPENDIX 9 CHILD-PUGH SCORE ........................................................................ 
APPENDIX 10 INJECTION SITE SELECTION AND PREPARATION AND 
ADMINISTRATION OF STUDY DRUG ............................................................. 
APPENDIX 11 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY 
................................................................................................................................. 
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1 
SYNOPSIS 
Protocol Title: Phase I/II pharmacokinetic multi-tumor study of subcutaneous formulation 
of nivolumab monotherapy 
Study Phase: Phase 1/Phase 2 
Rationale: This Phase 1/2 study will characterize the pharmacokinetics (PK), safety, and 
tolerability of high-concentration subcutaneous (SC) nivolumab (BMS-986298) with or without 
recombinant human hyaluronidase PH20 (rHuPH20), in participants with tumor types in which 
the effects on nivolumab clearance are similar. 
Parts A-E will evaluate the PK, safety, and tolerability of SC nivolumab (± rHuPH20) in 
participants with 1 of the following tumor types approved for, or currently being investigated 
for, treatment with nivolumab monotherapy: non-small cell lung cancer (NSCLC); renal cell 
carcinoma (RCC); unresectable or metastatic melanoma; hepatocellular carcinoma (HCC); or 
colorectal cancer (CRC) (microsatellite instability-high [MSI-H] or mismatch repair-deficient 
[dMMR]). For Part B only, addition of other solid tumors were considered, where nivolumab PK 
was well characterized and discussed with the Sponsor. In addition to the above tumors, Part E 
will also include participants with metastatic urothelial carcinoma (mUC). 
The initial SC dosing regimen was selected as SC nivolumab (BMS-986298) 720 mg once every 
4 weeks (Q4W) based on extrapolated bioavailability models for SC administration of biologics 
(with and without rHuPH20). Based on extrapolated bioavailability models and preliminary PK 
from Part A, this study proceeded with a dose of 960 mg Q4W for Part B (Groups 3 & 4). 
Revised Protocol 03 
PK results from Parts A and B of this study and the breadth of data from population PK analyses 
with nivolumab IV across the clinical program were used to establish an SC dose of nivolumab 
with rHuPH20 to be administered every 4 weeks that is expected to provide comparable exposure 
(Cavgd28) to the IV nivolumab. PK data for SC and IV nivolumab from this study were combined 
with existing IV nivolumab PK data to identify a dose expected to provide PK exposures that are 
non-inferior to the initially approved dosing regimen, IV nivolumab 3 mg/kg Q2W. 
 
Protocol Amendment 04 
To support characterization of Q2W dosing of SC nivolumab and to provide dosing optionality for 
participants, 600 mg Q2W coformulated with rHuPH20 will be investigated in Part E. For 
Parts A-D, SC nivolumab and rHuPH20 were mixed at the site pharmacy (coadministration) prior 


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to study drug administration. As of Protocol Amendment 04, coformulated drug product 
(SC nivolumab and rHuPH20 solutions pre-mixed in 1 vial with the same dose ratio) will be 
introduced for Part E. In addition, all ongoing participants in Parts C & D may switch to the 
coformulated drug product. 
 
In Part E, approximately 36 participants in total will be enrolled. In addition to participants with 
the tumor types described for Parts A-D, approximately 10 participants with mUC will be included. 
The clinical benefit of IV nivolumab has been demonstrated in mUC, and Part E will provide 
preliminary PK data for SC nivolumab in this tumor type. 
Study Population: 
The study population will include participants with 1 of the following advanced or metastatic 
tumors approved for treatment with nivolumab monotherapy: non-small cell lung cancer 
(NSCLC); renal cell carcinoma (RCC); unresectable or metastatic melanoma; hepatocellular 
carcinoma (HCC); microsatellite instability-high or mismatch repair-deficient colorectal cancer 
(MSI-H/dMMR CRC); or metastatic urothelial carcinoma (mUC [Part E only]). 


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Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
Parts A- D: To describe the pharmacokinetics of 
nivolumab administered subcutaneously, with or 
without rHuPH20 
Part E: To evaluate the pharmacokinetics of SC 
nivolumab 600 mg Q2W coformulated with rHuPH20 
• 
Serum nivolumab Parts A, B, D, and E: 
− 
Cmax 
− 
Tmax 
− 
AUC(TAU) 
− 
Ctau 
• 
Serum nivolumab Part C: 
− 
Ctrough 
Secondary 
To assess the safety profile of SC nivolumab. 
• 
Incidences of AEs, TRAEs, SAEs, TRSAEs, 
AEs/TRAEs leading to discontinuation, deaths, 
and laboratory abnormalities. 
To evaluate incidence of AEs in the broad standardized 
MedDRA query (SMQ) of Anaphylactic Reaction and 
the select AE hypersensitivity/infusion reaction 
category. 
• 
Incidence of AEs in the broad SMQ of 
Anaphylactic Reaction occurring within 2 days 
after study drug administration 
• 
Incidence of events within the 
hypersensitivity/infusion reaction select AE 
category occurring within 2 days after study drug 
administration. 
To assess the immunogenicity of nivolumab 
• 
Incidence of anti-nivolumab antibodies and 
neutralizing antibodies, if applicable 
Exploratory 
To evaluate preliminary efficacy in all participants 
• 
ORR, PFS, and OS 
To characterize biomarker measures 
• 
Including, but not limited to: summary measures 
of change (or % change) from baseline in various 
biomarkers and molecular characteristics of the 
tumor (Parts A-D, and based on tissue availability 
for Part E)/blood 
To assess the immunogenicity of rHuPH20 
• 
Incidence of anti-rHuPH20 antibodies and 
neutralizing antibodies, if applicable 
To assess the preliminary participant experience and 
preference for SC or IV administration of nivolumab. 
• 
Patient experience and preference questionnaire 
• 
Qualitative Patient Interviews 
Abbreviations: AE = adverse event; AUC(TAU) = area under the concentration-time curve over the dosing interval; 
Cmax = maximum observed serum nivolumab concentration; Ctau = observed serum nivolumab concentration at the 
end of the dosing interval; Ctrough = trough observed serum nivolumab concentration; IV = intravenous; 
MedDRA = Medical Dictionary for Regulatory Activities; ORR= objective response rate; OS = overall survival; 
PFS = progression-free survival; Q2W = every 2 weeks; rHuPH20 = recombinant human hyaluronidase PH20; 
SAE = serious adverse event; SC = subcutaneous; SMQ = standardized MedDRA queries; TRAE = treatment-related 
adverse event; TRSAE = treatment-related serious adverse event. 


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Overall Design: 
Study CA2098KX is a multicenter, randomized, open-label, multi-tumor Phase 1/2 study that will 
evaluate the PK, safety, and tolerability of nivolumab administered subcutaneously with and 
without rHuPH20 in participants with 1 of the following advanced or metastatic tumor 
types: non-small cell lung cancer (NSCLC); renal cell carcinoma (RCC); unresectable or 
metastatic melanoma; hepatocellular carcinoma (HCC); or colorectal cancer (CRC) (microsatellite 
instability-high [MSI-H] or mismatch repair deficient [dMMR]). For Part B only, addition of other 
solid tumors were considered, where nivolumab PK was well characterized and discussed with the 
Sponsor. In addition to the above tumors, Part E will also include participants with metastatic 
urothelial carcinoma (mUC). The study is divided into the following periods: a Screening period; 
a Treatment period consisting of Part A, Part B, Part C, Part D, and Part E; and a Safety Follow-up 
period. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
14 
Approved v 71.0 
930127317 7.0 
 
 
BMS-986298 
nivolumab SC 
+rHuPH20 
1200 mg Q4W 
BMS-936558 
nivolumab IV 
480 mg Q4W 
Figure 1: 
CA2098KX Study Schematica 
 
 
Part A 
Part B 
Part D c, d 
 
 
 
 
 
Group 1 
BMS-986298 
nivolumab SC 
+rHuPH20 
720 mg 
N=22 
Group 2 
BMS-986298 
nivolumab SC 
720 mg 
N=18 
Group 3 
BMS-986298 
nivolumab SC 
+rHuPH20 
960 mg 
N=10 
Group 4 
BMS-986298 
nivolumab SC 
960 mg 
N=17 
 
 
 
Part C c, d 
 
 
 
 
 
Abbreviations: BW = body weight; IV = intravenous; PK = pharmacokinetic; Q4W = every 4 weeks; 
mUC = metastatic urothelial carcinoma; rHuPH20 = recombinant human hyaluronidase PH20; Q2W = every 2 weeks; 
Q4W = every 4 weeks; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; SC = subcutaneous. 
a Schema represent the actual numbers of participants enrolled for Parts A, B, and D. 
b Actual enrollment: The first 10 participants were assigned to Group 3. The next 35 participants were randomized 
1:1 into Group 2 (n=18) and Group 4 (n=17). 
c Crossover into Part C and dosing in Part D (Group 5) will begin after the SC nivolumab (BMS-986298) dosing 
regimen is identified from analysis of PK data from Parts A & B. At the time of Protocol Amendment 04, enrollment 
for Part D has completed and actual enrollment was 36 participants. 
Note: Group 2 and Group 4 will receive SC nivolumab (BMS-986298) by syringe pump without rHuPH20. 
d Any ongoing participants on SC nivolumab + rHuPH20 treatment may switch over to nivolumab coformulated with 
rHuPH20 drug product. 
• 4 weeks 
• PK sampling 
Parts C, D and E: Treatment until 104 weeks total, withdrawal, toxicity, RECIST v1.1 progression, or death 
Group 5 
BMS-986298 
nivolumab SC 
+rHuPH20 
1200 mg 
Q4W 
N=36 
(approx. 10 with BW <65kg) 
Part E 
Group 6 
BMS-986298 
nivolumab SC 
coformulated with 
rHuPH20 
600 mg Q2W 
N=36 
(approx. 10 with mUC) 
After Part A participants dosed, 
Part B dosing begins 
N=45 b 
Part A enrolls first 
N=20 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
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Approved v 71.0 
930127317 7.0 
 
 
Number of Participants: 
Approximately 139 total participants will receive study treatment as follows (also see study design 
schematic in Figure 1). 
• In Part A, 22 participants received 720 mg SC nivolumab (BMS-986298) manually by syringe 
with rHuPH20. 
• In Part B, 45 participants were dosed. The first 10 participants were assigned to Group 3. The 
next 35 participants were randomized 1:1 into Group 2 (n=18) and Group 4 (n=17). 
• In Part D, approximately 36 participants (approximately 10 with baseline BW < 65 kg) will 
receive nivolumab (BMS-986298) 1200 mg with rHuPH20 administered SC manually by 
syringe every 4 weeks. 
• In Part E, approximately 36 participants, including approximately 10 participants with mUC, 
will receive nivolumab (BMS-986298) 600 mg coformulated with rHuPH20 administered SC 
manually by syringe every 2 weeks. 
 
Additional participants may have been assigned/randomized to study treatment for each participant 
who was unable to complete one of the following: 
• Planned Cycle 1 (SC study treatment) and/or Cycle 2 (IV nivolumab) treatments and PK 
sampling in Part A 
• Planned Cycle 1 (SC study treatment) and/or Cycle 2 (IV nivolumab) treatments and PK 
sampling in Part B 
• Planned Cycle 1 and/or Cycle 2 treatments and PK sampling in Part D 
 
For Part E, additional participants may be assigned for each participant who was unable to 
complete the first dose and up to 
of PK sampling. 
Each treatment group in Part A, Part B, and Part D 
by IHC or with MSI-H/dMMR (for CRC). For Part E, tissue PD-L1 assessment 
is optional. 
Randomization - where applicable - will not be stratified by tumor type or by any demographic or 
disease characteristic. 
Treatment Arms and Duration: 
Approximately 139 total participants with any of included advanced or metastatic tumor types will 
receive study treatment as follows: 
• Part A/B: 
− Part A 
♦ Group 1: Single dose of nivolumab (BMS-986298) 720 mg administered SC with 
rHuPH20 manually by syringe (n=22) 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
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Approved v 71.0 
930127317 7.0 
 
 
− Part B After participants are dosed in Part A, 45 participants were dosed in Part B. The 
first 10 participants were assigned to Group 3. The next 35 participants were randomized 
1:1 into Group 2 (n=18) and Group 4 (n=17): 
♦ Group 2: Single dose of nivolumab (BMS-986298) 720 mg administered SC without 
rHuPH20 by syringe pump 
♦ Group 3: Single dose of nivolumab (BMS-986298) 960 mg administered SC with 
rHuPH20 manually by syringe 
♦ Group 4: Single dose of nivolumab (BMS-986298) 960 mg administered SC without 
rHuPH20 by syringe pump 
− Four (4) weeks after the single SC nivolumab (BMS-986298) dose, all participants in 
Part A and Part B received IV nivolumab (BMS-936558) 480 mg Q4W dosing until 
Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable 
toxicity, withdrawal of consent, completion of 104 weeks of treatment, cross over to SC 
nivolumab dosing in Part C, or study termination by the Sponsor, whichever occurs first. 
• Part C: Participants in Part A and Part B will cross over from nivolumab (BMS-936558) IV 
dosing (four [4] weeks after last IV dose) to nivolumab (BMS-986298) 1200 mg administered 
SC with rHuPH20 manually by syringe every 4 weeks. 
• Part D (Approximately 36; of which approximately 10 with baseline BW < 65 kg): On Day 1 
of each treatment cycle, SC nivolumab (BMS-986298) 1200 mg administered SC with 
rHuPH20 manually by syringe every 4 weeks. 
• Part E (Approximately 36; of which approximately 10 with mUC): nivolumab (BMS-986298) 
600 mg coformulated with rHuPH20 administered SC manually by syringe every 2 weeks. 
 
For Parts A-D, SC nivolumab and rHuPH20 were mixed at the site pharmacy (coadministration) 
prior to study drug administration. As of Protocol Amendment 04, coformulated drug product 
(SC nivolumab and rHuPH20 solutions pre-mixed in 1 vial with the same dose ratio) will be 
introduced for Part E. In addition, all ongoing participants in Parts C & D may switch to the 
coformulated drug product. 
Parts A, B and D: Each treatment group in Part A, Part B, and Part D 
by IHC or with MSI-H/dMMR (for CRC). 
Part E: Tissue PD-L1 assessment is optional. 
Doses for Part B (Group 3 & 4) were adjusted based on PK and safety information from Part A to 
be 960 mg Q4W and confirmed by an administrative letter to the investigators. 
Parts A & B: Four weeks after the SC dose of study treatment (ie, Study Day 29), participants 
received 480 mg IV nivolumab (BMS-936558) Q4W until Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, completion of 
104 weeks of treatment, cross over to SC nivolumab dosing in Part C, or study termination by the 
Sponsor, whichever occurs first. For each participant who was unable to complete the planned 
Cycle 1 (SC study treatment) and Cycle 2 (IV nivolumab) treatments and PK sampling, an 
additional participant was assigned. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
17 
Approved v 71.0 
930127317 7.0 
 
 
Parts C & D: An outline of the considerations for Part C and Part D dose selection is presented in 
Section 10.3.8 (Interim Analyses). 
Part E: The dose in Part E is 600 mg SC nivolumab coformulated with rHuPH20 Q2W. 
 
For each participant who 
is unable to complete the planned study treatments and PK sampling following the first dose, an 
additional participant may be assigned via interactive response technology (IRT). 
Dosing in the study will continue until RECIST v.1.1 progression, unacceptable toxicity, 
withdrawal of consent, completion of 104 weeks of total treatment, or study termination by the 
Sponsor, whichever occurs first. 
Study Treatment: 
 
Study Drug for CA2098KX 
Medication 
Potency 
IP/Non-IP 
Nivolumab (BMS-986298) Solution for SC Injection 
960 mg (120 mg/mL) 
IP 
Nivolumab and rHuPH20 (BMS-986298) Solution for 
SC Injection 
600 mg ( 
mg/mL) 
and 
units (2000 units/mL) 
IP 
Nivolumab (BMS-936558-01) Solution for IV 
Injection 
100 mg (10 mg/mL) 
and 40 mg (10 mg/mL) 
IP 
Drug Product (rHuPH20)a 
Units/mL ( mg/mL) 
IPb 
Abbreviations: EU = European Union; IP = investigational product; IV = intravenous; rHuPH20 = recombinant human 
hyaluronidase PH20; SC = subcutaneous; US = United States. 
a  
is a formulation containing the enzyme rHuPH20 and is referred as rHuPH20 in the 
protocol. 
b rHuPH20 is classified as an IP per local guidelines (as an active ingredient in the US, and as an excipient in the 
EU). 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
18 
Approved v71.0 
930127317 7.0 
 
 
2 
SCHEDULE OF ACTIVITIES 
Table 2-1: 
Screening Procedural Outline (CA2098KX) - Parts A-D 
 
Procedure 
Screening 
Visit 
Notes 
Screening assessments must be performed within 28 days prior to the first dose in the study. 
Eligibility Assessments 
Informed Consent 
X 
A participant is considered enrolled only when a protocol-specific informed consent is signed. 
Inclusion/Exclusion Criteria 
X 
All inclusion/exclusion criteria should be assessed and confirmed prior to first dose. See Sections 6.1 and 6.2. 
Medical History 
X 
Include any toxicities or allergy related to previous treatments including prior anticancer/radiotherapy, smoking 
history (including electronic cigarettes), and alcohol history. 
ECOG 
X 
Within 14 days prior to first dose. See Appendix 7. 
Register participant in IRT 
X 
IRT contact must occur for IVRS participant number assignment at the time when informed consent is obtained. 
Microsatellite instability and 
mismatch repair status 
X 
Confirm documentation of prior local testing (high microsatellite instability [MSI-H] and/or mismatch repair 
deficient [dMMR]) for participants with colorectal cancer (CRC). 
Tumor Tissue Sample 
X 
Sufficient tumor tissue obtained up to 12 months prior to first study treatment in the metastatic setting or from an 
unresectable site (block 
is requested, obtained from core needle biopsy, excisional, or 
incisional biopsy). For fresh samples, the tumor should be amenable to biopsy and the lesion should be distinct 
from target lesions being evaluated for radiologic response, and the same lesion should be used for both the baseline 
and on-treatment sampling. Participants should not have received any systemic anticancer therapy after the date 
that the submitted tumor tissue was obtained. Up to 5 participants from each part of the trial (part A & B) and 
approximately 15 participants in Part D, who do not meet tissue requirements may be allowed treatment after 
discussion with the Medical Monitor. 
 
Assessment of tumor-cell PD-L1 expression by IHC must be performed centrally using pre-treatment tissue 
sample. 
must be collected for all participants in Part A prior to initiation of Part B. For participants with CRC, assessment 
of tumor PD-L1 expression is not required, since documentation of MSI-H/dMMR status is required. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-1: 
Screening Procedural Outline (CA2098KX) - Parts A-D 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
19 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Screening 
Visit 
Notes 
Screening assessments must be performed within 28 days prior to the first dose in the study. 
Safety Assessments 
Assessment of Signs and 
Symptoms 
X 
After obtaining informed consent, assess all signs and symptoms within 14 days prior to first dose. 
Physical Examination (PE) 
X 
Within 14 days of first dose. If the screening PE is performed within 24 hours prior to dosing on Day 1 then a 
single examination may count as both the screening and predose evaluation. 
Physical Measurements 
X 
Within 14 days of first dose. Include height and weight. 
Vital Signs 
X 
Includes body temperature, respiratory rate, and seated BP and HR. BP and HR should be measured after 
participant has been resting quietly for ≥5 minutes. Consider alternate position(s) for vital sign collection. 
Pulse Oximetry 
X 
Oxygen saturation at rest. Perform within 14 days prior to first dose. 
Concomitant Medication Use 
X 
Within 14 days of first dose 
Electrocardiogram (ECG) 
X 
12-lead ECGs should be recorded after the participant has been supine for at least 5 minutes. 
Serious Adverse Event 
(SAE) 
X 
Serious adverse event collection from signing of informed consent. 
Laboratory Tests 
Serology 
X 
See Section 9.4.4. 
Hematology 
X 
To be performed locally within 14 days prior to first dose. See Section 9.4.4. 
Liver Function Tests 
X 
To be performed locally within 14 days prior to first dose. See Section 9.4.4 
Chemistry 
X 
To be performed locally within 14 days prior to first dose. See Section 9.4.4. 
Thyroid Function Test 
X 
To be performed locally within 14 days prior to first dose. TSH with free triiodothyronine (T3) and free 
thyroxine (T4), or equivalent. See Section 9.4.4. 
Coagulation Panel 
X 
For participants with HCC only: prothrombin time (PT)/international normalized ratio (INR), activated partial 
thromboplastin time (aPTT), fibrinogen. To be performed locally within 14 days prior to first dose. If screening 
labs are drawn within 4 days of first treatment then these will also qualify as Day 1 (pre-dose). 
Pregnancy Test 
X 
For WOCBP only. Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) to 
be done at screening visit and within 24 hours prior to first dose. See Section 9.4.4. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-1: 
Screening Procedural Outline (CA2098KX) - Parts A-D 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
20 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Screening 
Visit 
Notes 
Screening assessments must be performed within 28 days prior to the first dose in the study. 
Efficacy Assessments 
Body Imaging 
X 
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or suspected sites 
of disease, within 28 days prior to date of first dose. See Section 9.1.1.1. 
Brain Imaging 
X 
MRI of the brain without and with contrast is required for participants with known or suspected brain metastases, 
unless participant has completed an imaging study of the brain within 30 days of study drug administration. CT 
of the brain without and with contrast can be performed if MRI is contraindicated. 
Disease Assessments 
X 
For participants with HCC only: serum alpha fetoprotein (AFP) 
Abbreviations: AFP = alpha fetoprotein; aPTT = activated partial thromboplastin time; BP = blood pressure; CRC = colorectal cancer; CT = computed tomography; 
dMMR = mismatch repair deficient; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HCC = hepatocellular carcinoma; HCG = human 
chorionic gonadotropin; HR = heart rate; IHC = immunohistochemistry; INR = international normalized ratio; IRT = Interactive Response Technology; 
MRI = magnetic resonance imaging; MSI-H = high microsatellite instability; PD-L1 = programmed death ligand 1; PE = physical examination; PT = prothrombin 
time; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-2: 
Screening Procedural Outline (CA2098KX) - Part E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
21 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Screening 
Visit 
Notesa 
Screening assessments must be performed within 28 days prior to the first dose in the study. 
Eligibility Assessments 
Informed Consent 
X 
Must be obtained prior to performing any screening procedures. 
Study allows for re-enrollment of a participant that has discontinued the study as a pre-treatment failure. If 
re-enrolled, the participant must be re-consented and assigned a new participant number from IRT. 
Inclusion/Exclusion Criteria 
X 
Must be confirmed prior to the first dose of study drug. 
Medical History 
X 
All medical history relevant to the disease under study. 
Contact IRT 
X 
Register in Interactive Response system to obtain participant number. 
Microsatellite instability and 
mismatch repair status 
X 
Confirm documentation of prior local testing (high microsatellite instability [MSI-H] and/or mismatch repair 
deficient [dMMR]) for participants with colorectal cancer (CRC). 
Tumor Sample Submission 
See Notes 
Tumor tissue sample submission is highly recommended, but optional for participants in Part E. 
For all participants in Part E, including mUC participants, submission of an archival FFPE tissue block 
(preferred) or unstained slides of tumor tissue from core biopsy, excisional biopsy, or surgical specimen obtained 
within 12 months of enrollment is highly recommended. For fresh samples, the tumor should be amenable to 
biopsy and the lesion should be distinct from target lesions being evaluated for radiologic response, and the same 
lesion should be used for both the baseline and on-treatment sampling. Fine needle aspirates or other cytology 
samples are not acceptable. 
Tumor PD-L1 expression by IHC is an optional assessment for participants in Part E. 
 
Please refer to Section 9.8 for additional information. 
Baseline Tumor Assessment 
X 
Must be performed within 28 days prior to the first dose of study drug. 
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other known and/or suspected sites 
of disease. See Section 9.1.1.1. 
MRI of the brain without and with contrast is required for participants with known or suspected brain metastases, 
unless participant has completed an imaging study of the brain within 28 days of study drug administration. CT 
of the brain (with and without contrast) can be performed if MRI is contraindicated. See Section 9.1.1.1. 
Disease Assessments 
X 
For participants with HCC only: serum alpha fetoprotein (AFP) 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-2: 
Screening Procedural Outline (CA2098KX) - Part E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
22 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Screening 
Visit 
Notesa 
Screening assessments must be performed within 28 days prior to the first dose in the study. 
Safety Assessments 
Assessment of Signs and 
Symptoms 
X 
Within 14 days prior to the first dose of study drug. 
Physical Examination, 
Measurements, Vital Signs, 
and Performance Status 
X 
Height, weight, performance status (Appendix 7), BP, HR, temperature and oxygen saturation by pulse oximetry 
at screening only. Must be collected within 14 days prior to the first dose of study drug. 
Concomitant Medication 
Collection 
X 
Within 14 days prior to the first dose of study drug. 
Vaccine use within 30 days prior to first study treatment. See Section 6.2. 
Electrocardiogram (ECG) 
X 
At rest. Within 14 days prior to the first dose of study drug. 
Serious Adverse Event 
(SAE) 
X 
Serious adverse event collected from signing of informed consent. 
COVID-19 or positive SARS-CoV-2 test results should be reported to BMS within 24 hours regardless of the 
seriousness criteria. 
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection collected from time of consent. See 
Section 9.2.1. 
Laboratory Tests 
Clinical Laboratory 
Assessments 
X 
On-site/local laboratory tests must be performed within 14 days prior to the first dose of study drug. 
Viral testing to be completed within 28 days prior to the first dose of study drug. For HIV: testing at sites where 
locally mandated; see Appendix 8. 
Refer to Section 9.4.4 for list of laboratory tests to conduct. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-2: 
Screening Procedural Outline (CA2098KX) - Part E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
23 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Screening 
Visit 
Notesa 
Screening assessments must be performed within 28 days prior to the first dose in the study. 
Coagulation Panel 
X 
For participants with HCC only: prothrombin time (PT)/international normalized ratio (INR), activated partial 
thromboplastin time (aPTT), fibrinogen. To be performed locally within 14 days prior to first dose. If screening 
labs are drawn within 4 days of first treatment then these will also qualify as Day 1 (pre-dose). 
Pregnancy Test (Women of 
Childbearing Potential 
[WOCBP] Only) 
X 
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) to be done at screening 
visit and repeated within 24 hours prior to first dose of study treatment. See Section 9.4.4. 
Abbreviations: AE = adverse event; AFP = alpha fetoprotein; aPTT = activated partial thromboplastin time; BMS = Bristol-Myers Squibb; BP = blood pressure; 
COVID-19 = coronavirus disease 2019; CRC = colorectal cancer; CRF = case report form; CT = computed tomography; dMMR = mismatch repair deficient; ECG 
= electrocardiogram; FFPE = formalin-fixed paraffin-embedded; HCC = hepatocellular carcinoma; HCG = human chorionic gonadotropin; HIV = human 
immunodeficiency virus; HR = heart rate; IHC = immunohistochemistry; INR = international normalized ratio; IRT = Interactive Response Technology; 
MRI = magnetic resonance imaging; MSI-H = high microsatellite instability; PD-L1 = programmed death ligand 1; PT = prothrombin time; SAE = serious adverse 
event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WOCBP = women of childbearing potential. 
a Some of the assessments referred to in this section may not be captured as data in the CRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations and should 
be documented in the patient's source notes. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-3: 
On-treatment Procedural Outline (CA2098KX) - Parts A-E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
24 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Randomization 
Randomization (Part B, 
Group 2 and 4) 
X 
Once participant eligibility has been confirmed, randomization can be 
performed. 
Eligibility Assessments 
ECOG Performance 
Status 
X 
Predose (Appendix 7) 
Safety Assessments 
Physical Examination 
X 
Predose 
Physical Measurements 
X 
Predose. Weight only 
Vital Signs 
X 
Predose. 
Pulse Oximetry 
X 
Predose. Oxygen saturation at rest. 
Child-Pugh Score 
X 
Participants with HCC only. Predose. See Appendix 9. 
Concomitant Medication 
Assessment 
Continuously 
Review prior to each dosing. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-3: 
On-treatment Procedural Outline (CA2098KX) - Parts A-E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
25 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Adverse Event 
Assessment and Serious 
Adverse Events (SAE) 
Continuously assessed using NCI CTCAE v.5 
Non-serious AEs will be collected starting with the first dose of the 
study drug and through 100 days after discontinuation of dosing. 
All SAEs must be collected which occur within 100 days of 
discontinuation of dosing or completion of the participant’s 
participation in the study if the last scheduled visit occurs at a later 
time, except in cases where a study participant has started a new anti- 
neoplastic therapy. However, any SAE occurring after the start of a 
new treatment that is suspected to be related to study treatment by the 
investigator will be reported. See Section 9.2. 
All AEs (SAEs and non-serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection will be followed until resolution, 
the condition stabilizes, or is deemed irreversible, or until the 
participant is lost to follow-up (as defined in Section 8.3). For 
suspected cases, participants should be followed until SARS-CoV-2 
infection is ruled out as per institutional policy on SARS-CoV-2. 
COVID-19 or positive SARS-CoV-2 test results should be reported to 
BMS within 24 hours regardless of the seriousness criteria. 
Assessment of post-SC 
injection reaction 
X 
Parts A-D: Perform on Day 2 of each cycle of SC treatment. 
Part E: Participants are contacted approximately 24 hours after the 
first 2 SC manual injections for reporting of any injection-site 
reactions. 
See Section 9.4.7. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-3: 
On-treatment Procedural Outline (CA2098KX) - Parts A-E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
26 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Laboratory Tests 
Parts A-D 
Cycle 1 and Cycle 2: The laboratory tests may be performed within 
48 hours prior to the first and second doses in the study. 
Cycle 3 and beyond: The laboratory tests may be performed within 72 
hours prior to dosing. 
Pregnancy testing must be performed within 24 hours prior to dosing. 
Part E 
Perform on site/local laboratory testing within 72 hours prior to each 
dose. 
For the first treatment visit, labs need not be repeated if they were 
performed within 72 hours and the results are available and have been 
reviewed for eligibility. 
Refer to Section 9.4.4 for the list of laboratory tests to be conducted. 
Chemistry 
Complete Blood Count 
with Differential and 
Platelets 
Thyroid Function Tests 
X 
Predose. See Section 9.4.4. 
Coagulation panel 
X 
For participants with HCC only. Within 72 hours of dosing. Including 
PT/INR, aPTT, and fibrinogen. 
Pregnancy Test 
(WOCBP only) 
X 
Serum or urine (minimum sensitivity equivalent units 25 IU/L or 
equivalent units of HCG) within 24 hours prior to administration of 
first dose of study treatment and then every 4 weeks (± 7 days) 
regardless of dosing schedule. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-3: 
On-treatment Procedural Outline (CA2098KX) - Parts A-E 
Protocol Amendment No.: 05 
Date: 08-Sep-2021 
27 
Approved v71.0 
930127317 7.0 
 
 
 
 
Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Pharmacokinetic and Immunogenicity Assessments 
PK and Immunogenicity 
Blood Sampling 
Biomarker Assessments 
Exploratory Biomarker 
Assessments 
See Section 9.8 and sampling schedule in Table 9.8-1 and Table 9.8-2. 
Additional Research 
Sampling 
See Section 9.8.4 and Table 9.8.4-1. 


Clinical Protocol 
BMS-986298 
CA2098KX 
nivolumab subcutaneous 
Table 2-3: 
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Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Efficacy Assessments 
Body Imaging 
X 
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, 
and all other known and/or suspected sites of disease should first 
occur at Week 12 (±7 days) starting from first dose date. Imaging 
should then occur every 8 weeks (±7 days) before the subsequent 
dose (namely within 7 days of dosing on Day 22 in treatment Cycles 
5, 7, 9, etc.) until investigator-assessed disease progression or 
treatment discontinuation (including treatment beyond progression), 
whichever occurs later. 
See Section 9.1.1.1 for further details. 
Brain Imaging 
X 
Participants with a history of brain metastasis should have a 
surveillance MRI approximately every 12 weeks, or sooner if 
clinically indicated. 
Disease assessment - AFP 
X 
Participants with HCC only. 
Clinical Drug Supplies 
Study Drug 
Administration 
X 
Part A/B: 
Day 1 Cycle 1: SC dose 
Day 1 Cycle ≥2: IV dosing 
Part C: 
Day 1 of each cycle: 
SC dosing manually by syringe 
Part D: 
Day 1 of each cycle: 
SC dosing manually by syringe 
The first dose must be administered within 3 calendar days following 
treatment assignment/randomization.c For Parts A-D, drug 
administration must occur on Day 1 of Cycle 1 and Cycle 2. For 
Cycle 3 and beyond, drug administration is ±3 days but no less than 
21 days from the previous dose. Study drug infusion start and stop 
times will be recorded for SC and IV administration. 
Part A and Part B 
All assigned/randomized participants receive SC nivolumab (BMS- 
986298) on Cycle 1 Day 1. On Day 1 of Cycle 2 and each cycle 
thereafter, all participants in treatment Groups 1, 2, 3, and 4 receive 
IV nivolumab (BMS-936558) every 4 weeks (Q4W). 


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Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Part E: 
of each 
cycle: 
SC dosing manually by syringe 
Part C 
Upon approval of revised protocol 03, Participants in Part A and Part 
B will cross over to Part C to receive 1200 mg SC nivolumab (BMS- 
986298) with rHuPH20 manually by syringe on Day 1 of each 
treatment cycle. 
Part D 
All assigned participants in Group 5 receive SC nivolumab (BMS- 
986298) with rHuPH20 manually by syringe on Day 1 of each cycle. 
Part E 
All assigned participants in Group 6 receive 600 mg SC nivolumab 
(BMS-986298) coformulated with rHuPH20 manually by syringe on 
of each cycle. For Part E, participants may be 
dosed 
from the previous dose. 
All participants in the study will be treated for a maximum of 
104 weeks total (nivolumab IV or/and SC) or until confirmed 
progression, unacceptable toxicity, withdrawal of informed consent, 
or discontinuation of the study by the Sponsor. Treatment for all 
participants can continue beyond initial investigator-assessed 
progression until a maximum of 104 weeks total (nivolumab IV 
or/and SC) (see Section 8.1.2). 


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Procedure 
Parts A-D: Day 1 of each 
treatment cycle 
(Cycle = 28 days) 
Part E: 
of 
each treatment cycle a 
(Cycle = 28 days) 
Timepoints Relative 
to Dosing Schedule 
Notesb 
Outcomes Research Assessments 
Patient Experience and 
Preference Questionnaire 
See Section 9.10.1 for further details. 
Qualitative Patient 
Interviews 
See Section 9.10.2 for further details. 
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BMS = Bristol-Myers Squibb; COVID-19 = coronavirus disease 2019; 
CRF = case report form; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; HCC = hepatocellular carcinoma; HCG = human chorionic 
gonadotropin; IgG = immunoglobulin G; INR = international normalized ratio; IV = intravenous; MRI = magnetic resonance imaging; NCI CTCAE v.5 = National 
Cancer Institute Common Terminology Criteria for Adverse Events version 5; PT = prothrombin time; Q4W = every 4 weeks; rHuPH20 = recombinant human 
hyaluronidase PH20; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus disease 2; SC = subcutaneous; WOCBP = 
women of childbearing potential. 
a If a dose is delayed, the procedures schedule for that same time point must also be delayed to coincide with when that time point’s dosing actually occurs, with 
the exception of tumor assessments which must occur as scheduled. 
b Some of the assessments referred to in this section may not be captured as data in the CRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations and should be 
documented in the patient's source notes. 
c Randomization/treatment assignment = randomization (Part B Groups 2, 4) /treatment assignment (Part A, Part B Group 3, Parts C, D, and E). 


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Procedure 
Follow-up 
Visit 1 and 
Visit 2 
Survival 
Follow-up 
Notesa 
Follow-up Visit 1 = 30 days from last dose ±7 days, or may be on date of 
discontinuation if the date of discontinuation is more than 30 days after last dose. 
Follow-up Visit 2 = approximately 100 days (± 7 days) from last dose. 
Targeted Physical 
Examination 
X 
Weight, BP, HR, temperature, ECOG performance status 
Vital Signs 
X 
See note in screening procedures. 
Serious and Non-serious 
Adverse Event 
Assessment 
X 
X* 
*Beyond 100 days from the last dose of study therapy, participants will be followed for 
drug-related AEs until AE resolves, returns to baseline, or is deemed irreversible, or until 
the participant is lost to follow-up or withdraws study consent. 
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection will be followed until resolution, the condition stabilizes, or is 
deemed irreversible, or until the participant is lost to follow-up (as defined in Section 8.3). 
For suspected cases, participants should be followed until SARS-CoV-2 infection is ruled 
out as per institutional policy on SARS-CoV-2. 
COVID-19 or positive SARS-CoV-2 test results should be reported to BMS within 
24 hours regardless of the seriousness criteria. 
Laboratory Tests 
X 
To be performed at Follow-up Visit 1, repeat at Follow-up Visit 2 if study drug-related 
toxicity persists. 
See Section 9.4.4. 
Review of Concomitant 
Medications 
X 
Subsequent Cancer 
Therapy 
X 
X 
Include documentation of subsequent cancer therapy (ie, systemic therapy, tumor-directed 
surgery, or radiation therapy). 
Pregnancy Test 
X 
Serum or urine 


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Body Imaging 
X 
X 
Participants who discontinue treatment for reasons other than tumor progression should 
continue to have tumor assessments: contrast-enhanced CT of the chest, CT/MRI of the 
abdomen, pelvis, and all other known and/or suspected sites of disease should occur every 
12 weeks (±1 week) until investigator-assessed disease progression or withdrawal of 
consent, whichever occurs first. Radiographic assessments should not be delayed until 
follow-up Visit 1 or Visit 2. 
See Section 9.1.1.1 for further details on imaging assessments. 
Brain Imaging 
X 
X 
Participants with a history of brain metastasis or symptoms should have surveillance MRIs 
per standard of care (approximately every 12 weeks) or sooner if clinically indicated. 
Collection of Survival 
Information 
X 
Every 3 months (± 14 days) from Follow-up Visit 2 until death, lost to follow-up, or 
withdrawal of study consent for up to 5 years following start of therapy. May be performed 
by phone contact or office visit. BMS may request that survival data be collected on all 
treated participants outside of the 3-month specified window. At the time of this request, 
each participant will be contacted to determine their survival status unless the participant 
has withdrawn consent for all contact. 
PK and Immunogenicity 
Blood Sampling 
X 
Biomarker Assessment 
Abbreviations: AE = adverse event; BMS = Bristol-Myers Squibb; BP = blood pressure; CRF = case report form; COVID-19 = coronavirus disease 2019; 
CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; HR = heart rate; MRI = magnetic resonance imaging; PK = pharmacokinetics; 
SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. 
a Some of the assessments referred to in this section may not be captured as data in the CRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulation and should be 
documented in the patient's source notes. 


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3 
INTRODUCTION 
In the last decade, there have been accelerated advances in our understanding of the role of the 
immune system and interplay with diseases, such as cancer. Research with agents that modulate 
the immune system, such as nivolumab, has transformed cancer therapeutics with notable clinical 
benefit observed across several tumors. Nivolumab has demonstrated durable responses as 
monotherapy and in combination with ipilimumab in several tumor types, including NSCLC, 
melanoma, RCC, cHL, SCLC, gastric cancer, SCCHN, urothelial cancer, HCC, and CRC. In 
confirmatory trials, nivolumab as monotherapy demonstrated a statistically significant 
improvement in OS as compared with the current standard of care in participants with advanced 
or metastatic NSCLC, unresectable or metastatic melanoma, advanced RCC, or recurrent or 
metastatic SCCHN. Nivolumab in combination with ipilimumab improved progression-free 
survival (PFS) and objective response rate (ORR) over ipilimumab alone in participants with 
unresectable or metastatic melanoma. 
Research with this pillar of therapy known as immuno-oncology (IO), of which nivolumab belongs 
to, continues with combination approaches and movement into earlier lines of therapy in 
tumors where nivolumab has been established. Due to this evolution with nivolumab and the 
treatment paradigm with IO, Bristol-Myers Squibb (BMS) is committed to improve the conditions 
for use of nivolumab, to meet the needs of patients, caregivers and health care practitioners 
(HCPs). 
Currently, nivolumab treatment as monotherapy or in combination with ipilimumab is 
administered via intravenous (IV) infusion over 30 to 60 minutes. As an alternative to IV infusion, 
BMS is evaluating SC administration of a high-concentration nivolumab with or without 
rHuPH20, a recombinant human hyaluronidase PH20 enzyme. The addition of rHuPH20 to 
nivolumab is to enhance permeation of high-volume fluids and allows for reduced administration 
times of less than five minutes. 
SC dosing incorporating a flat dose of a biologic drug product provides several potential 
advantages to HCPs that include reducing dosing errors; decreasing the time needed for dose 
preparation and administration; and alleviating IV infusion center occupancy. For the patient, this 
could also improve the drug administration experience by shortening injection time, and alleviating 
the need for IV infusion port (particularly if nivolumab is given as monotherapy or in combination 
with oral or SC drug regimens). Given the broadening use of nivolumab across various tumors, 
as monotherapy and in combination with other therapeutic agents, a quick subcutaneous injection 
has the potential to improve conditions for administering HCPs, caregivers and ultimately the 
patients. Additionally, the coronavirus disease 2019 (COVID-19) pandemic has caused significant 
disruptions to delivery of cancer care, with dose delays and discontinuation and a negative impact 
on patient quality of life.1 This disruption has heightened the criticality of providing alternative 
routes of cancer treatment, such as oral or SC delivery, as options for patients and providers. 


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3.1 
Study Rationale 
This Phase 1/2 study will characterize the PK, safety, and tolerability of high–concentration SC 
nivolumab (BMS-986298) with or without recombinant human hyaluronidase PH20 (rHuPH20), 
in participants with tumor types in which the effects on nivolumab clearance are similar. 
Parts A-E will evaluate the PK (pharmacokinetics), safety, and tolerability of SC nivolumab 
(± rHuPH20) in participants with 1 of the following tumor types approved for, or currently 
being investigated for, treatment with nivolumab monotherapy : non-small cell lung cancer 
(NSCLC); renal cell carcinoma (RCC); unresectable or metastatic melanoma; hepatocellular 
carcinoma (HCC); or colorectal cancer (CRC) (microsatellite instability-high [MSI-H] or 
mismatch repair-deficient [dMMR]).7,8 For Part B only, addition of other solid tumors were 
considered, where nivolumab PK was well characterized and discussed with the Sponsor. In 
addition to the above tumors, Part E will also include participants with metastatic urothelial 
carcinoma (mUC). 
The initial SC dosing regimen was selected as SC nivolumab (BMS-986298) 720 mg once every 
4 weeks (Q4W) based on extrapolated bioavailability models for SC administration of biologics 
(with and without rHuPH20). Based on extrapolated bioavailability models and preliminary PK 
from Part A, this study proceeded with a dose of 960 mg Q4W for Part B (Groups 3 & 4). 
Revised Protocol 03 
PK results from Parts A and B of this study and the breadth of data from population PK analyses 
with nivolumab IV across the clinical program were used to establish an SC dose of nivolumab 
with rHuPH20 to be administered every 4 weeks that is expected to provide comparable exposure 
(Cavgd28) to the IV nivolumab. PK data for SC and IV nivolumab from this study were combined 
with existing IV nivolumab PK data to identify a dose expected to provide PK exposures that are 
non-inferior to the initially approved dosing regimen, IV nivolumab 3 mg/kg Q2W. 
 
Protocol Amendment 04 
To support characterization of Q2W dosing of SC nivolumab and to provide dosing optionality for 
participants, 600 mg Q2W coformulated with rHuPH20 will be investigated in Part E. For 
Parts A-D, SC nivolumab and rHuPH20 were mixed at the site pharmacy (coadministration) prior 
to study drug administration. As of Protocol Amendment 04, coformulated drug product 
(SC nivolumab and rHuPH20 solutions pre-mixed in 1 vial with the same dose ratio) will be 
introduced for Part E. In addition, all ongoing participants in Parts C & D may switch to the 
coformulated drug product. 


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In Part E, approximately 36 participants in total will be enrolled. In addition to participants with 
the tumor types described for Parts A-D, approximately 10 participants with mUC will be included. 
The clinical benefit of IV nivolumab has been demonstrated in mUC, and Part E will provide 
preliminary PK data for SC nivolumab in this tumor type.5,6 
3.1.1 
Research Hypothesis 
Parts A-D: The purpose of Parts A-D is to characterize the PK, safety, and tolerability of 
nivolumab administered subcutaneously with and without rHuPH20 in participants with advanced 
or metastatic tumors. 
Part E: The purpose of Part E is to characterize the PK, safety, and tolerability of SC nivolumab 
600 mg Q2W coformulated with rHuPH20 in participants with advanced or metastatic tumors, 
including mUC. 
3.2 
Background 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses. 7,8,9 
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.10 Collectively, these signals govern the 
balance between T-cell activation and tolerance. 
3.2.1 
Nivolumab Mechanism of Action 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed 
death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a 
negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self- 


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antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. 
Nivolumab (OPDIVOTM) is approved for the treatment of several types of cancer in multiple 
regions, including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and 
Japan (Jul-2014). 
3.2.2 
Nivolumab Clinical Activity 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, cHL, SCLC, gastric cancer, SCCHN, urothelial 
cancer, HCC, and CRC. In confirmatory trials, nivolumab as monotherapy demonstrated a 
statistically significant improvement in OS as compared with the current standard of care in 
patients with advanced or metastatic NSCLC, unresectable or metastatic melanoma, advanced 
RCC, or recurrent or metastatic SCCHN. Details of the clinical activity in these various 
malignancies are provided in the USPI and SmPC. 
3.2.3 
Clinical Pharmacology of Nivolumab 
Nivolumab PK was assessed using a population PK approach for single-agent nivolumab. 
Nivolumab as a single agent: The PK of single-agent nivolumab was studied in patients over a 
dose range of 0.1 mg/kg to 20 mg/kg administered as a single dose or as multiple doses of 
nivolumab as a 60-minute infusion every 2 or 3 weeks. Nivolumab clearance (CL) decreases over 
time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 
24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 
8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered 
clinically relevant. Nivolumab clearance does not decrease over time in patients with completely 
resected melanoma, as the geometric mean population clearance is 24% lower in this patient 
population compared with patients with metastatic melanoma at steady state. The geometric mean 
volume of distribution at steady state (Vss) (%CV) is 6.8 L (27.3%), and geometric mean 
elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were 
reached by 12 weeks when administered at 3 mg/kg every 2 weeks (Q2W), and systemic 
accumulation was approximately 3.7-fold. The exposure to nivolumab increases dose 
proportionally over the dose range of 0.1 mg/kg to 10 mg/kg administered Q2W. The predicted 
exposure (Cavg and Cmax) of nivolumab after a 30-minute infusion is comparable to that observed 
with a 60-minute infusion. 
Specific Populations: The population PK analysis suggested that the following factors had no 
clinically important effect on nivolumab CL: age (29 to 87 years), weight (35 to 160 kg), gender, 
race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment, and mild 
hepatic impairment. 
Renal Impairment: 
The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK 
analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), moderate (eGFR 30 to 


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59 mL/min/1.73 m2), or severe (eGFR 15 to 29 mL/min/1.73 m2) renal impairment. No clinically 
important differences in the clearance of nivolumab were found between patients with renal 
impairment and patients with normal renal function. 
Hepatic Impairment: 
The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK 
analyses in patients with HCC and in patients with other tumors with mild hepatic impairment 
(total bilirubin [TB] less than or equal to the ULN and AST greater than ULN or TB greater than 
1 to 1.5 times ULN and any AST) and in HCC patients with moderate hepatic impairment (TB 
greater than 1.5 to 3 times ULN and any AST). No clinically important differences in the clearance 
of nivolumab were found between patients with mild/moderate hepatic impairment. 
Full details on the clinical pharmacology aspects of nivolumab can be found in the Investigator 
Brochure and product label. 
Nivolumab IV 480 mg Q4W is approved in the following indications: unresectable or metastatic 
melanoma, adjuvant treatment of melanoma, advanced renal cell carcinoma, classical Hodgkin 
lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck, locally 
advanced or metastatic urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch 
repair deficient (dMMR) metastatic colorectal cancer, hepatocellular carcinoma, and esophageal 
squamous cell carcinoma, and it was used in Parts A and B of this study. 
Revised Protocol 03 
Model-based assessment of nivolumab absorption when administered subcutaneously was 
conducted using population PK (PPK) approach. A previously developed PPK model with IV 
administration across several tumor types was used to further evaluate the rate (estimated as 
bioavailability) and extent of absorption. 
 
All the other PK parameters and the effect of covariates on PK 
parameters were consistent with those estimated previously with the IV population PK model. 
3.2.4 
Recombinant Human Hyaluronidase PH20 
Recombinant human hyaluronidase PH20 (rHuPH20, Halozyme Therapeutics, Inc.) is a 
glycosylated 447-amino acid single-chain recombinant human polypeptide that can temporarily 
depolymerize hyaluronan in the SC space locally at the site of injection. Hyaluronan is a repeating 
polymer of N-acetyl-glucosamine and glucuronic acid that contributes to the soluble gel-like 
component of the extracellular matrix of the skin. Depolymerization of hyaluronan results in a 
transient reduction in the viscosity of the gel-like phase of the extracellular matrix and increased 
hydraulic conductance that facilitates the dispersion and absorption of injected drugs (see 
rHuPH20 Investigator’s Brochure).11 This facilitates administration of greater volumes via the SC 
route as compared to SC administration without rHuPH20. rHuPH20 enables the delivery of large 
volumes for rapid SC injections, may shorten dose administration time, may reduce administration 
frequency, and may enable potential improvements to the PK profiles of co-administered drugs, 


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including improved absorption, increased bioavailability, accelerated Tmax, increased Cmax, and 
decreased PK variability. 
3.2.4.1 
Nonclinical Toxicity of Recombinant Human Hyaluronidase PH20 
General toxicity studies were performed in cynomolgus monkeys, and a developmental and 
reproductive toxicity program was performed in mice (see rHuPH20 IB). In a 39-week toxicity 
study in monkeys, rHuPH20 was well-tolerated, and 2 mg/kg administered SC weekly 
(~1,000,000 U for a 5 kg monkey), which was the highest dose tested, was determined to be the 
no-observed-adverse-effect level (NOAEL). In mice, at very high doses (≥ 9 mg/kg/day SC) of 
rHuPH20, embryo-fetal toxicity consisted of reduced fetal weights and a trend for late resorption; 
however, these high dose levels did not result in prenatal or postnatal developmental effects. 
Rabbit studies were also conducted to evaluate the potential effects of anti-rHuPH20 antibody 
exposure on reproduction and development. These studies showed no adverse effects on general 
toxicity endpoints, on male or female fertility, or on embryo-fetal development. Genotoxicity and 
carcinogenicity studies have not been conducted. 
See the rHuPH20 IB for detailed descriptions of the nonclinical pharmacology, PK, and toxicity 
studies of rHuPH20 and results. 
3.2.4.2 
Clinical Pharmacology of Recombinant Human Hyaluronidase PH20 
rHuPH20 may enable co-administered therapeutics to overcome administration, time, and volume 
barriers to SC drug delivery. Overall, data from a number of studies suggest that rHuPH20 can 
increase the utility of SC drug administration by improving ease of administration and the PK 
profile of concurrently administered large proteins. The half-life of rHuPH20 in skin is 
< 30 minutes,12 and the local permeability barrier in these tissues is restored to pre-injection levels 
within 24 hours to 48 hours after injection of hyaluronidase.13 A study of the PK of rHuPH20 
(Halozyme Study HALO-104-104) demonstrated a plasma t1/2 for IV doses of 10,000 or 30,000 
units of rHuPH20 in the range of less than 10 minutes. Knowledge of the mechanisms involved in 
the disappearance of injected hyaluronidase is limited. 
As of Nov-2017, rHuPH20 has been administered to 2321 participants in 28 clinical studies 
conducted under the US Investigational New Drug (IND) application for rHuPH20. In these 
clinical studies, the maximum duration of exposure was 12 weeks, and individual doses ranged 
from 15 U to 96,000 U rHuPH20. One study evaluated rHuPH20 injected intradermally as a single 
agent. A total of 26 studies evaluated rHuPH20 injected SC immediately prior to another agent or 
co-administered SC with another agent, including 11 studies evaluating rHuPH20 coformulated 
with recombinant human insulin (insulin-PH20) or rapid-acting insulin analogs (aspart-PH20 and 
lispro-PH20). One IV dosing study was conducted using 10,000 U or 30,000 U rHuPH20 in 
healthy volunteers. All but 2 studies were conducted in adult populations; pediatric exposure 
(< 18 years of age) in 2 clinical studies included 139 participants with mild-to-moderate 
dehydration who received SC infusions of isotonic fluids. In partnered trials, the maximum 
duration of participant exposure to rHuPH20 was up to 3.5 years (187.69 patient-years).14 


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Across all studies, SC injections of rHuPH20 were generally well-tolerated in healthy participants, 
dehydrated pediatric participants, hospice and palliative care participants, participants with type 1 
and 2 diabetes, and participants with rheumatoid arthritis. Subcutaneous injections of rHuPH20 
either alone or in combination with lactated Ringer’s, normal saline, co-injected drugs (morphine, 
ceftriaxone, insulin and insulin analogues) or biologic products (immunoglobulin G [IgG] and 
adalimumab) have been well-tolerated in all clinical trials. Most AEs were mild, transient 
injection-site reactions, including erythema, pain, bruising, pruritus, burning, tenderness, edema, 
induration, irritation, paresthesia, numbness and rash. Moderate injection-site reactions, which 
have occurred less frequently, include burning, erythema, pain and numbness. Mild-to-moderate 
headache was also commonly reported. Adverse events in these trials have otherwise generally 
reflected the adverse reaction profiles of the co-administered drug or have been associated with 
the rapid introduction of a relatively large volume of fluid into the SC space. 
Antibodies to rHuPH20 have been evaluated in several nonclinical and clinical studies. To date, 
no clinical signs or symptoms have been associated with positive rHuPH20 antibody titers in 
clinical trials with rHuPH20 and no rHuPH20-neutralizing antibody activity has been detected. 
In addition to these studies, a large clinical safety database exists for rHuPH20 as a tissue 
permeability enhancer in combination with several approved products in the US and/or EU 
including: 
• HYQVIA® (Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (PH20) (sequential SC administration)); 
• Herceptin® SC (trastuzumab coformulated with rHuPH20); 
• MabThera® SC/RITUXAN HYCELA® (rituximab coformulated with rHuPH20); 
• HYLENEX® (rHuPH20 alone; US only); 
• DARZALEX FASPRO™ (daratumumab and hyaluronidase-fihj); and, 
• PHESGO™ (pertuzumab, trastuzumab, and hyaluronidase-zzxf; US only). 
 
3.2.5 
Nonclinical Toxicity of Subcutaneous Nivolumab 
A nonclinical study was conducted in cynomolgus monkeys to evaluate local tolerance and 
systemic exposures to nivolumab when administered twice (3 weeks apart) as a SC formulation 
with and without rHuPH20.15 Nivolumab was supplied as 154.57 mg/mL (BMS-986298) and was 
administered by SC injection at doses of 0 mg/kg (vehicle), 50 mg/kg (no rHuPH20), or 50 mg/kg 
(with rHuPH20, 2000 U/mL), twice (Days 1 and 22/20 [males/females]), to groups of 3 monkeys 
per sex. All doses were administered at 0.5 mL/kg in a vehicle/carrier consisting of 20 mM 
histidine, 250 mM sucrose, 0.05% polysorbate-80, and 50 µM pentetic acid (histidine buffer). 
Samples for toxicokinetic analysis were collected following dosing on Day 1 and scheduled 
necropsies were conducted at 72 hours following dosing on Day 22/20 (males/females). 
 


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Table 3.2.5-1: 
Toxicokinetic Summary - 
 
SC Nivolumab (BMS-986298) 
 
a Value was calculated with all/exclusion of monkeys with detectable treatment-emergent anti-nivolumab antibodies. 
 
3.3 
Benefit/Risk Assessment 
Extensive details of the IV nivolumab safety profile is available in the nivolumab (BMS-936558) 
IB and will not be repeated herein. Overall, the safety profile of IV nivolumab monotherapy is 
manageable and generally consistent across completed and ongoing clinical trials, with no 
maximum tolerated dose reached at any dose tested up to 10 mg/kg.16,17,18,19 Most AEs were 
low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There was no 
pattern in the incidence, severity, or causality of AEs with respect to IV nivolumab dose level. A 
pattern of immune-related adverse events (IMAEs) has been defined, for which management 
algorithms have been developed (Appendix 6). Most high-grade IMAEs were manageable with 
the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. 
 
 
 
 
 
 
 
Based on the E-R analyses conducted thus far, this change 
in pharmacokinetic profile is not expected to alter the efficacy or safety profile of nivolumab. 
As outlined in the protocol, until the SC nivolumab (BMS-986298) dose was confirmed to ensure 
non-inferior Cavgd28 exposures to nivolumab IV 3mg/kg dosing, participants were transitioned 
mg/kg (no 
)a 
mg/kg (with 
)a 
Cmax (µg/mL) 
Tmax (h) 


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to IV nivolumab (BMS-936558) 480mg Q4W in Cycle 2+. In addition, since SC administration of 
nivolumab may be associated with a risk of local injection-site reactions not observed with IV 
administration, these risks were monitored, assessed, and managed in this study. The potential 
effect of immunogenicity on the safety and PK of SC nivolumab (BMS-986298) will also be 
assessed. However, these potential risks to participants seem reasonably compensated by the 
potential benefits of decreased administration times and decreased need for visits to specialized IV 
infusion centers. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the SC nivolumab (BMS-986298) IB and IV nivolumab (BMS-936558) IB. 
 
 
 
 
 
 
BMS is collecting 
immunogenicity data for rHuPH20 throughout this study. 
Revised Protocol 03 
Interim analyses from Parts A & B include safety experience of SC Nivolumab 720 mg and 960 mg 
(with rHuPH20). There were thirty-two participants dosed with SC nivolumab (720 mg or 960 mg 
with rHuPH20) on Cycle 1 Day 1 (C1D1) followed by IV nivolumab. Specifically, twenty-two 
participants in Group 1 (720 mg SC nivolumab + rHuPH20) and ten participants in Group 3 (960 
mg SC nivolumab + rHuPH20) were included for safety considerations with the co-administered 
formulation. Demographics and baseline characteristics of study population included participants 
with broad representation of ages, weights & tumors (advanced/metastatic setting in line with 
 
 
 
Revised Protocol 03 introduces 
this dose for Parts C & D to assess primary objective of characterizing PK of SC nivolumab. 
Objectives include assessment of safety of SC nivolumab in these settings (from initiation of 
therapy and in the context of switching from IV nivolumab). The predicted exposures are expected 
to fall within nivolumab 10 mg/kg Q2W IV dosing previously explored in early nivolumab studies. 
Since these early trials have shown that a similar clinical profile can be anticipated relative to 
3 mg/kg Q2W, this dose is expected to provide a similar benefit risk profile to previous studies. 
current previously studied patient populations). 


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Protocol Amendment 04 
Safety results from 28 participants in Part C (data cutoff date: 30-Sept-2020; Part A/B participants 
who were treated with nivolumab [BMS-986298] 720 mg or 960 mg [with or without rHuPH20], 
followed by nivolumab IV 480 mg Q4W, and later transitioned to nivolumab SC 1200 mg Q4W 
 
 
Across treatment groups, ADAs were reported with nivolumab (BMS-986298) with and without 
 
 
rHuPH20. 
with rHuPH20) 
. 
Safety results from 36 participants in Part D 
showed that 


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4 
OBJECTIVES AND ENDPOINTS 
Table 4-1: 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
Parts A- D: To describe the pharmacokinetics of 
nivolumab administered subcutaneously, with or 
without rHuPH20 
Part E: To evaluate the pharmacokinetics of SC 
nivolumab 600 mg Q2W coformulated with rHuPH20 
• 
Serum nivolumab Parts A, B, D, and E: 
− 
Cmax 
− 
Tmax 
− 
AUC(TAU) 
− 
Ctau 
• 
Serum nivolumab Part C: 
− 
Ctrough 
Secondary 
To assess the safety profile of SC nivolumab. 
• 
Incidences of AEs, TRAEs, SAEs, TRSAEs, 
AEs/TRAEs leading to discontinuation, deaths, 
and laboratory abnormalities. 
To evaluate incidence of AEs in the broad standardized 
MedDRA query (SMQ) of Anaphylactic Reaction and 
the select AE hypersensitivity/infusion reaction 
category. 
• 
Incidence of AEs in the broad SMQ of 
Anaphylactic Reaction occurring within 2 days 
after study drug administration 
• 
Incidence of events within the 
hypersensitivity/infusion reaction select AE 
category occurring within 2 days after study drug 
administration. 
To assess the immunogenicity of nivolumab 
• 
Incidence of anti-nivolumab antibodies and 
neutralizing antibodies, if applicable 
Exploratory 
To evaluate preliminary efficacy in all participants 
• 
ORR, PFS, and OS 
To characterize biomarker measures 
• 
Including, but not limited to: summary measures 
of change (or % change) from baseline in various 
biomarkers and molecular characteristics of the 
tumor (Parts A-D, and based on tissue availability 
for Part E)/blood 
To assess the immunogenicity of rHuPH20 
• 
Incidence of anti-rHuPH20 antibodies and 
neutralizing antibodies, if applicable 
To assess the preliminary participant experience and 
preference for SC or IV administration of nivolumab. 
• 
Patient experience and preference questionnaire 
• 
Qualitative Patient Interviews 
Abbreviations: AE = adverse event; AUC(TAU) = area under the concentration-time curve over the dosing interval; 
Cmax = maximum observed serum nivolumab concentration; Ctau = observed serum nivolumab concentration at the 
end of the dosing interval; Ctrough = trough observed serum nivolumab concentration; IV = intravenous; 
MedDRA = Medical Dictionary for Regulatory Activities; ORR= objective response rate; OS = overall survival; 
PFS = progression-free survival; Q2W = every 2 weeks; rHuPH20 = recombinant human hyaluronidase PH20; 
SAE = serious adverse event; SC = subcutaneous; SMQ = standardized MedDRA queries; TRAE = treatment-related 
adverse event; TRSAE = treatment-related serious adverse event. 


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5 
STUDY DESIGN 
5.1 
Overall Design 
Study CA2098KX is a multicenter, randomized, open-label, Phase 1/2 study that will evaluate the 
PK, safety, and tolerability of SC nivolumab (BMS-986298) administered with and without 
rHuPH20 subcutaneously in participants with 1 of the following tumor types: NSCLC; RCC; 
unresectable or metastatic melanoma; HCC; or CRC (MSI-H or dMMR). Additional tumors were 
permitted in Part B where PK was well characterized and discussed with the Sponsor. In addition 
to the above tumors, Part E will also include participants with mUC. 
The study is divided into the following periods: a Screening period; a Treatment period consisting 
of Part A, Part B, Part C, Part D, and Part E; and a Safety Follow-up period. 
Parts A-E: Approximately 139 total participants will receive study treatment as follows (also see 
study design schematic in Figure 5.1-1): 
• Part A/B: 
− Part A : 
♦ Group 1: Single dose of nivolumab (BMS-986298) 720 mg administered SC with 
rHuPH20 manually by syringe (n=22) 
− Part B : After participants were dosed in Part A, 45 participants were dosed in Part B. The 
first 10 participants were assigned to Group 3. The next 35 participants were randomized 
1:1 into Group 2 (n=18) and Group 4 (n=17). 
♦ Group 2: Single dose of nivolumab (BMS-986298) 720 mg administered SC without 
rHuPH20 by syringe pump 
♦ Group 3: Single dose of nivolumab (BMS-986298) 960 mg administered SC with 
rHuPH20 manually by syringe 
♦ Group 4: Single dose of nivolumab (BMS-986298) 960 mg administered SC without 
rHuPH20 by syringe pump 
− Four (4) weeks after the single SC nivolumab (BMS-986298) dose, all participants in 
Part A and Part B received IV nivolumab (BMS-936558) 480 mg Q4W dosing until 
Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable 
toxicity, withdrawal of consent, completion of 104 weeks of treatment, cross over to SC 
nivolumab dosing in Part C, or study termination by the Sponsor, whichever occurs first. 
• Part C: Participants in Part A and Part B crossed over from nivolumab (BMS-936558) IV 
dosing (four [4] weeks after last IV dose) to nivolumab (BMS-986298) 1200 mg administered 
SC with rHuPH20 manually by syringe every 4 weeks. 
• Part D: (Approximately 36; of which approximately 10 with baseline BW < 65kg): On Day 1 
of each treatment cycle, nivolumab (BMS-986298) 1200 mg administered SC with rHuPH20 
manually by syringe every 4 weeks. 
• Part  E:  (Approximately  36;  of  which  approximately  10  with  mUC): 
nivolumab (BMS-986298) 600 mg coformulated with rHuPH20 administered SC manually by 
syringe every 2 weeks. 


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For Parts A-D, SC nivolumab and rHuPH20 were mixed at the site pharmacy (coadministration) 
prior to study drug administration. As of Protocol Amendment 04, coformulated drug product 
(SC nivolumab and rHuPH20 solutions pre-mixed in 1 vial with the same dose ratio) will be 
introduced for Part E. In addition, all ongoing participants in Parts C & D may switch to the 
coformulated drug product. 
Parts A, B and D: Each treatment group in Part A, Part B, and Part D 
by immunohistochemistry (IHC) or with MSI-H/dMMR (for 
CRC). 
Part E: Tissue PD-L1 assessment is optional. 
Doses for Part B (Group 3 & 4) were adjusted based on PK and safety information from Part A to 
be 960 mg Q4W and confirmed by an administrative letter to the investigators. 
Parts A & B: Four weeks after the SC dose of study treatment (ie, Study Day 29), participants 
received 480 mg IV nivolumab (BMS-936558) Q4W until Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, completion of 
104 weeks of treatment, cross over to SC nivolumab dosing in Part C, or study termination by the 
Sponsor, whichever occurs first. For each participant who was unable to complete the planned 
Cycle 1 (SC study treatment) and Cycle 2 (IV nivolumab) treatments and PK sampling, an 
additional participant was assigned. 
Parts C & D: An outline of the considerations for Part C and Part D dose selection is presented in 
Section 10.3.8 (Interim Analyses). 
Part E: The dose in Part E is 600 mg SC nivolumab coformulated with rHuPH20 Q2W. 
 
 
For each participant who 
is unable to complete the planned study treatments and PK sampling following the first dose, an 
additional participant may be assigned via interactive response technology (IRT). 
Dosing in the study will continue until RECIST v.1.1 progression, unacceptable toxicity, 
withdrawal of consent, completion of 104 weeks of total nivolumab treatment (IV and SC 
combined), or study termination by the Sponsor, whichever occurs first. 
 
Approximately 750 mL of blood (for PK, biomarker and safety assessments) in total will be drawn 
from each participant during the entire study (two-year period). 


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BMS-986298 
nivolumab SC 
+rHuPH20 
1200 mg Q4W 
BMS-936558 
nivolumab IV 
480 mg Q4W 
Figure 5.1-1: 
CA2098KX Study Design Schematica 
 
Part A 
Part B 
Part D c, d 
 
 
 
 
 
Group 1 
BMS-986298 
nivolumab SC 
+rHuPH20 
720 mg 
N=22 
Group 2 
BMS-986298 
nivolumab SC 
720 mg 
N=18 
Group 3 
BMS-986298 
nivolumab SC 
+rHuPH20 
960 mg 
N=10 
Group 4 
BMS-986298 
nivolumab SC 
960 mg 
N=17 
 
 
 
Part C c, d 
 
 
 
 
 
Abbreviations: BW = body weight; IV = intravenous; PK = pharmacokinetic; Q4W = every 4 weeks; 
mUC = metastatic urothelial carcinoma; rHuPH20 = recombinant human hyaluronidase PH20; Q2W = every 2 weeks; 
Q4W = every 4 weeks; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; SC = subcutaneous. 
a Schema represent the actual numbers of participants enrolled for Parts A, B, and D. 
b Actual enrollment: The first 10 participants were assigned to Group 3. The next 35 participants were randomized 
1:1 into Group 2 (n=18) and Group 4 (n=17). 
c Crossover into Part C and dosing in Part D (Group 5) begin after the SC nivolumab (BMS-986298) dosing regimen 
is identified from analysis of PK data from Parts A & B. At the time of Protocol Amendment 04, enrollment for 
Part D has completed and actual enrollment was 36 participants. 
Note: Group 2 and Group 4 will receive SC nivolumab (BMS-986298) by syringe pump without rHuPH20. 
d Any ongoing participants on SC nivolumab + rHuPH20 treatment may switch over to nivolumab coformulated with 
rHuPH20 drug product. 
 
 
Safety monitoring will consist of physical examinations, vital sign measurements, and clinical 
laboratory evaluations at selected times throughout the dosing interval. Participants will be closely 
monitored for adverse events (AEs) throughout the study. Collection of AEs and severity per 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5 
criteria will also include local injection-site reactions after SC administration and IV-related 
infusion reactions. 
• 4 weeks 
• PK sampling 
Parts C, D and E: Treatment until 104 weeks total, withdrawal, toxicity, RECIST v1.1 progression, or death 
Group 5 
BMS-986298 
nivolumab SC 
+rHuPH20 
1200 mg 
Q4W 
N=36 
(approx. 10 with BW <65kg) 
Part E 
Group 6 
BMS-986298 
nivolumab SC 
coformulated with 
rHuPH20 
600 mg Q2W 
N=36 
(approx. 10 with mUC) 
After Part A participants dosed, 
Part B dosing begins 
N=45 b 
Part A enrolls first 
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5.1.1 
Screening Period 
Participants will provide written informed consent to participate in the study before completing 
any protocol-specified procedures or evaluations not considered to be part of the participants’ 
standard care. After signing the informed consent form (ICF), participants will be evaluated for 
entry criteria during the Screening period within 28 days before administration of study drug. 
Rescreening after screen failure will be allowed. The participant is enrolled using IRT. 
Parts A-D: Sufficient, recent tumor tissue obtained within 12 months prior to enrollment from a 
metastatic tumor lesion or from an unresectable primary tumor lesion that has not been previously 
irradiated (formalin-fixed paraffin-embedded block (FFPE) 
, obtained 
from core needle biopsy, excisional, or incisional biopsy) will be submitted. Where possible, the 
biopsied lesion should be distinct from target lesions being evaluated for radiologic response, and 
the same lesion should be used for both the baseline and on-treatment sampling. Pre-treatment 
tissue must be collected and locally confirmed for adequate tissue quantity and quality during the 
screening period prior to first dose of study treatment and then sent to the central laboratory for 
testing. Please refer to lab manual for detailed biopsy collection instructions. Up to 5 participants 
(part A & B) who did not meet tissue requirements were allowed treatment after discussion with 
the Medical Monitor. 
Approximately 15 participants (Part D) who do not meet tissue requirements will be allowed 
treatment after discussion with the Medical Monitor. Participants should not have received any 
systemic anticancer therapy after the date that the submitted tumor tissue was obtained. Tumor- 
cell 
must be assessed by IHC, but participants 
may receive treatment before results are available. Participants with CRC must have 
documentation of prior local testing for MSI-H/dMMR status. Each treatment group in Part A, 
Part B, and Part D 
by IHC or with 
MSI-H/dMMR (for CRC). Additional participants may be enrolled to meet this minimum accrual 
at the Sponsor’s discretion. 
 
Part E: Tumor tissue collection is highly recommended, but optional. For all participants in Part E, 
including mUC participants, submission of an archival FFPE tissue block (preferred) or unstained 
slides of tumor tissue from core biopsy, excisional biopsy, or surgical specimen obtained within 
12 months of enrollment is highly recommended. 
 


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See Section 9.8.1 for more details. 
Participants will be evaluated based on the assessments as outlined in Table 2-1 for Parts A-D and 
Table 2-2 for Part E and inclusion and exclusion criteria (Section 6). IRT contact must occur for 
participant number assignment at the time informed consent is obtained. 
5.1.2 
Treatment Period 
Each treatment cycle (28 days) is associated with evaluations and procedures specific to each 
tumor type. For each participant, on-study tumor assessments will first occur at Week 12 (± 7 days) 
from first dose date, then every 8 weeks (± 7 days) before the subsequent dose, namely within 
7 days of dosing on Day 22 in Cycles 5, 7, 9, etc., up to Week 104 of total treatment until 
investigator-assessed disease progression or treatment is discontinued, whichever occurs later (see 
Section 9.1.1). Results of the assessments must be reviewed and documented before administering 
the first dose of the next cycle. Every effort should be made to schedule visits within the protocol- 
specified windows. Assessments and frequency are described in Section 2. 
Dosing in Parts A through E of the study will continue until RECIST v.1.1 progression, 
unacceptable toxicity, withdrawal of consent, completion of 104 weeks of total nivolumab 
treatment (IV and SC), death, or study termination by the Sponsor, whichever occurs first. In 
certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise 
stable or improved performance and clinical status may continue to be treated in the event of a 
perceived benefit per Investigator; see Section 8.1.2 for treatment beyond progression criteria. 
5.1.3 
Safety Follow-up Period 
The Safety Follow-up Period (Table 2-4) begins when the decision to discontinue a participant 
from study therapy is made (ie, no further treatment with study therapy). All participants who 
discontinue study treatment will be followed for drug-related toxicities until these toxicities 
resolve, return to baseline or are deemed irreversible. All AEs will be documented at visits 
scheduled on Day 30 and Day 100 from the last study drug dose to monitor for AEs. After 
completion of the first two follow-up visits, participants will be followed every 3 months for 
survival for up to 5 years. 
Beyond 100 days from the last dose of study therapy, participants will be followed for drug-related 
AEs until AE resolves, returns to baseline, or is deemed irreversible, or until the participant is lost 
to follow-up or withdraws study consent. 
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection will be followed until resolution, the condition stabilizes, or is deemed irreversible, or 
until the participant is lost to follow-up (as defined in Section 8.3). For suspected cases, 
participants should be followed until SARS-CoV-2 infection is ruled out as per institutional policy 
on SARS-CoV-2. 
Response/Survival follow-up: Participants who discontinue treatment for reasons other than tumor 
progression should continue to have tumor assessments if clinically feasible (contrast-enhanced 
computed tomography [CT] of the chest, CT/magnetic resonance imaging [MRI] of the abdomen, 
pelvis, and all other known and/or suspected sites of disease) every 12 weeks (± 7 days) until 


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investigator-assessed disease progression or withdrawal of consent, whichever occurs first. 
Radiographic assessments for these participants should not be delayed until the planned follow-up 
visits. 
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol-defined window as detailed in Section 2. At the time of this request, each participant 
will be contacted to determine their survival status unless the participant has withdrawn consent 
for all contact. 
5.1.4 
Data Monitoring Committee and Other External Committees 
A data monitoring committee and other external committees will not be used in this study. 
5.2 
Number of Participants 
Approximately 139 total participants with any of the included advanced or metastatic tumor types 
will receive study treatment as follows: 
• In Part A, 22 participants received 720 mg SC nivolumab (BMS-986298) manually by syringe 
with rHuPH20. 
• In Part B, 45 participants were dosed. The first 10 participants were assigned to Group 3. The 
next 35 participants were randomized 1:1 into Group 2 (n=18) and Group 4 (n=17). 
• In Part D, approximately 36 participants (approximately 10 with baseline BW < 65 kg) will 
receive nivolumab (BMS-986298) 1200 mg with rHuPH20 administered SC manually by 
syringe every 4 weeks. 
• In Part E, approximately 36 participants, including approximately 10 participants with mUC, 
will receive nivolumab (BMS-986298) 600 mg coformulated with rHuPH20 administered SC 
manually by syringe every 2 weeks. 
 
Additional participants may have been assigned/randomized to study treatment for each participant 
who was unable to complete one of the following: 
• Planned Cycle 1 (SC study treatment) and/or Cycle 2 (IV nivolumab) treatments and PK 
sampling in Part A 
• Planned Cycle 1 (SC study treatment) and/or Cycle 2 (IV nivolumab) treatments and PK 
sampling in Part B 
• Planned Cycle 1 and/or Cycle 2 treatments and PK sampling in Part D 
 
For Part E, additional participants may be assigned to study treatment for each participant who is 
unable to complete the first dose and up to 
of PK sampling. 
Each treatment group in Part A, Part B, and Part D 
by IHC or with MSI-H/dMMR (for CRC). For Part E, tissue PD-L1 assessment 
is optional. 
Randomization- where applicable - will not be stratified by tumor type or by any demographic or 
disease characteristic. 


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5.3 
End of Study Definition 
The start of the study is defined as first visit for first participant screened. End of trial is defined 
as the last visit or scheduled procedure shown in the Schedule of Activities for the last participant. 
Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected, if this is not the same. 
5.4 
Scientific Rationale for Study Design 
BMS is evaluating ways to improve the conditions for use of nivolumab to meet the needs of 
patients and HCPs. Currently, nivolumab treatment as monotherapy is administered via IV 
infusion. As an alternative to IV infusion, BMS is developing a SC formulation of nivolumab with 
rHuPH20, a recombinant human hyaluronidase PH20 enzyme that enhances permeation of 
subcutaneously administered fluids, to significantly decrease administration times of nivolumab 
and improve accessibility to treatment. SC dosing incorporating a flat dose of a biologic drug 
product provides several potential advantages to HCPs that include reducing dosing errors, 
decreasing the time needed for dose preparation and administration, and alleviation of IV infusion 
center occupancy. 
In the current study, multiple dose regimens of nivolumab are assessed to gather information on 
the pharmacokinetic and safety profile of SC nivolumab (BMS-986298). PK results from Parts A 
and B of this study were used to establish the recommended SC dose of nivolumab with rHuPH20 
in Parts C, D, and E as well as for future studies utilizing the SC nivolumab formulation. 
5.4.1 
Rationale for Subcutaneous Administration 
Because systemic exposures of IV nivolumab at or above those historically achieved in clinical 
studies correlate with response, BMS proposes to dose SC nivolumab to meet average systemic 
exposures based on the scientific rationale that systemic nivolumab exposure, irrespective of the 
route of administration, is associated with safety and efficacy. Nivolumab (BMS-936558) 
exposures with 240 mg Q2W and 480 mg Q4W flat-dose IV regimens across tumor types are 
maintained at levels comparable to 3 mg/kg Q2W dosing and well below the corresponding 
exposures observed with the well-tolerated 10 mg/kg IV nivolumab Q2W dose regimen. 
Intravenous flat doses of 240 mg Q2W nivolumab, 360 mg Q3W nivolumab, and 480 mg Q4W 
nivolumab have been incorporated in monotherapy and combination oncology studies, and the 
240 mg Q2W and 480 mg Q4W nivolumab dose regimens are approved in multiple indications. 
Q4W dosing regimens can reduce the burden to patients of frequent, lengthy IV treatments and 
provide more flexibility in combining with the dosing schedules of other agents. 
5.4.2 
Rationale for Selection of Tumor Types 
The PK properties of nivolumab after IV administration have been characterized across multiple 
tumors including NSCLC, RCC, melanoma, CRC, urothelial carcinoma, squamous cell carcinoma 
of the head and neck, and classic Hodgkin lymphoma (cHL). The patient population for this study 
include participants with 1 of the following tumor types currently approved for treatment with IV 
nivolumab  (BMS-936558):  NSCLC,  RCC,  advanced/metastatic  melanoma,  HCC, 
MSI-H/dMMR CRC, and mUC. 


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Selection of tumor types in Parts A-E of this study is based on their similar IV PK properties 
(specifically clearance). Analysis of the effect of covariate tumor type on clearance showed that 
these tumor types do not have statistically significant effects on the clearance of nivolumab, while 
the effects of other tumors with statistically significant effects on clearance (eg, cHL) were not 
considered to be clinically meaningful.22 The enrollment of participants with mUC in Part E will 
enable characterization of the PK profile after SC nivolumab in this tumor type. Enrolling multiple 
tumor types with similar nivolumab systemic PK properties, and minimizing the variability in 
systemic PK, will allow for adequate characterization of the absorption PK properties of 
nivolumab following SC administration. 
In Part B, in addition to the tumor types listed above, other solid tumor types were considered for 
enrollment at the discretion of the Sponsor. 
5.4.3 
Rationale for PK and Immunogenicity Sampling Plan 
The PK sampling plan is devised to collect data that would also be informative in a PPK model. 
The PK sampling for nivolumab will be relatively intense after SC dosing to characterize 
absorption after SC administration to enable non-compartmental analysis as well as PPK analysis. 
Because the PK of IV nivolumab (BMS-936558) is well characterized, BMS does not plan to 
conduct intense PK sampling following IV nivolumab. 
BMS plans to collect nivolumab immunogenicity samples. See Section 2 (Schedule of Activities) 
and Section 9.5.1 (PK and Anti-drug Antibody Sample Collection and Processing). 
For this PK study of SC nivolumab, BMS does not plan to collect PK data for rHuPH20. The 
pharmacological effects of rHuPH20 are exclusively local at the site of injection. The plasma t1/2 
of IV administered rHuPH20 is < 10 minutes, and blood levels are barely above detectable levels 
> 45 minutes after administration of IV doses of 10,000 U.14 Systemic exposure to SC doses of 
rHuPH20 has been undetectable in studies involving SC doses up to 30,000 U.23 
BMS plans to collect immunogenicity data for rHuPH20. However, no clinical signs or symptoms 
have been associated with positive rHuPH20 antibody titers in clinical trials with rHuPH20, and 
no confirmed rHuPH20-neutralizing antibody activity has been detected.20 
5.4.4 
Rationale for Two Year Duration of Treatment 
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 
2-4 months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. A retrospective pooled analysis of two melanoma studies suggest the majority of 
patients who discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the 
absence of further treatment.24 Furthermore, a limited duration of ipilimumab, including only 
4 induction doses, resulted in long term survival in patients with metastatic melanoma, with a 
sustained plateau in survival starting around 2 years after the start of treatment.25 


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Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 patients with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 patients with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 patients were alive >5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the overall survival (OS) curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.26 These 
survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2 year OS rates of 23% and 
29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC respectively).27 
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low. 
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
PFS compared to those who were randomized to stop treatment, with median PFS 
(post-randomization) not reached vs 10.3 months, respectively; hazard ratio = 0.42 (95% 
confidence interval [CI], 0.25 to 0.71). With a median follow-up of 14.9 months 
post-randomization, there also was a trend for patients on continued treatment to live longer (OS 
hazard ratio = 0.63 [95% CI: 0.33, 1.20]). Of note, the PFS curves in both groups plateau 
approximately 1 year after randomization (ie, 2 years after treatment initiation), suggesting that 
there may be minimal benefit in extending treatment beyond a total of 2 years. 28 
Collectively, these data suggest that there is minimal if any benefit derived from continuing IO 
treatment beyond two years in advanced tumors. Even though immunotherapy is well tolerated, 
patients will be at risk for additional toxicity with longer term treatment. Therefore, in this study, 
treatment will be given for a maximum of 2 years from the start of study treatment. 
5.5 
Justification for Dose 
5.5.1 
Justification for 480 mg Q4W IV Dose 
The IV flat dose of nivolumab 480 mg in Parts A and B was selected based on comprehensive PPK 
analyses and E-R data using Cavgd28 as the primary driver of efficacy across multiple tumor types. 
The IV nivolumab 480 mg Q4W regimen presents a comparable benefit-risk profile as the IV 
nivolumab 3 mg/kg Q2W dosing regimen across multiple tumor types. 


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In exposure-efficacy analyses using Cavgd28 as the driver of efficacy, probabilities of achieving 
a response and survival probabilities at 1 year and 2 years for IV nivolumab 480 mg Q4W were 
similar to those of IV 3 mg/kg Q2W. 
Exposure-safety analysis showed that the exposure margins for safety were maintained following 
IV nivolumab 480 mg Q4W, and the predicted risks of AEs leading to discontinuation/death, 
Grade ≥ 3 AEs, and Grade ≥ 2 IMAEs were shown to be similar following IV nivolumab 480 mg 
Q4W relative to IV nivolumab 3 mg/kg Q2W across tumor types. Safety analyses using available 
data following IV nivolumab 3 mg/kg Q2W and 10 mg/kg Q2W administration indicated there 
were no differences in AE profiles across body weight groups. Finally, initial evidence shows that, 
following administration of 480 mg Q4W, nivolumab has been shown to be well tolerated. 
5.5.2 
Justification of Subcutaneous Doses of Nivolumab 
Studies have consistently shown that the mean population estimate for bioavailability of 
monoclonal antibodies following SC administration approximates 75% of that with IV 
administration, with a lower Cmax and a delayed Tmax.29 The PK data from the nonclinical 
toxicokinetic study of SC nivolumab (BMS-986298) in cynomolgus monkeys support this 
prediction; higher weight-based (mg/kg) doses of SC nivolumab than those planned in CA2098KX 
were well tolerated (see Section 3.2.5). 
 
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Based on the outcomes of Part A, a single SC dose of 960 mg was tested in Group 3 and Group 4 
to acquire additional SC nivolumab PK data. The Cmax with SC nivolumab (BMS-986298) 960 
mg is within the safety margin established with nivolumab IV 10 mg/kg Q2W. The Cycle 1 doses 
for Group 3 and Group 4 was confirmed by administrative letter to the investigators. 
5.5.3 
Revised Protocol 03: Selection of SC Nivolumab Dose in Part C and D 
(1200 mg Q4W) 
PK data from participants enrolled in Parts A and B where nivolumab (720 mg and 960 mg) was 
administered SC with rHuPH20 and historical IV data across several tumor types was used to 
characterize the absorption profile of nivolumab when given subcutaneously. 
All the other PK parameters and effects of 
covariates on these parameters were consistent with that estimated previously with IV PPK model. 
 


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5.5.4 
Protocol Amendment 04: Rationale for SC Nivolumab Dose 
Coformulated with rHuPH20 in Part E (600 mg Q2W) 
In interim PPK analysis 03, PK data from participants who received 720 mg, 960 mg, and 1200 mg 
of SC nivolumab with or without rHuPH20, and historical IV nivolumab data across several tumor 
types (data from ~ 3,000 patients) were used to update the characterization of the absorption profile 
of nivolumab when given SC. The typical value (90% CI) bioavailability and first-order rate of 
absorption were estimated to be 70% (66% to 74%) and 0.250 (0.225 to 0.274) day-1, 
 
6 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
6.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Participants must have signed and dated an Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approved written informed consent form (ICF) in accordance with 
regulatory and institutional guidelines. This must be obtained before the performance of 
any protocol-related procedures that are not part of normal patient care. Part E 
participants, refer to Appendix 2 for details. 
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, patient preference questionnaires and other requirements of the study. 
2) Type of Participant and Target Disease Characteristics 
a) Participants must have histologic or cytologic confirmation of advanced (metastatic and/or 
unresectable) solid tumors of one of the following tumor types: 
i) Parts A -E: Metastatic squamous or non-squamous NSCLC 
(1) Participants must have experienced disease recurrence or progression during or 
after one prior platinum doublet-based chemotherapy regimen for advanced or 
metastatic disease. 
(2) Participants with epidermal growth factor receptor or anaplastic lymphoma kinase 
genomic tumor aberrations should have disease progression on approved therapy 
for these aberrations prior to receiving nivolumab treatment. 
ii) Parts A -E: Renal cell carcinoma, advanced or metastatic: 
(1) Participants who had experienced disease progression during or after 1 or 2 prior 
anti-angiogenic therapy regimens (including, but not limited to sunitinib, sorafenib, 
pazopanib, axitinib, tivozanib, and bevacizumab) in the advanced or metastatic 
setting. 
respectively.21 


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iii) Parts A-E: Melanoma 
(1) Unresectable or metastatic melanoma, previously untreated except for prior anti- 
BRAF/MEK targeted therapy in the adjuvant setting 
iv) Parts A-E: Hepatocellular carcinoma not amenable for management with curative 
intent by surgery or local therapeutic measures 
(1) Must have received sorafenib or lenvatinib treatment and be either intolerant or 
have had documented radiographic or symptomatic progression during or after 
sorafenib or lenvatinib therapy 
(2) Child-Pugh A (ie, Child-Pugh score ≤ 6) (Appendix 9) 
(3) AST and ALT ≤ 5x times the upper limit of normal (ULN) 
(4) Not applicable per Protocol Amendment 04. See (a) immediately below for all 
Parts A-E. Total bilirubin < 3 mg/dL. 
(a) Total bilirubin ≤ 3 mg/dL 
(5) Prothrombin International normalized ratio (INR) ≤ 2.3 or prothrombin time (PT) 
≤ 6 seconds above control 
(6) Albumin ≥ 2.8 g/dL 
(7) Participants with chronic hepatitis B virus (HBV) infection must be on antiviral 
therapy and must have HBV DNA < 500 IU/mL. 
(8) Platelets ≥ 60x103/µL 
v) Parts A-E: Colorectal cancer, metastatic (MSI-H or dMMR): 
(1) MSI-H or dMMR CRC that has progressed following treatment with a 
fluoropyrimidine, oxaliplatin, and irinotecan. 
vi) Part B only: other solid tumor types were permitted where PK was well characterized 
and discussed with the Sponsor. 
vii) Part E only: Metastatic urothelial carcinoma: 
(1) Participants with metastatic or locally advanced (cT4b, or any N+ [N1-N3], or any 
M1) urothelial carcinoma (including mixed histology with elements of other 
subtypes) of the renal pelvis, ureter, bladder, or urethra. 
(2) Participants must have progression 
(a) After treatment with at least 1 platinum-based chemotherapy regimen for 
metastatic or locally advanced disease 
OR 
(b) Within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy. 
b) Measurable disease as per RECIST version 1.1 criteria (see Appendix 5 for criteria) 
c) Participants must have an ECOG performance status of 0 or 1 (see Appendix 7 for ECOG 
Performance Status scales). 
d) All participants must have the ability to comply with treatment, patient-reported outcomes, 
PK, pharmacodynamic sample collection, and study follow-up requirements. 
e) Prior radiotherapy must have been completed at least 2 weeks prior to study treatment 
administration. 


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f) Screening laboratory values must meet the following criteria (using CTCAE v.5). The 
laboratory values for platelets, AST/ALT, and total bilirubin are adjusted for participants 
with HCC and are defined under Inclusion Criteria 2, Letter a, iv. 
i) White blood cell (WBC) count ≥ 2000/µL 
ii) Neutrophils ≥ 1500/µL 
iii) Platelets ≥ 100x103/µL 
iv) Hemoglobin ≥ 9.0 g/dL 
v) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance (CrCL) > 40 mL/min (using the Cockcroft Gault formula): 
Female CrCL = (140- age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/ dL 
Male CrCL = (140- age in years) x weight in kg x 1.00 
72 x serum creatinine in mg/ dL 
vi) AST ≤ 3.0 x ULN 
vii) ALT ≤ 3.0 x ULN 
viii) 
Total bilirubin ≤ 1.5 x ULN (except participants with Gilbert Syndrome who 
must have a total bilirubin level of < 3.0x ULN) 
g) Participants may be re-enrolled if the participant has discontinued the study as a pre- 
treatment failure (ie, participant has not been treated/randomized). If re-enrolled, the 
participant must re-consent. 
h) Parts A-D: Participants must provide either a FFPE tissue block or unstained tumor tissue 
sections, obtained within 12 months prior to enrollment with an associated pathology 
report, for submission to the core laboratory for inclusion. Pre-treatment tissue must be 
collected and locally confirmed for adequate tissue quantity and quality during the 
screening period prior to first dose of study treatment and then sent to the central laboratory 
for testing. Up to 5 participants (part A & B) who did not meet tissue requirements were 
allowed treatment after discussion with the Medical Monitor. Part D: Approximately 15 
participants who do not meet tissue requirements may be allowed treatment after discussion 
with the Medical Monitor. Biopsy should be excisional, incisional, or core needle. Fine 
needle aspiration, drainage of pleural effusions with cytospins, or punch biopsies are 
unacceptable for submission. Biopsies of bone lesions that do not have a soft tissue 
component or decalcified bone tumor samples are also not acceptable. Where possible, the 
biopsied lesion should be distinct from target lesions being evaluated for radiologic 
response, and the same lesion should be used for both the baseline and on-treatment 
sampling. Participants should not have received any systemic anticancer therapy after the 
date that the submitted tumor tissue was obtained. 
i) Part E: Tumor tissue collection/submission is optional for participants in Part E. Refer 
to Section 9.8.1 for further details, including for mUC participants. 


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i) Participants must have abdominal skin free of any skin disease, condition (including but 
not limited to scarring, tattoos, or stretch marks), or skin pigmentation that could interfere 
with an assessment of an SC injection site. 
j) Participants must be assessed for tumor PD-L1 expression by IHC. Results of PD-L1 
testing from Part A are required prior to opening study Part B, Part C, and Part D. 
Participants are able to receive therapy prior to availability of results of PD-L1 assessment. 
Tumor PD-L1 assessment is not required for participants with CRC with prior documented 
MSI-H/dMMR status. Not applicable for Part E. 
i) Part E: Tumor PD-L1 expression by IHC is an optional assessment. 
3) Age and Reproductive Status 
a) Male and female participants must be ≥ 18 years old or age of majority at the time of 
informed consent. 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 24 hours prior to the start of study treatment. Not applicable 
for Part E. 
i) Part E: WOCBP must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 
24 hours prior to the start of study treatment. An extension up to 72 hours prior to the 
start of study treatment is permissible in situations where results cannot be obtained 
within the standard 24-hour window. 
ii) All Parts (Parts A-E): Additional requirements for pregnancy testing during and after 
study intervention are located in Section 2, Schedule of Activities. 
c) Not applicable per Protocol Amendment 04. See i) immediately below for all 
Parts A-E. Women must not be breastfeeding. 
i) A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
(1) Is not a WOCBP 
OR 
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, as described in Appendix 4 
during the intervention period and for at least 5 months and agrees not to donate 
eggs (ova, oocytes) for the purpose of reproduction for the same time period. 
d) Not applicable per Protocol Amendment 04. See i) and ii) immediately below for all 
Parts A-E. WOCBP must agree to follow instructions for method(s) of contraception (see 
Appendix 4: Women of Childbearing Potential Definitions and Methods of Contraception) 
for the duration of treatment with study treatment plus 5 months after the last dose of study 
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i) WOCBP must agree to follow instructions for method(s) of contraception defined in 
Appendix 4 and as described below and included in the ICF. 
ii) WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4). 
e) Not applicable per Protocol Amendment 04. See h) below for all Parts A-E. Males who 
are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception (Appendix 4) for the duration of treatment with study treatment plus 
7 months after the last dose of study treatment. In addition, male participants must be 
willing to refrain from sperm donation during this time. 
f) Not applicable per Protocol Amendment 04. See h) below for all Parts A-E. Males who 
are azoospermic are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section. 
g) Part E: Female Participants: 
i) Women who are not of childbearing potential are exempt from contraceptive 
requirements. 
ii) Women participants must have documented proof that they are not of childbearing 
potential. 
iii) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
h) Male Participants. No additional contraceptive measures are required to be used. 
 
For all Parts A-E per Protocol Amendment 04: Investigators shall counsel WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy, and the 
potential of fetal toxicity occurring due to transmission of study drug to a developing fetus. 
6.2 
Exclusion Criteria 
1) Medical Conditions 
a) Participants must not have active brain metastases or leptomeningeal metastases. 
Participants with brain metastases are eligible if these have been treated and there is no 
MRI evidence of progression for at least 4 weeks after treatment is complete and within 
28 days prior to first dose of study drug administration. There must also be no requirement 
for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone 
equivalents) for at least 2 weeks prior to study drug administration. Not applicable for 
Part E. 
i) Part E: Untreated, symptomatic CNS metastases. Participants are eligible if CNS 
metastases are asymptomatic and do not require immediate treatment, or have been 
treated and participants have neurologically returned to baseline (except for residual 
signs or symptoms related to the CNS treatment). In addition, participants must have 
been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent) for at least 2 weeks prior to treatment assignment. Imaging 
performed within 28 days prior to treatment assignment must document radiographic 


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stability of CNS lesions and be performed after completion of any CNS-directed 
therapy 
ii) Part E: Leptomeningeal metastases 
b) Participants must not have ocular melanoma 
c) Participants with HCC must not have the following: 
i) Any history of hepatic encephalopathy 
ii) Any prior (within 1 year) or current clinically significant ascites as measured by 
physical examination and that requires active paracentesis for control 
iii) Active coinfection with both hepatitis B and C 
iv) Hepatitis D infection in participants with hepatitis B 
d) Participants must not have active, known, or suspected autoimmune disease. Participants 
with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll. 
e) Participants must not have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days of start of treatment assignment/randomization. Inhaled or 
topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent 
are permitted in the absence of active autoimmune disease. Not applicable for Part E. 
i) Part E: Participants with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other 
immunosuppressive medications within 30 days of treatment assignment. Inhaled or 
topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease. 
f) Participants must not have a prior malignancy active within the previous 2 years except for 
locally curable cancers that have been apparently cured, such as basal or squamous cell 
skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast. Not 
applicable for Part E. 
i) Part E: Concurrent malignancy (present during screening) requiring treatment or 
history of prior malignancy active within 2 years prior to treatment assignment (ie, 
participants with a history of prior malignancy are eligible if treatment was completed 
at least 2 years before treatment assignment and the patient has no evidence of disease). 
Participants with history of prior early stage basal/squamous cell skin cancer or non- 
invasive or in situ cancers that have undergone definitive treatment at any time are also 
eligible. 
g) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways 
h) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally (see Appendix 8). Not applicable for Part E. 


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i) Part E: Known human immunodeficiency virus (HIV) positive with an AIDS defining 
opportunistic infection within the last year, or a current CD4 count < 350 cells/μL. 
Participants with HIV are eligible if 
(1) They have received antiretroviral therapy (ART) for at least 4 weeks prior to 
treatment assignment as clinically indicated while enrolled on study. 
(2) They continue on ART as clinically indicated while enrolled on study. 
(3) CD4 counts and viral load are monitored per standard of care by a local health care 
provider. 
NOTE: Testing for HIV must be performed at sites where mandated locally. HIV 
positive participants must be excluded where mandated locally (see Appendix 8). 
i) Positive pregnancy test at enrollment or prior to administration of study medication. 
j) Not applicable for per Protocol Amendment 04. See Section 6.1, 3) c). Women who are 
breastfeeding. 
k) Participants must not have any serious or uncontrolled medical disorder that, in the opinion 
of the investigator, may increase the risk associated with study participation or study 
treatment administration, impair the ability of the participant to receive protocol therapy, 
or interfere with the interpretation of study results. Not applicable for Part E. 
i) Part E: Participants must not have any serious or uncontrolled medical disorder or 
severe infection within 4 weeks prior to screening. 
(1) Note: In the case of prior SARS-CoV-2 infection, acute symptoms must have 
resolved based on investigator clinical judgment and, in consultation with the 
Medical Monitor, there are no sequelae that would place the participant at a higher 
risk of receiving investigational treatment to be eligible. 
l) Participants must not have received any vaccines containing live/attenuated virus within 
30 days prior to start of study treatment. 
i) Treatment with any live attenuated vaccine (including any live attenuated COVID-19 
vaccine) within 30 days of first study treatment. Details regarding COVID-19 
vaccination are available in Section 7.7.1. 
m) Participants must not have treatment with botanical preparations (eg, herbal supplements 
or traditional Chinese medicines) intended for general health support or to treat the disease 
under study within 2 weeks prior to treatment assignment/randomization. Refer to 
Section 7.7.1 for prohibited therapies. Not applicable for Part E. 
i) Part E: Treatment with complementary medications (eg, herbal supplements or 
traditional Chinese medicines) to treat the disease under study within 2 weeks prior to 
first study treatment. Such medications are permitted if they are used as supportive 
care. Refer to Section 7.7.1 for prohibited therapies. 
n) Participants must not have evidence of organ dysfunction or any clinically significant 
deviation from normal in physical examination, vital signs, ECG or clinical laboratory 
determinations beyond what is consistent with the target population. 
o) Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by 
either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE 
preferred test) within 6 months prior to start of study treatment. Only applicable to first- 
in-human Parts A, B, C, and D. Not applicable for Part E. 


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p) Positive urine screen for drugs of abuse. Not applicable per Protocol Revision 02. 
q) Participants must not have any positive test result for HBV or hepatitis C virus (HCV) 
indicating presence of virus, eg, hepatitis B surface antigen (HBsAg, Australia antigen) 
positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative). For 
HCC, participants with chronic HBV infection are permitted and must be on antiviral 
therapy and must have HBV DNA < 500 IU/mL. Not applicable for Part E. 
i) Part E: Any positive test result for hepatitis B virus (HBV) indicating presence of 
virus, eg Hepatitis B surface antigen (HBsAg, Australia antigen) positive. 
ii) Part E: Any positive test result for hepatitis C virus (HCV) indicating presence of 
active viral replication (detectable HCV-RNA). Note: Participants with positive HCV 
antibody and an undetectable HCV RNA are eligible to enroll. 
r) Participants currently in other interventional trials for COVID-19, including investigational 
COVID-19 vaccination trials that are not authorized or approved by relevant Health 
Authorities, should not participate in BMS clinical trials until the protocol-specific washout 
period is achieved. If a study participant has received an investigational COVID-19 vaccine 
prior to screening, enrollment should be delayed until the full dosing schedule of the 
vaccine has been completed and the impact of the vaccine is stabilized, UNLESS a delay 
would compromise the patient’s health or suitability for enrollment, as determined by the 
investigator, and in discussion with the BMS Medical Monitor. 
s) Prior radiation therapy within 2 weeks prior to first study treatment. Participants must have 
recovered (ie, Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study 
treatment. 
2) Allergies and Adverse Drug Reaction 
a) Participants must not have a history of allergy to immunotherapies (eg, anti-PD-1/PD-L1 
or anti-CTLA-4 treatment or any other antibody or drug specifically targeting T-cell 
costimulation or immune checkpoint pathways) or related compounds. 
b) Participants must not have a history of any significant drug allergy (such as anaphylaxis or 
hepatotoxicity). 
c) Participants must not have a history of allergy or hypersensitivity to study drug 
components. 
3) Other Exclusion Criteria 
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a participant. Strict 
conditions apply and Bristol-Myers Squibb approval is required.) 
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness. 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 
6.3 
Lifestyle Restrictions 
Not applicable. No restrictions are required 


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6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently assigned to treatment/randomized in the study/included in the analysis 
population. A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, as applicable, and to respond to queries from regulatory authorities. 
6.4.1 
Retesting During Screening or Lead-In Period 
This study permits the re-enrollment of a participant that has discontinued the study as a 
pre-treatment failure. Retesting of laboratory parameters and/or other assessments during the 
Screening will be permitted per the inclusion criteria (this does not include parameters that require 
a confirmatory result). 
Testing for asymptomatic COVID-19, for example by reverse transcriptase polymerase chain 
reaction (RT-PCR) or viral antigen, is not required. However, some participants may develop 
suspected or confirmed symptomatic COVID-19, or be discovered to have asymptomatic 
COVID-19 during the screening period. In such cases, participants may be considered eligible for 
the study after meeting all inclusion/exclusion criteria (including those related to active COVID-19 
infection), and after meeting all of the following criteria: 
• At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or test result (eg, positive RT-PCR or viral antigen), and 
• At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and 
• Acute symptoms (eg, cough, shortness of breath) have resolved, and 
• In the opinion of the investigator, there are no COVID-19-related sequelae that may place the 
participant at a higher risk of receiving investigational treatment, and 
• Negative follow-up COVID-19 test (for example by RT-PCR or viral antigen) based on 
institutional, local, or regional guidelines. 
 
The most current result prior to treatment assignment/randomization is the value by which study 
inclusion will be assessed, as it represents the participant’s most current, clinical state. 
7 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation. 
An investigational product (IP, also known as investigational medicinal product [IMP] in some 
regions) is defined a pharmaceutical form of an active substance or placebo being tested or used 
as a reference in a clinical study, including products already with a marketing authorization but 
used or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 


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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non- 
investigational products. 
IPs used in this trial are provided in Table 7-1. There are no non-investigational products in this 
trial. 


 
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Table 7-1: 
Study Treatments for CA2098KX 
 
Product Description/Class and 
Dosage Form 
Potency 
IP/Non- 
IMP 
Blinded or 
Open Label 
Packaging/ 
Appearance 
Storage Conditions 
(per label) 
Nivolumab (BMS-986298) Solution 
for SC Injection 
960 mg (120 mg/mL) 
IP 
Open-label 
Vial or various packaging 
configurations 
Refer to the label on 
container and/or pharmacy 
manual 
Nivolumab and rHuPH20 
(BMS-986298) Solution for SC 
Injection 
600 mg and 
units 
( 
mg and 2000 
units/mL) 
IP 
Open-label 
Vial and various 
packaging configurations 
Refer to the label on 
container and/or pharmacy 
manual 
Nivolumab (BMS-936558-01) 
Solution for IV Injection 
100 mg (10 mg/mL) 
and 40 mg (10 mg/mL) 
IP 
Open-label 
Vial and various 
packaging configurations 
Refer to the label on 
container and/or pharmacy 
manual 
 
(rHuPH20)a 
Units/mL 
( mg/mL) 
IPb 
Open-label 
Vial and various 
packaging configurations 
Refer to the label on 
container and/or pharmacy 
manual 
Abbreviations: EU = European Union; IMP = investigational medicinal product; IP = investigational product; rHuPH20 = recombinant human hyaluronidase PH20; 
SC = subcutaneous; US = United States. 
a 
is a formulation containing the enzyme rHuPH20 and is referred as rHuPH20 in the protocol. 
b rHuPH20 is classified as an IP per local guidelines (as an active ingredient in the US, and as an excipient in the EU). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.1 
Treatments Administered 
Table 7.1-1 presents the selection and timing of dose for each participant. 
Table 7.1-1: 
Selection and Timing of Dose 
 
Study Treatment 
Unit dose strength(s)/ 
Dosage level(s) 
Dosage formulation 
Frequency of Administration 
Route of 
Administration 
Study Part A 
Group 1 
SC Nivolumab (BMS-986298) + 
(rHuPH20) 
Nivolumab 720 mg + 
rHuPH20 2000 
Units/mL 
Solution for SC injection/ 
Cycle 1 Day 1 
SC injection 
manually by 
syringe 
All Treatment Groups: 
Nivolumab (BMS-936558-01) 
Solution for IV Injection 
Nivolumab 480 mg 
All Treatment Groups: 
Solution for IV injection/ 
Q4W Cycle ≥2 Day1 
IV 
Study Part B 
Group 2 
SC Nivolumab (BMS-986298) 
Nivolumab 720 mg 
Solution for SC injection/ 
Cycle 1 Day 1 
SC injection 
by syringe 
pump 
Group 3 
SC Nivolumab (BMS-986298) + 
(rHuPH20) 
Nivolumab 960 mga+ 
rHuPH20 2000 
Units/mL 
Solution for SC injection/ 
Cycle 1 Day 1 
SC injection 
manually by 
syringe 
Group 4 
SC Nivolumab (BMS-986298) 
Nivolumab 960 mgb 
Solution for SC injection/ 
Cycle 1 Day 1 
SC injection 
by syringe 
pump 
All Treatment Groups: 
Nivolumab (BMS-936558-01) 
Solution for IV Injection 
Nivolumab 480 mg 
All Treatment Groups: 
Solution for IV injection/ 
Q4W Cycle ≥2 Day 1 
IV 
Study Part Ca 
SC Nivolumab (BMS-986298) + 
(rHuPH20) 
Nivolumab 1200 mg+ 
rHuPH20 2000 
Units/mL 
Solution for SC injection 
SC injection 
manually by 
syringe 
Study Part Da 
Group 5 
SC Nivolumab (BMS-986298) + 
(rHuPH20) 
Nivolumab 1200 mg + 
rHuPH20 2000 
Units/mL 
Solution for SC injection 
Cycle ≥1 Day 1 
SC injection 
manually by 
syringe 
Study Part E 
Group 6 
Nivolumab Coformulated with 
rHuPH20 (BMS-986298) Solution 
for SC Injection 
Nivolumab 
mg/mL 
coformulated with 
rHuPH20 2000 
Units/mL 
Solution for SC injection 
Cycle ≥1 
SC injection 
manually by 
syringe 
Note: A treatment cycle is defined as 28 days/4 weeks. 
Abbreviations: 
IV = intravenous; Q4W = every 4 weeks; rHuPH20 = recombinant 
human hyaluronidase PH20; SC = subcutaneous. 
a Any ongoing participant on SC nivolumab + 
 treatment may switch over to nivolumab coformulated with 
rHuPH20 drug product. Nivolumab and rHuPH20 solutions are pre-mixed in 1 vial when they are coformulated. 
b Cycle 1 dose was confirmed by administrative letter to the investigator. 


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7.1.1 
Intravenous Administration of Nivolumab Injection 
In Part A and Part B only, participants received IV nivolumab (BMS-936558) at a dose of 480 mg 
nivolumab as a 30-minute (± 5 minutes) infusion on Day 1 of treatment Cycle 2 and beyond until 
progression, unacceptable toxicity, withdrawal of consent, completion of a total of 104 weeks of 
treatment, cross over to SC nivolumab dosing in Part C, or the study ends, whichever occurs first. 
Participants in Part B began study treatment within 3 calendar days of assignment/randomization. 
There will be no dose escalations or reductions of nivolumab allowed. After Cycle 2, participants 
may be dosed within a ± 3-day window. Premedications are not recommended for the first dose of 
nivolumab. 
Participants were monitored for approximately 60 minutes post infusion on Cycle 2 Day 1. 
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4. 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. 
Instructions for preparation of the IV nivolumab (BMS-936558) dose are provided in the Pharmacy 
Manual. Guidelines for administration of IV nivolumab (BMS-936558) doses are described in the 
IV nivolumab (BMS-936558) IB. 
Participants in Part A and Part B will receive SC nivolumab (BMS-986298) dosing in Part C 
(characterization of PK and safety outlined in Section 10.3.8). 
7.1.2 
Subcutaneous Administration of Nivolumab 
Detailed instructions for the preparation of the SC study treatments are provided in the CA2098KX 
Pharmacy Manual. 
In Part A and Part B, SC nivolumab (BMS-986298) was administered in the abdomen only. 
Appendix 10 provides instructions for choice of SC injection site and preparation for 
administration of SC injection for both manual injection by syringe and injection by external 
syringe pump. The site of SC injection must be recorded in the electronic case report form (eCRF). 
7.1.3 
Subcutaneous Administration of Nivolumab with rHuPH20 
Revised Protocol 03 
In Part C and Part D, 1200 mg SC nivolumab (BMS-986298) + rHuPH20 (rHuPH20 concentration 
of 2,000 U/mL), should be administered via manual injection in one of the quadrants of the 
abdomen or, alternatively, in the thigh as steadily as possible (ie, no start or stop, and at a steady 
rate) over a period of approximately 3-5 minutes. Participants will be monitored for approximately 
60 minutes following first manual injection of 1200 mg SC nivolumab + rHuPH20. Participants 
receiving subsequent SC injections may be monitored for approximately 15-30 minutes post 
injection at the discretion of the investigator. The site of SC injection, duration and needle type 
must be recorded in the electronic case report form (eCRF). Instructions for preparation of the SC 
nivolumab (BMS-986298) dose are provided in the Pharmacy Manual. 


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Protocol Amendment 04 
In  Part E,  600  mg SC  nivolumab  (BMS-986298)  coformulated  with rHuPH20 
10,000 units (2000 Units/mL) should be administered on 
 of each treatment 
cycle, via manual injection in one of the quadrants of the abdomen or, alternatively, in the thigh 
as steadily as possible (ie, no start or stop, and at a steady rate) over a period of approximately 
2-5 minutes. Participants will be evaluated for approximately 30 minutes post 
SC injections. In addition, all participants will be contacted approximately 24 hours after the 
SC injection and 
 SC injection for reporting of any injection-site reactions. The site of SC 
injection, duration, and needle type must be recorded in the electronic case report form (eCRF). 
For Parts A-D, SC nivolumab and rHuPH20 were mixed at the site pharmacy (coadministration) 
prior to study drug administration. As of Protocol Amendment 04, coformulated drug product 
(SC nivolumab and rHuPH20 solutions pre-mixed in 1 vial with the same dose ratio) will be 
introduced for Part E. In addition, all ongoing participants in Parts C & D may switch to the 
coformulated drug product. 
Instructions for preparation of the SC nivolumab (BMS-986298) coformulation dose are provided 
in the Pharmacy Manual. 
7.1.3.1 
Subcutaneous Administration of Nivolumab without rHuPH20 
The appropriate volume of SC nivolumab injection (BMS-986298) is pulled into a syringe. For 
example, for a 720 mg SC dose, the total dose volume to be administered is approximately 6.0 mL, 
and using a syringe pump (external infusion pump), the dose is administered subcutaneously over 
approximately 30 minutes. 
7.2 
Method of Treatment Assignment 
All participants in the study will be centrally assigned or randomized using an IRT. Before the 
study is initiated, each user will receive log in information and directions on how to access the 
IRT. 
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
In Part B, approximately 45 participants were dosed. The first 10 participants were assigned to 
Group 3. The next set participants were randomized 1:1 into Group 2 and Group 4. Participants 
will be assigned or randomized in Part B to receive different dose levels of nivolumab with 
rHuPH20 or to nivolumab alone according to a computer-generated randomization scheme 
prepared by a Randomization Coordinator within the Drug Supply Management Department of 
BMS Research and Development. Randomization assignments will be released to the bioanalytical 
laboratory, as needed, in order to minimize unnecessary analysis of samples. 
During the screening visit, the investigative site will call into the enrollment option of the IRT 
designated by BMS for assignment of a 5-digit participant number that will be unique across all 
sites. Enrolled participants, including those not dosed, will be assigned sequential participant 
numbers starting with 
, (eg, 
). The patient identification 
number (PID) will ultimately be comprised of the site number and participant number. For 
example, the first participant screened (ie, enrolled) at site number 1, will have a PID of 


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. Once it is determined that the participant meets the eligibility criteria following the 
screening visit, the investigative site will call the IRT to assign/randomize the participant into the 
open Part B dose group. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dosage Modification 
7.4.1 
Dose Modifications 
Dose delay criteria apply for all drug-related adverse events (regardless of whether the event is 
attributed to nivolumab). Delay administration of nivolumab if any of the delay criteria in Table 
7.4.1-1 are met. Delay nivolumab dosing for any AE, laboratory abnormality, or intercurrent 
illness which, in the judgment of the investigator, warrants delaying the dose of study medication. 
For participants who require delay of nivolumab, re-evaluate weekly, or more frequently, if 
clinically indicated and resume dosing when criteria to resume treatment are met (see 
Section 7.4.3). Continue tumor assessments per protocol even if dosing is delayed. 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Gastrointestinal 
Colitis or Diarrhea 
Grade 2 
Delay dose 
Dosing may resume when AE resolves to baseline 
Grade 3 
Delay dose 
Dosing may resume when AE resolves to baseline 
Grade 4 
Permanently 
discontinue 
Renal 
Serum Creatinine Increased 
Grade 2 or 3 
Delay dose 
Dosing may resume when AE resolves to 
Grade ≤ 1 or baseline value 
Grade 4 
Permanently 
discontinue 
Pulmonary 
Pneumonitis 
Grade 2 
Delay dose 
Dosing may resume after pneumonitis has resolved 
to ≤ Grade 1 
Grade 3 or 4 
Permanently 
discontinue 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Hepatic 
AST, ALT, or T.bili increased 
(For non-HCC participants; 
For HCC participants, see 
Section 7.4.2 and Section 7.4.3) 
AST or ALT > 3× and ≤ 5× upper limit of 
normal (ULN) or T.Bili >1.5× and ≤ 3× 
ULN, regardless of baseline value 
Delay dose 
Dosing may resume when laboratory values return 
to baseline. 
AST or ALT > 5× ULN or T. bili > 3× ULN, 
regardless of baseline value 
Delay dose or 
permanently 
discontinue 
In most cases of AST or ALT > 5× ULN, study 
treatment will be permanently discontinued. If the 
investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of 
study treatment, a discussion between the 
investigator and the Medical Monitor/ designee 
must occur and approval from Medical Monitor 
prior to resuming therapy. 
Concurrent AST or ALT > 3× ULN and T.bili 
> 2× ULN, regardless of baseline value 
Permanently 
discontinue 
Endocrinopathy 
Adrenal Insufficiency 
Grade 2 adrenal insufficiency 
Delay dose 
Dosing may resume after adequately controlled 
with hormone replacement 
Grade 3 or 4 adrenal insufficiency or adrenal 
crisis 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming 
therapy. If adrenal insufficiency resolves or is 
adequately controlled with physiologic hormone 
replacement, participant may not require 
discontinuation of study drug 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Hyperglycemia 
Hyperglycemia requiring initiation or change 
in daily management (Grade 2 or 3) 
Delay dose 
Dosing may resume if hyperglycemia resolves to 
Grade ≤ 1 or baseline value, or is adequately 
controlled with glucose-controlling agents 
Grade 4 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming 
therapy. If hyperglycemia resolves, or is 
adequately controlled with glucose-controlling 
agents, participant may not require discontinuation 
of study drug 
Hypophysitis/Hypopituitarism 
Symptomatic Grade 1-3 that is also associated 
with corresponding abnormal lab and/or 
pituitary scan 
Delay dose 
Dosing may resume if endocrinopathy resolves to 
be asymptomatic, or is adequately controlled with 
only physiologic hormone replacement 
Grade 4 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming 
therapy. If endocrinopathy resolves or is 
adequately controlled with physiologic hormone 
replacement, participant may not require 
discontinuation of study drug 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Hyperthyroidism or 
Hypothyroidism 
Grade 2 or 3 
Delay dose 
Dosing may resume if endocrinopathy resolves to 
be asymptomatic, or is adequately controlled with 
only physiologic hormone replacement or other 
medical management 
Grade 4 
Delay dose or 
permanently 
discontinue 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming 
therapy. If endocrinopathy resolves or is 
adequately controlled with physiologic hormone 
replacement or other medical management, 
participant may not require discontinuation of 
study drug 
Skin 
Rash 
Grade 2 rash covering >30% body surface 
area or Grade 3 rash 
Delay dose 
Dosing may resume when rash reduces to ≤ 10% 
body surface area 
Suspected Stevens-Johnson syndrome (SJS), 
toxic epidermal necrolysis (TEN) or drug 
reaction with eosinophilia and systemic 
symptoms (DRESS) 
Delay dose 
Dosing may resume if SJS, TEN, or DRESS is 
ruled out and rash reduces to is ≤ 10% body 
surface area 
Grade 4 rash or confirmed SJS, TEN, or 
DRESS 
Permanently 
discontinue 
Neurological 
Guillain-Barre Syndrome (GBS) 
Any Grade 
Permanently 
discontinue 
Myasthenia Gravis (MG) 
Any Grade 
Permanently 
discontinue 
Encephalitis 
Any Grade encephalitis 
Delay dose 
After workup for differential diagnosis 
(ie, infection, tumor-related), if encephalitis is not 
drug-related, then dosing may resume when AE 
resolves 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Encephalitis (continued) 
Any Grade drug-related encephalitis 
Permanently 
discontinue 
Myelitis 
Any Grade myelitis 
Delay dose 
After workup for differential diagnosis 
(ie, infection, tumor-related), if myelitis is not 
drug-related, then dosing may resume when AE 
resolves 
Any Grade drug-related myelitis 
Permanently 
discontinue 
Neurological (other than GBS, MG, 
encephalitis, or myelitis) 
Grade 2 
Delay dose 
Dosing may resume when AE resolves to baseline 
Grade 3 or 4 
Permanently 
discontinue 
Cardiovascular 
Myocarditis 
Symptoms induced from mild to moderate 
activity or exertion 
Delay dose 
Dosing may resume after myocarditis has resolved 
Severe or life threatening, with symptoms at 
rest or with minimal activity or exertion, 
and/or where intervention indicated 
Permanently 
discontinue 
Other Clinical AEs 
Pancreatitis: 
Amylase or Lipase Increased 
Grade 3 with symptoms 
Delay dose 
Note: Grade 3 increased amylase or lipase without 
signs or symptoms of pancreatitis does not require 
dose delay 
Dosing may resume when participant becomes 
asymptomatic 
Grade 4 
Permanently 
discontinue 
Uveitis 
Grade 2 uveitis 
Delay dose 
Dosing may resume if uveitis responds to topical 
therapy (eye drops) and after uveitis resolves to 
Grade ≤ 1 or baseline. If participant requires oral 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
steroids for uveitis, then permanently discontinue 
study drug 
Grade 3 or 4 uveitis 
Permanently 
discontinue 
Other Drug-related AE 
(not listed above) 
Grade 2 non-skin AE, except fatigue 
Delay dose 
Dosing may resume when AE resolves to 
Grade ≤ 1 or baseline value 
Grade 3 AE - First occurrence lasting ≤ 7 days 
Delay dose 
Dosing may resume when AE resolves to 
Grade ≤ 1 or baseline value 
Grade 3 AE- First occurrence lasting > 7 days 
Permanently 
discontinue 
Recurrence of Grade 3 AE of any duration 
Permanently 
discontinue 
Grade 4 or Life-threatening adverse reaction 
Permanently 
discontinue 
Other Laboratory Abnormalities 
Other Drug-related Laboratory 
Abnormality (not listed above) 
Grade 3 
Delay dose 
Exceptions: 
No delay required for: Grade 3 lymphopenia 
Permanent Discontinuation for: Grade 3 
thrombocytopenia > 7 days or associated with 
bleeding 
Grade 4 
Permanently 
discontinue 
Exceptions: The following events do not require 
discontinuation of study drug: 
• 
Grade 4 neutropenia ≤ 7 days 
• 
Grade 4 lymphopenia or leukopenia 
• 
Grade 
4 
isolated 
electrolyte 
imbalances/abnormalities 
that 
are 
not 
associated with clinical sequelae and are 


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Table 7.4.1-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Subcutaneous Nivolumab with or 
without rHuPH20 
 
Drug-related AE per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
responding 
to 
supplementation/appropriate 
management within 72 hours of their onset 
Infusion Reactions 
(manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like reactions) 
Hypersensitivity reaction or 
infusion reaction 
Grade 3 or 4 
Permanently 
discontinue 
See Section 7.7.4 (Management of 
Treatment-related Infusion Reactions) 
SARS-CoV-2 infection either 
confirmed or suspected 
Delay dose 
Participants with SARS-CoV-2 infection (either 
confirmed or suspected) may resume treatment 
after 1) at least 10 days (20 days for severe/critical 
illness) have passed since symptoms first appeared 
or positive test result (eg, RT-PCR or viral 
antigen), 2) resolution of acute symptoms 
(including at least 24 hours has passed since last 
fever without fever-reducing medications), 
3) evaluation by the Investigator with confirmation 
that there are no sequelae that would place the 
participant at a higher risk of receiving 
investigational treatment, and 4) consultation with 
the BMS Medical Monitor. For suspected cases, 
treatment may also resume if SARS-CoV-2 
infection is ruled-out as per institutional policy for 
testing of SARS-CoV-2 and other criteria to 
resume treatment are met 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; DRESS = drug reaction with eosinophilia and systemic symptoms; GBS = Guillain-Barre Syndrome; HCC = hepatocellular carcinoma; MG = Myasthenia Gravis; 
RT-PCR = reverse transcriptase polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SJS = Stevens-Johnson syndrome; 
T.bili = total bilirubin; TEN = toxic epidermal necrolysis; ULN = upper limit of normal. 


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7.4.2 
Dose Delay Criteria 
Delay administration of nivolumab if any of the delay criteria in Table 7.4.1-1 and Section 7.4.1 
are met. Nivolumab administration should also be delayed for the following: 
• For participants with HCC: 
− Any Grade 3 drug-related laboratory abnormality with the following exceptions: 
♦ Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. 
− Dose delay for changes in AST or ALT as follows: 
♦ If a participant has a baseline AST or ALT that is within normal limits, delay dosing 
for drug-related Grade ≥ 2 toxicity (2 grade shift) 
♦ If a participant has baseline AST or ALT within the Grade 1 toxicity range, delay 
dosing for drug-related Grade ≥ 3 toxicity (2 grade shift) 
♦ If a participant has baseline AST or ALT > within the Grade 2 toxicity range, delay 
dosing for a 2-fold drug-related increase in AST or ALT or for AST or ALT values 8× 
ULN (whichever is lower) 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met. For 
participants with HCC, it is recommended to monitor elevations in AST or ALT approximately 
every 3 days till levels peak or begin to decline. 
If dosing is resumed after a delay, study treatment may be resumed as soon as possible after the 
criteria to resume treatment are met (see Section 7.4.3). 
7.4.3 
Criteria to Resume Treatment 
Participants may resume treatment with study drug if they have completed AE 
management (ie corticosteroid taper) or are on ≤ 10 mg prednisone or equivalent, and meet the 
requirements per Table 7.4.1-1. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the Medical 
Monitor (or designee) must be consulted. Continue tumor assessments per protocol even if dosing 
is delayed. Continue periodic study visits to assess safety and laboratory studies every 6 weeks in 
Parts A-D or every 2 weeks in Part E or more frequently if clinically indicated during such dosing 
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• Participants with HCC 
− Participants with baseline Grade 1 AST, ALT, or total bilirubin who require dose delays 
for reasons other than a drug-related hepatic event may resume treatment in the presence 
of Grade 2 AST, ALT, or total bilirubin. 
− Participants who require dose delays for drug-related elevations in AST, ALT, or total 
bilirubin may resume treatment when these values have returned to their baseline CTCAE 
Grade or normal, provided the criteria for permanent discontinuation are not met 
(Section 8.1.1). 
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and approved 
by BMS medical monitor or designee. 
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS medical monitor or 
designee. 
For all AEs, corticosteroid therapy must be tapered to prednisone 10 mg/day or equivalent prior to 
resuming study therapy unless being used as adrenal replacement steroid therapy. 
If the criteria to resume treatment are met, the participant should restart treatment at the next 
scheduled timepoint per protocol. If treatment is delayed > 6 weeks from the last dose, the 
participant must be permanently discontinued from study therapy, except as specified in Section 
8.1.1 and Section 8.1.2. Please see also Appendix 6 (Management Algorithms) for guidance on 
appropriate management and follow-up of adverse events. For hepatic AE management, see 
Section 7.4.4.2. 
7.4.4 
Management Algorithms for Immuno-Oncology Agents 
7.4.4.1 
Program Safety Management Algorithms 
Immuno-oncology (IO) agents are associated with AEs that can differ in severity and duration than 
AEs caused by other therapeutic classes. Nivolumab is considered as an IO agent and the 


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management algorithms in Appendix 6 provide guidance on assessing and managing the following 
groups of AEs: 
• Gastrointestinal 
• Renal 
• Pulmonary 
• Hepatic 
• Endocrinopathy 
• Skin 
• Neurological 
• Myocarditis 
 
Appendix 6 provides the management algorithms for AEs in the above categories. Note that the 
program management algorithm for Hepatic AEs in participants with HCC has been modified for 
this protocol (see the following Section 7.4.4.2). 
7.4.4.2 
Recommendations for Management of Hepatic Events in Nivolumab 
Participants with HCC 
The nivolumab program has developed a standardized approach for the management of hepatic 
events based on cumulative data across the program in participants with normal hepatic function. 
Across most nivolumab studies, the eligibility criteria for inclusion are based on a maximum AST 
or ALT < 3× ULN; therefore, only participants with normal to Grade 1 liver function tests have 
been enrolled. Participants with advanced HCC generally have underlying cirrhosis with decreased 
hepatic function. They may also have a concomitant chronic viral infection. For CA2098KX, the 
upper limits for inclusion were therefore adjusted to account for baseline liver dysfunction. 
Participants with AST or ALT elevations within the CTCAE Grade 2 range are eligible for 
inclusion. In contrast, the majority of participants included in prior nivolumab studies have had no 
higher than a CTCAE Grade 1 AST or ALT elevation. Criteria for dose delay, resumption, & 
discontinuation are in Section 7.4.2, Section 7.4.3, and Section 8.1.1. The tumor-specific approach 
for the management of hepatic events is as follows: 
• If AST or ALT levels do not improve with a dose delay of 3-5 days or if the levels worsen, 
initiate steroid therapy at 0.5-2 mg/kg/day methylprednisolone or oral equivalent. 
• For ALT or AST levels > 8× ULN, initiate steroid therapy promptly at 1-2 mg/kg/day 
methylprednisolone or oral equivalent. 
• For all participants initiating steroids, consult the BMS Medical Monitor within 24 hours after 
initiation of steroids. Gastroenterology consult is recommended. 


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• If AST or ALT levels do not improve within 3-5 days or the levels worsen after the start of 
steroid therapy, discuss with the BMS Medical Monitor the possibility of adding 
mycophenolate mofetil at 1 g BID. 
− If no response to mycophenolate mofetil, consider treatment with tacrolimus or other 
immunosuppressants per local guidelines and in discussion with the BMS Medical 
Monitor. Avoid infliximab due to potential risk of liver failure. 
• Tapering of steroids can start once AST or ALT levels have declined by 1 CTCAE grade. 
Taper steroids slowly over no less than 1 month. 
 
As outlined in Section 7.4.3, nivolumab therapy may resume when AST or ALT have returned to 
near baseline unless the criteria for permanent discontinuation are reached (Section 8.1.1). 
7.5 
Preparation/Handling/Storage/Accountability 
For nivolumab, refer to the current version of the IV nivolumab (BMS-936558) IB, SC nivolumab 
(BMS-986298) IB, and/or Pharmacy Manual for complete storage, handling, dispensing, and 
infusion information. For rHuPH20, refer to the current version of the rHuPH20 IB for complete 
storage, handling, dispensing, and infusion information. 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed, and BMS should be contacted immediately. 
Study treatment not supplied by BMS will be stored in accordance with the package insert. 
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets). 
Instructions for the preparation of SC study treatments are described in detail in the Pharmacy 
Manual. Further guidance and information for final disposition of unused study treatment are 
provided in Pharmacy Manual. 
7.5.1 
Retained Samples for Bioavailability / Bioequivalence 
Not applicable. 
7.6 
Treatment Compliance 
Study treatment compliance will be periodically monitored by drug accountability, medical record, 
and eCRF. Drug accountability should be reviewed by the site study staff at each visit to confirm 
treatment compliance. 


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Sites should discuss discrepancies with the participant at each on-treatment study visit. 
7.7 
Concomitant Therapy 
Concomitant medications are recorded at baseline and throughout the treatment phase of the study 
in the appropriate section of the eCRF. All medications (prescriptions or over-the-counter 
medications) continued at the start of the study or started during the study and different from the 
study treatment must be documented in the concomitant therapy section of the eCRF. 
7.7.1 
Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described below. Medications taken within 4 weeks prior to study drug administration must be 
recorded on the CRF. 
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE): 
• Immunosuppressive agents. 
• Immunosuppressive doses of systemic corticosteroids. Participants are permitted the use of 
topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption). Adrenal replacement steroid doses > 10 mg daily prednisone are 
permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast 
dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted. 
• Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
or standard or investigational agents for treatment of malignancy). 
• Any non-palliative radiation therapy. Radiation therapy administered with palliative 
intent (ie, for pain, bleeding, spinal cord compression, brain metastasis, new or impending 
pathologic fracture, superior vena-cava syndrome, or obstruction) is permitted. 
• Any complementary preparation (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as 
supportive care. 
• Any live/attenuated vaccine (eg, live COVID-19 vaccines, varicella, zoster, yellow fever, 
rotavirus, oral polio, and measles, mumps, rubella [MMR]) within 30 days prior to 
randomization/treatment assignment, during treatment, and until 100 days post last dose. 
• COVID-19 vaccines that are NOT live * are permitted prior to study, during the study, and 
after the last dose of nivolumab. 
• The effect of taking COVID-19 vaccines in patients taking nivolumab is unknown. Therefore, 
the decision to vaccinate should be made by the principal investigator after careful risk/benefit 
analysis. 
• To avoid potential overlap between side effects with COVID-19 vaccine and nivolumab 
treatment, consider not giving the vaccination on the same week as nivolumab administration. 
NOTES: 
*The following categories are NOT considered live vaccines: inactivated vaccines including 
heat-killed and formalin-killed, subunit vaccines, toxoid vaccines, nucleic acid vaccines that do 


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not encode potentially infectious virus, and replication incompetent recombinant vector vaccines. 
Please contact the Medical Monitor or designee with any questions related to COVID-19 vaccines 
or other vaccines for participants on study. 
If a study participant has received a live COVID-19 vaccine prior to screening, enrollment should 
be delayed until the impact of the vaccine is stabilized, UNLESS a delay would compromise 
patient health, as determined by the investigator in consultation with Medical Monitor. For 
COVID-19 vaccines requiring more than 1 dose, the full series (eg, both doses of a 2-dose series) 
should be completed prior to enrollment when feasible, and when a delay in enrollment would not 
put the study participant at risk. Ideally, enrollment would occur after any acute reactions (eg, 
reactions occurring within 24 hours of vaccine administration) resolve. 
7.7.2 
Other Restrictions and Precautions 
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
assignment/randomization are excluded. Inhaled or topical steroids, as well as adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
7.7.2.1 
Imaging Restriction and Precautions 
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated GFR < 30 mL/min/1.73 m2) are at 
increased risk of nephrogenic systemic fibrosis. MRI contrast should not be given to this 
participant population. In addition, participants may be excluded from MRI if they have tattoos, 
metallic implants, pacemakers, etc. 
Gentle hydration before and after IV contrast should follow local standard of care. 
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee. 
7.7.3 
Permitted Therapy 
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
7.7.4 
Treatment of Infusion-related Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 


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to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. Report all Grade 3 or 4 
infusion reactions within 24 hours as an SAE if it meets the criteria. 
Treatment recommendations are provided below and based on CTCAE v5 grading definitions and 
may be modified based on local treatment standards and guidelines, as appropriate: 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
• Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 mg to 1000 mg at least 30 minutes 
before additional nivolumab administrations 
 
For Grade 2 symptoms: (Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hrs): 
• Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant 
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 mg to 1000 mg; remain at bedside and monitor participant 
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant 
closely. If symptoms recur, then no further study treatment will be administered at that visit. 
• For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 mg to 
1000 mg should be administered at least 30 minutes before infusion. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for clinical sequelae. Grade 4: Life-threatening 
consequences; urgent intervention indicated): 
• Immediately discontinue infusion of study treatment. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for SC administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Monitor participant until the Investigator judges that the symptoms 
will not recur. Study drug will be permanently discontinued. Follow institutional guidelines 
for the treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of 
the symptoms. 


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In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids). 
7.8 
Treatment After the End of the Study 
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS-supplied study treatment for the maximum treatment duration specified 
in protocol Section 5.1.2. Study treatment will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee, or through another 
mechanism at the discretion of BMS. 
Should the study be terminated before the end of the treatment period specified in Section 7.1, 
participants who continue to demonstrate clinical benefit will be eligible to receive BMS-supplied 
study treatment for the protocol-specified maximum treatment duration at the discretion of BMS. 
BMS reserves the right to terminate access to BMS-supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of SC nivolumab is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; or c) the participant can obtain medication from a government-sponsored or 
private health program. In all cases BMS will follow local regulations. 
8 
DISCONTINUATION CRITERIA 
8.1 
Discontinuation from Study Treatment 
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
• Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information 
• Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant 
• Pregnancy 
• Termination of the study by BMS 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.) 
• Additional protocol-specified reasons for discontinuation (Table 7.4.1-1) 
• Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation of study drug, with the following exceptions: 


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− Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed 
− Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Medical Monitor (or designee) 
 
Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed. 
In the case of pregnancy, the investigator must immediately notify within 24 hours of awareness 
of the pregnancy, the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 (Pregnancy). 
All participants who discontinue study treatment should comply with protocol-specified follow- 
up procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness). 
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page. 
8.1.1 
Nivolumab Dose Discontinuation 
Nivolumab treatment must be permanently discontinued per criteria in Table 7.4.1-1 in 
Section 7.4.1. Discontinue nivolumab for any adverse event, laboratory abnormality, or 
intercurrent illness which, in the judgment of the Investigator, presents a substantial clinical risk 
to the participant with continued nivolumab dosing. 
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation of study drug, with the following exceptions: 
• Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events are 
allowed. 
• Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related reasons 
may be allowed if approved by the Medical Monitor (or designee). 
 
In participants with HCC, nivolumab treatment should be permanently discontinued for the 
following: 
• Hepatotoxicity as evidenced by the following: 
− AST or ALT > 10 x ULN for > 2 weeks, 
− AST or ALT > 15 x ULN irrespective of duration, 
− Total bilirubin > 5 x ULN for those with normal total bilirubin at entry or > 8 x ULN for 
participants with elevated bilirubin at study entry, irrespective of duration. 


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8.1.2 
Nivolumab Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease (PD).30 
Participants treated with nivolumab will be permitted to continue nivolumab treatment beyond 
initial RECIST v1.1 defined PD, as assessed by the investigator, up to a maximum of 24 months 
from the date of the first dose as long as they meet the following criteria: 
• Investigator-assessed clinical benefit 
• Tolerance of study treatment 
• Stable performance status 
• Participant provides written informed consent prior to receiving additional nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply 
 
Continue radiographic assessment/scan(s) in accordance with the Section 2 Schedule of Activities 
for the duration of the treatment beyond progression. Balance the assessment of clinical benefit 
with clinical judgment as to whether the participant is clinically deteriorating and unlikely to 
receive any benefit from continued treatment with nivolumab. 
For the participants who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden with a minimum 5 mm 
absolute increase from time of initial PD. This includes an increase in the sum of diameters of all 
target lesions and/ or the diameters of new measurable lesions compared to the time of initial PD. 
Upon documentation of further progression, permanently discontinue nivolumab treatment unless 
the clinical judgement of the investigator is that continuing treatment is in the patient’s best 
interest. 
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm. 
8.1.3 
Criteria to Resume Treatment 
See Section 7.4.3 for criteria to resume treatment. 
8.1.4 
Post Study Drug Follow-up 
In this study, OS is an exploratory endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 


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Participants who discontinue study treatment must continue to be followed for the collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study. 
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (see Schedule of Activities, Section 2). At the time of this request, 
each participant will be contacted to determine their survival status unless the participant has 
withdrawn consent for all contacts or is lost to follow-up. 
8.2 
Discontinuation from the Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
• Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
• The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. 
• In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 
8.3 
Lost to Follow-Up 
• All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant. 
• Lost to follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records. 
• If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death. 
• If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
• The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 


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• If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records. 
 
9 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and timing are summarized in the Schedule of Activities (Section 2). 
• Protocol waivers or exemptions are not allowed. 
• All immediate safety concerns must be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 2), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment assignment/randomization. The 
investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided that the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities (Section 2). 
 
Perform additional measures, including non-study required laboratory tests, as clinically indicated 
or to comply with local regulations. Laboratory toxicities (eg, suspected drug induced liver enzyme 
evaluations) will be monitored during the follow-up phase via on-site/local labs until all study 
drug-related toxicities resolve, return to baseline, or are deemed irreversible. 
Evaluate participant immediately to rule out cardiac or pulmonary toxicity if participant shows 
cardiac or pulmonary-related signs (hypoxia, abnormal heart rate or changes from baseline) or 
symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations). 
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations. 
9.1 
Efficacy Assessments 
9.1.1 
Imaging Assessment for the Study 
Images will be submitted to an imaging core laboratory and may undergo blinded independent 
central review (BICR) at any time during the study. Prior to scanning the first participant, sites 
should be qualified and understand the image acquisition guidelines and submission process as 
outlined in the CA2098KX Imaging Manual provided by the imaging core lab. 
Screening and on study images should be acquired as outlined in Section 2 (Schedule of Activities). 


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Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible. Unscheduled CT/MRI scans should 
be submitted to the central imaging vendor. X-rays and bone scans that clearly demonstrate interval 
progression of disease (for example, most commonly as unequivocal lesions that are unmistakably 
new since the prior CT/MRI) should be submitted to central imaging vendor. Otherwise, x-rays 
and bone scans do not need to be submitted centrally. 
9.1.1.1 
Methods of Measurement 
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known and/or suspected sites 
of disease should be performed for tumor assessments. 
Images should be acquired with slice thickness of 5 mm or less with no intervening gap 
(contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging timepoints. Tumor measurements should 
be made by the same investigator or radiologist for each assessment whenever possible. Change 
in tumor measurements and tumor response to guide ongoing study treatment decisions will be 
assessed by the Investigator using the RECIST v1.1 criteria. 
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. 
Should a participant have contraindication for both MR and CT intravenous contrasts, a non- 
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable. 
Guidelines for use of CT component of a PET-CT scanner are as follows. Combined modality 
scanning such as with PET-CT is increasingly used in clinical care, and is a modality/technology 
that is in rapid evolution; therefore, the recommendations outlined here may change rather quickly 
with time. At present, low dose or attenuation correction CT portions of a combined PET-CT are 
of limited use in anatomically based efficacy assessments; therefore, it is suggested that they 
should not be substituted for dedicated diagnostic contrast-enhanced CT scans for anatomically 
based RECIST v1.1 measurements. However, if a site can document that the CT performed as part 
of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then 
the CT portion of the PET-CT can be used for RECIST v1.1 measurements. Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed. 
Bone scan or PET scan is not adequate for assessment of RECIST v1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain 
non-target organs, those non-target organs may be evaluated less frequently. For example, bone 


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scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected. 
Bone scans may be collected per local standards, as clinically indicated. 
MRI of the brain should be acquired as outlined in Section 2 (Schedule of Activities). CT of the 
brain (without and with contrast) can be performed if MRI is contraindicated. 
9.1.1.2 
Imaging and Clinical Assessment 
Tumor assessments should continue even if dosing is delayed or discontinued. Changes in tumor 
measurements and tumor responses will be assessed by the same investigator using RECIST v1.1 
criteria. Investigators will report the number and size of new lesions that appear while on study. 
The timepoint of tumor assessments will be reported on the eCRF based on the investigator’s 
assessment using RECIST v1.1 criteria (See Appendix 5 for specifics of RECIST v1.1 criteria to 
be utilized in this study). A best overall response (BOR) of stable disease (SD) requires a minimum 
of 78 days on study date of first dose to the date of the first imaging assessment. 
9.2 
Adverse Events 
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or caused the participant to 
discontinue before completing the study. 
Use CTCAE v5 definitions and grading for safety reporting of all AE and SAEs on the case report 
form. 
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s case 
report form. 
Contacts for SAE reporting are specified in Appendix 3. 
9.2.1 
Time Period and Frequency for Collecting AE and SAE Information 
Appendix 1 in the nivolumab (BMS-936558) IB and SC nivolumab (BMS-986298) IB represent 
the Reference Safety Information to determine expectedness of SAEs for expedited reporting. 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 100 days of discontinuation of dosing. 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure (eg, a follow-up skin biopsy). For 


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participants assigned/randomized to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of treatment assignment/randomization. 
Collect all nonserious AEs (not only those deemed to be treatment-related) continuously during 
the treatment period and for a minimum of 100 days following discontinuation of study treatment. 
• Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module. 
• All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available. 
 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor. 
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3. 
COVID-19 or positive SARS-CoV-2 test results should be reported to BMS within 24 hours 
regardless of the seriousness criteria. 
All SAEs and AEs/SAEs related to SARS-CoV-2 must be collected from the date of the 
participant’s written consent until 100 days following discontinuation of dosing. For participants 
who are enrolled but not randomized, all SAEs and AEs/SAEs related to SARS-CoV-2 must be 
collected for 30 days from the date of signing consent. For participants randomized but never 
treated with study drug, collect for an additional 30 days from date of randomization. Collect all 
nonserious AEs continuously during the treatment period and for a minimum of 100 days 
following discontinuation of study treatment. 
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection will be followed until resolution, the condition stabilizes, or is deemed irreversible, or 
until the participant is lost to follow-up (as defined in Section 8.3). For suspected cases, 
participants should be followed until SARS-CoV-2 infection is ruled out as per institutional policy 
on SARS-CoV-2. 
9.2.2 
Method of Detecting AEs and SAEs 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AE and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgment in the context of known 
AEs, when appropriate for the program or protocol. 


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All nonserious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
Every AE must be assessed by the investigator with regard to whether it is considered immune- 
mediated. For events that are potentially immune-mediated, additional information will be 
collected on the participant’s case report form. 
9.2.3 
Follow-up of AEs and SAEs 
• Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3). 
• Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate. 
•  All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study. 
 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2) will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3). 
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection will be followed until resolution, the condition stabilizes, or is deemed irreversible, or 
until the participant is lost to follow-up (as defined in Section 8.3). For suspected cases, 
participants should be followed until SARS-CoV-2 infection is ruled out as per institutional policy 
on SARS-CoV-2. 
Further information on follow-up procedures is given in Appendix 3. 
9.2.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met. 
• An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
 
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements. 


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9.2.5 
Pregnancy 
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least for 
5 months after study product administration then the investigator must immediately notify the 
BMS Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or reinitiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
9.2.6 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning. 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted 
• Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
9.2.7 
Potential Drug-induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details). 
Potential drug-induced liver injury in participants without HCC is defined as: 
1) AT (ALT or AST) elevation > 3 x ULN 
AND 
2) Total bilirubin > 2 x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
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3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
The following definition takes into account anticipated baseline compromise of liver function in 
participants with HCC. Potential drug induced liver injury for participants with HCC is defined as: 
1) Concurrent ALT ≥ 10 x ULN 
AND 
2) Total bilirubin ≥ 2 times ULN or baseline value (if elevated bilirubin at study entry) 
AND 
3) No other immediately apparent possible causes of ALT elevation and hyperbilirubinemia, 
including, but not limited to, tumor progression, acute viral hepatitis, cholestasis, pre-existing 
hepatic disease or the administration of other drug(s), herbal medications and substances 
known to be hepatotoxic. 
 
9.2.8 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, X-ray filming, any 
other potential safety assessment required or not required by protocol should also be recorded as a 
nonserious or serious AE, as appropriate, and reported accordingly. 
9.3 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3). 
9.4 
Safety 
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2). 
9.4.1 
Physical Examinations 
Refer to Schedule of Activities (Section 2). 
9.4.2 
Vital signs 
Refer to Schedule of Activities (Section 2). 
9.4.3 
Electrocardiograms 
Refer to Schedule of Activities (Section 2). 
9.4.4 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report. 
All clinical safety laboratory assessments will be performed locally per the Schedule of Activities 
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A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests. Results of clinical laboratory tests performed on Day -1 must be available prior to dosing. 
Table 9.8-1 and Table 9.8-2 list other various serologic tumor markers, gene mutation status, and 
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Table 9.4.4-1: 
Laboratory Assessment Panels 
 
 
Hematology - Complete Blood Count (CBC) 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Chemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Creatinine 
Blood urea nitrogen (BUN) or serum urea 
Fasting glucose 
Serum alpha-fetoprotein (HCC only) 
Serology (at screening) 
 
 
 
 
 
 
 
 
 
Albumin - screening only 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphorus 
TSH, free T3, and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is abnormal - on 
treatment 
 
 
Hepatitis B/C (HBV sAG, HCV antibody, or HCV RNA) 
Testing for HIV-1 and HIV-2 must be performed at sites where mandated by local requirements (see 
Appendix 8). 
 
Coagulation Panel (HCC only) 
 
PT/INR 
aPTT 
Fibrinogen 
 
Other Analyses 
 
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG). 
Follicle stimulating hormone (FSH) screening (only required to confirm menopause in women aged < 55 years) 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
aPTT = activated partial thromboplastin time; BUN = blood urea nitrogen; CBC = complete blood count; 
FSH = follicle stimulating hormone; fT3 = free triiodothyronine; fT4 = free thyroxine; HBV = hepatitis B virus; HCC 
= hepatocellular carcinoma; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV-1/2 = human 
immunodeficiency virus 1/2; INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin 
time; RNA = ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; WOCBP 
= women of childbearing potential. 
 
 
9.4.5 
Suicidal Risk Monitoring 
Not applicable. 


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9.4.6 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.4.7 
Assessment of Subcutaneous Injection Site 
The Investigator or designated study staff will assess the proposed injection site for signs of local 
irritation and inflammation. The proposed injection site will be evaluated prior to all SC doses and 
approximately 60 minutes after the Cycle 1 Day 1 injection (Parts A, B and D) and following the 
first SC injection after transitioning to 1200 mg dose in Part C. Part E participants will be 
monitored for approximately 30 minutes following the 
 and 
 SC manual injections. 
Participants receiving subsequent SC injections may be monitored post injection as clinically 
warranted and at the discretion of the investigator. There will be five pre-specified injection site 
reactions of interest: injection site erythema; injection site pain, injection site pruritus, injection 
site hematoma, and injection site swelling. Injection site reactions will be recorded as AEs on the 
appropriate page of the CRF. In addition, all participants will be contacted approximately 24 hours 
after the first 2 SC injections for reporting of injection site reactions. The injection site will also 
be evaluated predose at the next dosing visit. 
9.5 
Pharmacokinetics 
Full details on the clinical pharmacology aspects of nivolumab can be found in the nivolumab IB. 
The PK of nivolumab (BMS-936558 and BMS-986298) will be derived from serum concentration 
versus time measurements. The PK parameters to be assessed include: 
• Cmax: Maximum observed serum nivolumab concentration 
• Tmax: Time to maximal concentration 
• AUC(TAU): Area under the concentration-time curve over the dosing interval 
• Ctau: Observed serum nivolumab concentration at the end of the dosing interval 
• Ctrough: Trough observed serum nivolumab concentration 
 
Individual participant PK parameter values will be derived by non-compartmental and, if 
appropriate, population PK methods by a validated pharmacokinetic analysis program. Actual 
times of collection will be used in all PK analyses. 
9.5.1 
Pharmacokinetics and Anti-drug Antibody Sample Collection and 
Processing 
 
time points are relative to the start of study drug administration. Predose samples should be 
collected within 30 minutes before the start of dose administration. End-of-infusion (EOI) samples 
should be taken just prior to the end of the IV infusion (preferably within 2 minutes from 
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completing the saline flush). Details of sample collection, processing, and shipment will be 
provided in the laboratory procedures manual. 
Draw blood samples from a site other than the infusion site (ie, contralateral arm) on days of 
infusion for all predose and end of infusion-PK (EOI-PK) samples. 
On-treatment PK samples are intended to be drawn relative to actual dosing days. If a dose occurs 
on a different day within the cycle due to delays or minor schedule adjustments, PK samples should 
be adjusted accordingly. 
Immunogenicity of nivolumab will assessed per the standard nivolumab immunogenicity analysis 
plan. PK data for rHuPH20 will not be collected in this study; however, immunogenicity data for 
rHuPH20 will be collected and may be analyzed and reported separately. 


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9.5.2 
Pharmacokinetics and Immunogenicity Sample Analyses 
The samples will be analyzed for nivolumab and ADA (anti-nivolumab and anti-rHuPH20 
antibodies) by validated immunoassays. Samples with a positive ADA response may also be 
analyzed for neutralizing ADA response to nivolumab and/or rHuPH20. Neutralizing ADA testing 
is conditional upon assay availability. 
In addition, selected serum samples may be analyzed by an exploratory method that measures 
nivolumab or detect ADAs for technology exploration purposes; exploratory results will not be 
reported. The corresponding serum samples designated for either PK, immunogenicity or 
biomarker assessments may also be used for any of those analyses, if required (eg, insufficient 
sample volume to complete testing or to follow up on a suspected immunogenicity-related AE). 
9.6 
Pharmacodynamics 
Pharmacodynamic parameters evaluated in this study are described in the Biomarkers section 
(Section 9.8). 
9.7 
Pharmacogenomics 
Refer to Section 9.8 (Biomarkers). 
9.8 
Biomarkers 
Features within the periphery and in the tumor microenvironment (TME) have been established as 
pharmacodynamic (PD) biomarkers of nivolumab biological activity. In the periphery, these 
include increased soluble factors including, but not limited to, CXCL9, CXCL10, and soluble 
PD-1. In the TME, these include increases in intratumoral inflammation, as measured by increases 
in tumor-infiltrating lymphocytes (TILs) and increases in PD-L1 protein expression. Pre- and 
on-treatment peripheral blood and tumor biopsies will be collected and will be used to characterize 
the PD activity of subcutaneous nivolumab. Optional peripheral blood and tumor biopsies will also 
be collected at disease progression (Table 9.8-1, Table 9.8-2). In addition to characterizing the PD 
activity of subcutaneous nivolumab, 
. All samples 
collected may also be used for exploratory analyses to assess biomarkers associated with a specific 
indication and/or with immunotherapy treatment. Complete instructions on the collection, 
processing, handling, and shipment of all samples described herein will be provided in a separate 
procedure manual. 


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Table 9.8-1: 
Biomarker Sampling Schedule - Part A, Part B, and 
Part D - Study CA2098KX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: 
SAE = serious adverse event. 
a Predose samples should be collected just before the administration of the nivolumab (preferably within 30 minutes). 
c For Part A the tumor biopsy is highly recommended, but optional. For Part B and Part D, participants will be 
required to undergo on-treatment biopsy at acceptable clinical risk as judged by the investigator. Biopsy should be 
collected on Cycle 1 Day 15, preferably from the same lesion as the pre-treatment biopsy. 
d 
serum sample collection should occur within ± 5 days of Cycle 1 Day 15. 
Study Day 
1 Cycle = 4 Weeks 
Time 
(Event) 
Houra 
Tumor 
Biopsy 
Serum 
Screening 
X 
Cycle 1 Day 1 
Predose 
X 
Cycle 1 Day 2 
-- 
X 
Cycle 1 Day 4 
(±1 days) 
-- 
X 
Cycle 1 Day 8 
(±2 days) 
-- 
X 
Cycle 1 Day 15 
-- 
Xc 
Xd 
Cycle 1 Day 21 
(±5 days) 
-- 
X 
Cycle 2 Day 1 
Predose 
X 
N/A = not applicable; 


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Table 9.8-2: 
Biomarker Sampling Schedule - Part E - Study CA2098KX 
 
Study Day 
(1 Cycle = 4 
weeks) 
Time 
(Event) 
Houra 
Tumor 
Biopsy 
Serum 
Screening 
(Optional) 
Xb 
Cycle 1 Day 1 
Predose 
X 
Cycle 1 Day 2 
-- 
X 
Cycle 1 Day 8 
(+/- 2 days) 
-- 
X 
Cycle 1 Day 15 
Predose 
Xb 
X 
Cycle 2 Day 1 
Predose 
X 
Abbreviations: 
DNA = deoxyribonucleic acid; SAE = serious adverse event; 
a Predose samples should be collected just before the administration of the nivolumab (preferably within 30 minutes). 
b For Part E, screening and Cycle 1 Day 15 tumor biopsies are highly recommended, but optional. 


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9.8.1 
Tumor Tissue Specimens 
For Part A, the Cycle 1 Day 15 tumor biopsy is highly recommended but optional. For Part B and 
Part D, participants will be required to undergo on-treatment biopsy unless judged as posing 
unacceptable risk by the investigator. Sufficient, recent tumor tissue FFPE block from a metastatic 
tumor lesion or from an unresectable primary tumor lesion, which has not been previously 
irradiated, must be submitted. If a participant had a biopsy in the preceding 12 months, participants 
can be enrolled without needing a repeat biopsy after discussion with the Medical Monitor and 
availability of FFPE blocks 
as delineated below. For Part E, 
screening and on-treatment tumor biopsies are highly recommended, but optional. 
 
1) Parts A-D only: Pre-treatment tissue must be collected and locally confirmed for adequate 
tissue quantity and quality during the screening period prior to first dose of study treatment 
and then sent to the central laboratory for testing. Please refer to lab manual for detailed biopsy 
collection instructions. Up to 5 participants from each part of the trial (Part A and B) who do 
not meet tissue requirements may be allowed treatment after discussion with the Medical 
Monitor. Other exceptions may be provided at the discretion of the Medical Monitor. 
a) Approximately 15 participants in Part D, who do not meet tissue requirements may be 
allowed treatment after discussion with the Medical Monitor. 
b) Participants should not have received any systemic anticancer therapy after the date that 
the submitted tumor tissue was obtained. Exceptions may be made with Medical Monitor 
approval in cases where fresh tumor tissue or recent tumor tissue are inaccessible. 
2) Part E: Tumor tissue collection is highly recommended, but optional. For all participants in 
Part E, including mUC participants, submission of an archival FFPE tissue block (preferred) 
or unstained slides of tumor tissue from core biopsy, excisional biopsy, or surgical specimen 
obtained within 12 months of enrollment is highly recommended. 
3) The tumor tissue specimen must be a core biopsy, excisional biopsy, or surgical specimen. 
Fine needle biopsies, drainage of pleural effusions with cytospins, or punch biopsies are not 
considered adequate for biomarker review. Biopsies of bone lesions that do not have a soft 
tissue component or decalcified bone tumor samples are also not acceptable. Where possible, 
the biopsied lesion should be distinct from target lesions being evaluated for radiologic 
response, and the same lesion should be used for both the baseline and on-treatment sampling. 


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time points indicated in the biomarker tables (Table 9.8-1 and Table 9.8-2). 
Separate blood samples will be collected and 
processed for serum 
be assessed by ELISA 
and then put in frozen storage. Serum 
samples may 
9.8.2 
Biomarker assessments in tumor 
Pre- and on-treatment PD-L1 expression will be assessed using the Dako PharmDx 28-8 assay. 
PD-L1 stained tissue sections will be assessed by a pathologist and membranous PD-L1 expression 
 
In addition to PD-L1 assessment, the pre-treatment and on-treatment tumor sample may be used 
to assess other putative predictive and PD biomarkers of SC nivolumab to better characterize the 
TME. 
 
 
 
9.8.3 
Biomarker assessments in peripheral blood 
A variety of biomarkers that may inform on 
PD activity of nivolumab will 
be investigated in peripheral blood specimens taken from all participants prior to and during 
treatment. Several analyses will be completed and are described briefly below. Additional 
biomarker assessments may also be performed if samples are available. 
 
9.8.3.2 
Exploratory Serum 
Biomarkers 
Blood samples for exploratory serum 
biomarker analyses will be drawn at the specified 
scored in tumor, provided a minimum of 100 evaluable tumor cells are present. 


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9.8.4 
Additional Research Collection 
 
 
For All US sites: 
Additional research is required for all study participants except where prohibited by IRBs/ethics 
committees, or academic/institutional requirements. Where one or more of these exceptions 
occurs, participation in the additional research should be encouraged but will not be a condition of 
overall study participation. 
• If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional research 
as a requirement for inclusion in the study. 
• If optional participation is permitted and approved, then the study participants may opt out of 
the additional research retention and/or collection. 
 
For non-US sites: 
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
BMS, and will support as yet undefined research aims that will advance our understanding of 
disease and options for treatment. It may also be used to support health authority requests for 
analysis, and advancement of pharmacodiagnostic development to better target drugs to the right 


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patients. This may also include genetic/genomic exploration aimed at exploring disease pathways, 
progression and response to treatment, etc. 
Sample Collection and Storage 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities. 
Samples kept for future research will be stored at the BMS Biorepository 
or an 
independent, BMS-approved storage vendor. 
 
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual. Further details of sample collection and processing 
will be provided to the site in the procedure manual. 
Table 9.8.4-1: 
Residual Sample Retention for Additional Research Schedule 
 
 
9.8.5 
Immunogenicity Assessments 
Samples for testing potential nivolumab and rHuPH20 immunogenicity will be collected per the 
PK and immunogenicity sampling schedule 
. 
9.9 
Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study. 
Timepoints for which Residual Samples Will Be Retained 
All 
Abbreviations: 
PK = pharmacokinetic; 
PK 
Sample Type 


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9.10 
Patient-reported Outcomes 
9.10.1 
Patient Experience and Preference Questionnaire 
In order to better understand experiences with and preferences for mode of nivolumab 
administration, participants will complete a Patient Experience and Preference Questionnaire at 
various time points during the study. The core questionnaire contains items assessing patient 
perceptions regarding the convenience and acceptability of the mode of administration, 
treatment-related symptoms, and satisfaction with treatment. 
The questionnaire will be administered immediately following completion of the injection or 
infusion on Day 1 of treatment Cycle 1 and Cycle 2 in Part A and Part B, and on Day 1 Cycle 1 of 
Part C, Part D, and Part E. 
9.10.2 
Qualitative Patient Interviews 
Qualitative interviews will be performed with participants to gather insights not covered by the 
Patient Experience and Preference Questionnaire. The interviews will be conducted via telephone 
by a trained interviewer using a semi-structured interview guide. They will be conducted in the 
participant’s native language and will be audio recorded and transcribed for analysis using 
qualitative data analysis techniques. Interviews conducted in languages other than English will be 
translated to English prior to analysis. Interviews will be conducted within 14 days of completing 
Cycle 1 Day 1 and Cycle 2 Day 1 in Part A, Part B, and Part C. For Part D and Part E, interviews 
will be conducted within 14 days of completing Cycle 1 Day 1 or any other cycle thereafter, if not 
captured at Cycle 1 Day 1. Participation in the interviews is optional and will be subject to the 
availability of interview materials and the fluency of trained interviewers. Failure to complete 
either interview will not constitute a protocol deviation. 
10 
STATISTICAL CONSIDERATIONS 
10.1 
Sample Size Determination 
Calculation of precision estimates is based on AUC(TAU). 
In Part A and Part B, administration of SC nivolumab (BMS-986298) to 20 participants will 
provide 
 % confidence that the range between 
 % and 
 % of the point estimate of geometric 
mean AUC(TAU) will encompass the true value. Administration of SC nivolumab (BMS-986298) 
to 10 participants will provide 
% confidence that the range between 
 % and 
 % of the point 
estimate of geometric mean AUC(TAU) will encompass the true value. These calculations assume 
that AUC is log-normally distributed with standard deviation of 
 for log(AUC[TAU]), based 
on coefficient of variation estimates for IV nivolumab 480 mg of  % for AUC. 
In Part D, administration of 1200 mg SC nivolumab Q4W to 36 PK evaluable participants will 
provide 
 % confidence that the range between 
 % and 
 % of the point estimate of geometric 
mean AUC(TAU) will encompass the true value. Administration of 1200 mg SC nivolumab Q4W 
to 10 PK evaluable participants will provide 
% confidence that the range between 
% and 
% of the point estimate of geometric mean AUC(TAU) will encompass the true value. This 
calculation assumes that AUC is log-normally distributed with standard deviation of 
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log(AUC[TAU]), based on an estimated coefficient of variation for nivolumab SC of 
 % 
(for AUC[TAU]). Variability has been estimated via modelling and simulation. 
In Part E, administration of 600 mg SC nivolumab Q2W to 
 PK evaluable participants will 
provide 
 % confidence that the range between 
 % and 
 % of the point estimate of geometric 
mean AUC(TAU) will encompass the true value. Administration of 600 mg SC nivolumab Q2W 
to 
 PK evaluable participants will provide 
% confidence that the range between 
% and 
% of the point estimate of geometric mean AUC(TAU) will encompass the true value. This 
calculation assumes that AUC is log-normally distributed with standard deviation of 
 for 
log(AUC[TAU]), based on an estimated coefficient of variation for nivolumab SC of % (for 
AUC[TAU]). Coefficient of variation of 
% for AUC(TAU) has been observed in interim 
analysis 4 for the 1200 mg SC nivolumab Q4W dosing regimen. 
Precision of measurements were calculated by nQuery Advisor 7.0. 
10.2 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
• All Enrolled Participants: all participants who sign an ICF and are registered into the IRT. 
This is the dataset for disposition. 
• All Randomized Participants: all participants who are assigned/randomized to any treatment 
arm in the study. This dataset will be used for efficacy analyses. 
• All Treated Participants: all participants who receive at least 1 dose of nivolumab. This is 
the dataset for safety analyses. 
• PK Participants: All treated participants with available PK data. 
• Evaluable PK Participants: The Evaluable PK Participants population is a subset of the PK 
Participants Population who have adequate dosing and adequate nivolumab serum 
concentration time data for estimation of PK endpoints. All available derived PK parameter 
values will be included in the PK data set and reported, but only participants in the Evaluable 
PK Participants population will be included in the summary statistics and statistical analysis. 
• Immunogenicity Evaluable Participants: All treated participants who have a baseline and at 
least 1 post-baseline immunogenicity assessment. 
 
10.3 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses and the procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints. 
A description of the participant population will be included in the reported statistical output, 
including subgroups of age, gender, race, and tumor type. Frequency distributions of gender and 
race will be tabulated by treatment. Summary statistics for age, body weight, height, and body 
surface area (BSA) will be tabulated by treatment. 


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10.3.1 
Efficacy Analyses 
All efficacy analyses are exploratory and will be described in the statistical analysis plan finalized 
before database lock. 
10.3.2 
Safety Analyses 
Safety analyses will be performed on the All Treated Participants population. Descriptive statistics 
of safety will be presented using NCI CTCAE v.5 by treatment group. 
 
Endpoint 
Statistical Analysis Methods 
Incidences of AEs, TRAEs, 
SAEs, TRSAEs, AEs/TRAEs 
leading to discontinuation, 
and deaths 
All on-study AEs, TRAEs, SAEs, TRSAEs, and AEs/ TRAEs 
leading to discontinuation will be tabulated using worst grade 
per NCI CTCAE v.5 criteria by system organ class and 
preferred term. 
Frequency distribution of treated participants with AE using 
the worst CTC grade. Participants will only be counted: (1) 
once at the PT level, (2) once at the SOC level, and (3) once 
in the “total participant” row at their worst CTC grade, 
regardless of SOC or PT. 
Deaths will be summarized by treatment group. 
Incidence of clinical 
laboratory test abnormalities 
On study laboratory parameters including hematology, 
chemistry, liver function, and renal function will be 
summarized using worst grade NCI CTCAE v.5 criteria. 
Incidence of AEs in the 
MedDRA Anaphylactic 
Reaction broad scope SMQ 
occurring within 2 days after 
study drug administration 
Descriptive statistics will be presented using NCI CTCAE v.5 
criteria by treatment group. 
Incidence of events within the 
hypersensitivity/infusion 
reaction select AE category 
occurring within 2 days after 
any study drug administration 
Descriptive statistics will be presented using NCI CTCAE v.5 
criteria by treatment group. 
Abbreviations: AE = adverse event; CTC = Common Terminology Criteria; MedDRA = Medical Dictionary for 
Regulatory Activities; NCI CTCAE v5 = National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5; PT = preferred term; SAE = serious adverse event; SMQ = standardized MedDRA query; SOC = system 
organ class; TRAE = treatment-related adverse event; TRSAE = treatment-related serious adverse event. 


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10.3.3 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be conducted using non-compartmental analysis and, if appropriate, 
PPK analysis. These analyses will be used to characterize the PK of SC nivolumab in Part A, 
Part B, Part D, and Part E, as well as to inform future clinical trials using SC nivolumab. Analyses 
from Part A and Part B were used to inform dose selection for Part C, Part D, and additional 
treatment groups in Part B. 
Primary Pharmacokinetic Analysis: PK parameters will be summarized by cycle (dose and route 
of administration). Evaluable PK parameters will be summarized as follows: 
For Parts A, B, D, and E: Geometric means and coefficients of variation will be presented for 
Cmax, Ctau, and AUC(TAU). Means and standard deviations will also be provided. Medians and 
ranges will be presented for Tmax. Other exposure measures may be summarized as appropriate. 
For Part C: Geometric means and coefficients of variation will be presented for Ctrough. 
To assess the dependency on dose after subcutaneous administration of the SC nivolumab 
(BMS-986298) formulation, scatter plots of Cmax and AUC versus dose will be provided. 
Population PK analysis will be conducted as appropriate to determine a subcutaneous dose for 
future nivolumab trials as outline in Section 10.3.7.1. 
10.3.4 
Immunogenicity Analyses 
All immunogenicity analyses will be performed on the immunogenicity-evaluable population. 


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Endpoint 
Statistical Analysis Methods 
Incidence of anti-nivolumab 
antibodies and neutralizing 
antibodies, if applicable. 
Frequency distribution of baseline ADA-positive 
participants and ADA-positive participants after 
initiation of the treatment, as well as neutralizing 
antibody-positive participants will be presented. 
Baseline ADA-positive participant is defined as a 
participant who has an ADA-positive detected sample at 
baseline. 
ADA-positive participant is a participant with at least 1 
ADA-positive sample relative to baseline after initiation 
of the treatment. 
Incidence of anti-rHuPH20 
antibodies and neutralizing 
antibodies, if applicable 
Frequency distribution of baseline ADA-positive 
participants and ADA-positive participants after 
initiation of the treatment, as well as neutralizing 
antibody-positive participants will be presented. 
Baseline ADA-positive participant is defined as a 
participant who has an ADA-positive detected sample at 
baseline. 
ADA-positive participant is a participant with at least 1 
ADA-positive sample relative to baseline after initiation 
of the treatment. 
Abbreviations: ADA = anti-drug antibody; rHuPH20 = recombinant human hyaluronidase PH20. 
 
10.3.5 
Outcomes Research 
All outcomes research and patient preferences analyses are exploratory and will be described in 
the statistical analysis plan finalized before database lock. 
10.3.6 
Biomarker Analyses 
Descriptive summary statistics of biomarker assessments will be presented at baseline and at each 
on-study time point described in Section 9.8, Table 9.8-1, and Table 9.8-2, unless otherwise 
specified. 
10.3.7 
Other Analyses 
Further exploratory analyses not specified here will be described in the Statistical Analysis Plan, 
which will be finalized before database lock and may be presented separately from the main 
clinical study report. 
10.3.7.1 
Population Pharmacokinetic Analysis of SC Nivolumab 
The nivolumab serum concentration versus time data obtained in this study will be combined with 
data from other studies in the nivolumab clinical development program to develop PPK models. 
These studies will inform the systemic PK parameters of nivolumab disposition. The SC 
nivolumab PK data gathered from the Study CA2098KX will inform the absorption kinetics of 
nivolumab from the SC space to the systemic circulation. Thus, PPK models will inform the effect 


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of route of administration on nivolumab pharmacokinetics. These models may be further used to 
evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab to determine 
measures of individual exposure (eg, steady-state peak, trough, and time-averaged concentration). 
Model-determined exposures may be used for E-R analyses of selected efficacy and safety 
endpoints. If these analyses are conducted, the results of PPK and E-R analyses will be reported 
separately. 
10.3.8 
Interim Analyses 
PK and safety analyses will be performed in the study on an ongoing basis. Interim analyses will 
be conducted in this study to select the SC nivolumab (BMS-986298) dose for Part C and for 
long-term dosing in Part D, and to inform additional dosing regimens to be assessed in Part B. 
Interim analysis are planned also for Parts C, D, and E as specified below. Details regarding interim 
analyses can be found in the Statistical Analysis Plan. 
The following will be considered as part of determination of the SC dose: 
• Interim analysis 1 included the first 
 participants in Part A after single dose of subcutaneous 
nivolumab. Participants in Part A - Group 1 were analyzed. 
• Interim analysis 2 occurred when all participants in Part B Group 3 had completed the single 
dose of subcutaneous nivolumab. Participants in Part A - Group 1 and Part B - Group 3 were 
analyzed. 
 
Data from at least 
 participants from Part A and from additional participants from Part B, were 
used to identify the SC nivolumab (BMS-986298) dose regimen in Part C and Part D of this study. 
Based on preliminary PK results from Part A and Part B, SC dose of 1200 mg Q4W nivolumab is 
selected for Part C and Part D participants. 
Interim analysis 3 will occur when the first 10 participants in Part D have completed the single 
dose of subcutaneous nivolumab. All participants enrolled in all Parts of the study up to the lock 
will be analyzed. 
Interim analysis 4 will occur when all participants in Part D have completed the single dose of 
subcutaneous nivolumab. All participants enrolled in all Parts of the study up to the lock will be 
analyzed. 
Interim analysis 5 will occur when all participants in Part E have completed a minimum of 
6 months of follow-up from first dose date. All participants enrolled in all Parts of the study up to 
the lock will be analyzed. 
Additional analysis for internal decision making or external publication purposes may be 
performed. No formal comparisons or inferences requiring any adjustment to statistical 
significance level will be performed. 


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11 
REFERENCES 
 
1 Salako O, Okaunade K, Allsop M, et al. Upheaval in cancer care during the COVID-19 
outbreak. Ecancermedicalscience 2020;14:3d97 
 
5 Sharma P, Retz M, Siefer-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after 
platinum therapy (Checkmate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 
2017;18(3):312-22. 
6 Siefker-Radtke A, Baron AD, Necchi A, et al. Nivolumab monotherapy in patients with 
advanced platinum-resistant urothelial carcinoma: efficacy and safety update from CheckMate 
275. J Clin Oncol 2019; 37(15 suppl):4524. 
7 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39. 
8 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27. 
9 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8. 
10 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
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11  rHuPH20 Investigator’s Brochure. Version 9. Halozyme Therapeutics Inc; 2021. 
12 Bookbinder LH, Hofer A, Haller MF, et al. A recombinant human enzyme for enhanced 
interstitial transport of therapeutics. J Control Release. 2006;114:230-41. 
13 Bywaters EG, Holborow EJ, Keech MK. Reconstitution of the dermal barrier to dye-spread 
after hyaluronidase injection. Br Med J. 1951;2:1178-83. 
14 Wasserman RL, Melamed I, Stein MR, et al. Long-term tolerability, safety, and efficacy of 
recombinant 
human 
hyaluronidase-facilitated 
subcutaneous 
infusion 
of 
human 
immunoglobulin for primary immunodeficiency. J Clin Immunol. 2016;36:571-82. 
15 Nivolumab (BMS-936558 and BMS-986298): A single-dose intravenous and repeat-dose 
(Q3WX2) subcutaneous pharmacokinetic, pharmacodynamic, and local tolerance study in 
monkeys (Study DN18044). Bristol-Myers Squibb Company; study ongoing. 


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16 McDermott DF, Drake CG, Sznol M, et al. Survival, Durable Response, and Long-Term Safety 
in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J 
Clin Oncol 2015; 33(18): 2013-20. 
17 Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: 
Results of a Randomized Phase II Trial. J Clin Oncol 2015; 33(13): 1430-7. 
18 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, Activity, and Immune Correlates of Anti- 
PD-1 Antibody in Cancer. N Engl J Med 2012. 
19 Choueiri TK FM, Escudier BJ, Kim JJ,et al. ;. Immunomodulatory activity of nivolumab in 
previously treated and untreated metastatic renal cell carcinoma (mRCC): Biomarker-based 
results from a randomized clinical trial. J Clin Oncol 32:5s, 2014 (suppl; abstr 5012) 
20 Rosengren S, Dychter SS, Printz MA, et al. Clinical immunogenicity of rHuPH20, a 
hyaluronidase enabling subcutaneous drug administration. AAPS J. 2015;17:1144-56. 
21 BMS-986298. Nivolumab Subcutaneous; Investigator Brochure. Version 02. Bristol-Myers 
Squibb Research and Development. Lawrenceville NJ. 03-Jul-2019. 
22 Nivolumab (BMS-936558/MDX-1106). Nivolumab population pharmacokinetic analysis in 
participants with recurrent or metastatic colorectal cancer (CRC) or recurrent glioblastoma 
multiforme (GBM) and other solid tumors. Bristol-Myers Squibb Company; 2016. Document 
Control No. 930107426. 
23 Kirschbrown WP, Wynne C, Kågedal M, et al. Development of a Subcutaneous Fixed -Dose 
Combination of Pertuzumab: Results From the Phase Ib Dose Finding Study. J Clin Pharm. 
2019;59:702-716. 
24 Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with 
advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of 
adverse events: a pooled analysis of randomized Phase II and III trials. J Clin Oncol 
2017;35:3807-14. 
25 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from 
Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin 
Oncol 2015;33:1889-94. 
26 Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of 
nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics 
of long-term survivors. Oral presentation at the American Association for Cancer Research 
(AACR) Annual Meeting; 2017 Apr 1-5; Washington, DC, USA. 
27 Felip Font E, Gettinger SN, Burgio MA, et al. Three-year follow-up from Checkmate 017/057: 
nivolumab versus docetaxel in patients with previously treated advanced non-small lung cancer 
(NSCLC). Poster discussion presentation at the European Society of Medical Oncology 
Annual Meeting; 2017 Sep 8-12; Madrid, Spain. Poster 1301PD. 


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28 Spigel DR, McLeod M, Hussein MA, et al. Randomized results of fixed-duration (1-yr) vs 
continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC). 
Oral presentation at the European Society of Medical Oncology Annual Meeting; 2017 Sep 8- 
12; Madrid, Spain. 
29 Davda JP, Dodds MG, Gibbs MA, et al. A model-based meta-analysis of monoclonal antibody 
pharmacokinetics to guide optimal first-in-human study design. mAbs. 2014;6:1094-102. 
30 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20. 


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12 
APPENDICES 


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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
 
Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AFP 
alpha fetoprotein 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to infinite time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration 
AUC(TAU) 
area under the concentration-time curve over the dosing interval 
β-HCG 
beta-human chorionic gonadotrophin 
BMS 
Bristol-Myers Squibb 
BOR 
best overall response 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BW 
body weight 
C1D1 
Cycle 1 Day 1 
Cavg 
average concentration 
Cavgd28 
time-averaged concentration over 28 days 
CBC 
complete blood count 
ccRCC 
clear cell renal cell carcinoma 
CD 
cluster of differentiation 
CI 
confidence interval 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
CLss 
steady state clearance 
cm 
centimeter 
Cmax 
maximum observed serum nivolumab concentration 


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Term 
Definition 
CMV 
cytomegalovirus 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRC 
colorectal cancer 
CrCL 
creatinine clearance 
CRF 
case report form, paper or electronic 
CRR 
complete response rate 
CT 
computed tomography 
CTAg 
clinical trial agreement 
Ctau 
observed serum nivolumab concentration at the end of the dosing interval 
CTC 
Common Terminology Criteria 
CTLA 
cytotoxic T lymphocyte antigen 
Ctrough 
trough observed serum nivolumab concentration 
CV 
coefficient of variation 
dL 
deciliter 
DLBCL 
diffuse large B cell lymphoma 
dMMR 
mismatch repair deficient 
DS 
drug substance 
DSM IV 
Diagnostic and Statistical Manual of Mental Disorders (4th Edition) 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFS 
event-free survival 
eg 
exempli gratia (for example) 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EOI 
end-of-infusion 
EU 
European Union 
FDA 
Food and Drug Administration 


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Term 
Definition 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 
fT3 
free triiodothyronine 
fT4 
free thyroxine 
g 
gram 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
h 
hour 
HBsAG 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
ICH 
International Conference on Harmonisation 
ie 
id est (that is) 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IHC 
immunohistochemistry 
IL 
interleukin 
IMP 
investigational medicinal products 
IND 
Investigational New Drug Exemption 
INR 
international normalized ratio 
IO 
immuno-oncology 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IU 
International Unit 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
KA 
first order absorption rate constant 


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Term 
Definition 
kg 
kilogram 
L 
liter 
LAM 
lactation amenorrhea method 
LDH 
lactate dehydrogenase 
MDSC 
myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MICA 
MHC class I chain-related A 
MLR 
mixed lymphocyte reaction 
MRI 
magnetic resonance imaging 
MSI-H 
high microsatellite instability 
MTD 
maximum tolerated dose 
mUC 
metastatic urothelial carcinoma 
N 
number of subjects or observations 
N/A 
not applicable 
Nab 
neutralizing antibody 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
ODAC 
Oncologic Drugs Advisory Committee 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PD-1 
programmed death receptor 1 
PD-L1/2 
programmed death ligand 1/2 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PT 
prothrombin time 
PT 
preferred term 
PTT 
partial thromboplastin time 
QnW 
every n weeks 


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Term 
Definition 
Q2W 
every 2 weeks 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rHuPH20 
recombinant human hyaluronidase PH20 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAE 
serious adverse event 
sAG 
surface antigen 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SD 
standard deviation 
SMQ 
standardized MedDRA queries 
SNP 
single nucleotide polymorphism 
SOC 
system organ class 
t1/2 
half life 
T3 
triiodothyronine 
T4 
thyroxine 
TB/T.bili 
total bilirubin 
TIL 
tumor-infiltrating lymphocyte 
Tmax 
time of maximum observed concentration 
TME 
tumor microenvironment 
TRAE 
treatment-related adverse event 
TRSAE 
treatment-related serious adverse event 
TSH 
thyroid stimulating hormone 
TTE 
transthoracic echocardiogram 
US 
United States 
Vss/F (or Vss) 
apparent volume of distribution at steady state 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 


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APPENDIX 2 
STUDY GOVERNANCE CONSIDERATIONS 
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study. 
REGULATORY AND ETHICAL CONSIDERATIONS 
GOOD CLINICAL PRACTICE 
This study will be conducted in accordance with: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
• as defined by the International Council on Harmonisation (ICH) 
• in accordance with the ethical principles underlying European Union Directive 2001/20/EC 
• United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
• applicable local requirements. 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study. 
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 


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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to: 
• IRB/IEC 
• Regulatory Authority(ies), if applicable by local regulations (per national requirements) 
 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS. 
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
FINANCIAL DISCLOSURE 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
INFORMED CONSENT PROCESS 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki. 


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Investigators must: 
• Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
• Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study. 
• Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
• Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information. 
 
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant. 
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization. 
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
SOURCE DOCUMENTS 
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records). 


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When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS 
Records for study treatment with rHuPH20 
 
(whether supplied by 
BMS, its vendors, or the site) must substantiate study treatment integrity and traceability from 
receipt, preparation, administration, and through destruction or return. Records must be made 
available for review at the request of BMS/designee or a Health Authority. 
 
If 
Then 
Supplied by BMS (or its vendors): 
Records or logs must comply with applicable 
regulations and guidelines and should include: 
• amount received and placed in storage 
area 
• amount currently in storage area 
• label identification number or batch 
number 
• amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
• amount transferred to another area/site for 
dispensing or storage 
• nonstudy disposition (e.g., lost, wasted) 
• amount destroyed at study site, if 
applicable 
• amount returned to BMS 
• retain samples for 
bioavailability/bioequivalence, if 
applicable 
• dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form. 
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy) 
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy. 


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BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements. 
 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study. 
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals 
MONITORING 
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 


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Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents. 
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential. 
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study. 
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed. 
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT 
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
 
If.. 
Then 
Study treatments supplied by BMS (including 
its vendors 
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics). 
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor. 
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 


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study treatments sourced from the sites stock according to the institutional guidelines and 
or 
commercial 
supply, 
or 
a 
specialty procedures. 
pharmacy) 
 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers. 
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee. 
CLINICAL STUDY REPORT AND PUBLICATIONS 
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria: 
• External Principal Investigator designated at protocol development 
• National Coordinating Investigator 
• Participant recruitment (eg, among the top quartile of enrollers) 
• Involvement in trial design 
• Regional representation (eg, among top quartile of enrollers from a specified region or country) 
• Other criteria (as determined by the study team) 


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The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg. 


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APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING 
ADVERSE EVENTS 
 
Adverse Event Definition: 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term. 
Events NOT Meeting the AE Definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 


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SERIOUS ADVERSE EVENTS 
 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
• medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason) 
• admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 


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Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 
for reporting pregnancies). 
EVALUATING AES AND SAES 
 
 
The causal relationship to study treatment is determined by a physician and should be used 
to assess all adverse events (AE). The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study treatment 
administration and the AE. 
Not related: There is not a reasonable causal relationship between study treatment 
administration and the AE. 
• The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Assessment of Causality 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial SAE 
report. 
All SAEs must be followed to resolution or stabilization. 
Follow-up of AEs and SAEs 


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REPORTING OF SAES TO SPONSOR OR DESIGNEE 
 
• SAEs, whether related or not related to study treatment, and pregnancies must be 
reported to BMS (or designee) immediately within 24 hours of awareness of the event. 
• SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
• Surveillance Form (electronic or paper forms). 
• The preferred method for SAE data reporting collection is through the eCRF. 
• The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning. 
• For studies capturing SAEs through electronic data capture (EDC), electronic 
submission is the required method for reporting. In the event the electronic system is 
unavailable for transmission, paper forms must be used and submitted immediately. 
When paper forms are used, the original paper forms are to remain on site. 
• The process for Paper SAE Reporting and Contact Details will be made available 
locally. 


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APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study. 
DEFINITIONS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause. 
 
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels. 
• 1-week minimum for vaginal hormonal products (rings, creams, gels) 
• 4-week minimum for transdermal products 
• 8-week minimum for oral products 


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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal. 
End of Relevant Systemic Exposure 
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 
5 half-lives of the IMP to pass. 
METHODS OF CONTRACEPTION 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation. (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol.)b 
− Oral (birth control pills) 
− Intravaginal (rings) 
− Transdermal 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy. 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation. (This 
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol.)b 
− Oral 
− Injectable 
• 
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy. 


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Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation. (This method of contraception can only be used by WOCBP participants in studies 
where hormonal contraception is permitted by the study protocol.)b 
• Intrauterine device. 
• 
Intrauterine hormone-releasing system (IUS). (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol.)b,c 
• Bilateral tubal occlusion. 
• 
Vasectomized partner 
Having a vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
A vasectomy is a highly effective contraception method provided that the participant is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. 
• Continuous abstinence must begin at least 30 days prior to initiation of study therapy. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence. 
• Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception for this study. 


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NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and 
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized. For information specific to this study regarding permissibility of 
hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.7.1 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol. 
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone 
exposures from intrauterine devices do not alter contraception effectiveness. For information specific to this 
study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.7.1 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol. 
 
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of > 1% per year when used consistently and correctly. 
• Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously. 
• Diaphragm with spermicide. 
• Cervical cap with spermicide. 
• Vaginal sponge with spermicide. 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action. (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited.) 
Unacceptable Methods of Contraception 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods). 
• Withdrawal (coitus interruptus). 
• Spermicide only. 
• LAM. 
 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and Appendix 3. 


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APPENDIX 5 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS 
1 
EVALUATION OF LESIONS 
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
1.1 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm). 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions. 
1.2 
Non-Measurable 
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions. 


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1.3 
Special considerations regarding lesion measurability 
1.3.1 
Bone lesions 
• Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
• Blastic bone lesions are non-measurable. 
1.4 
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded). 
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’). 
2 
RESPONSE CRITERIA 
2.1 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 


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• Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
 
2.1.1 
Special Notes on the Assessment of Target Lesions 
2.1.1.1 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions. 
2.1.1.2 
Target lesions that become ‘too small to measure’ 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 


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error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
2.1.1.3 
Lesions that split or coalesce on treatment 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
2.2 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
• Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (< 10mm short axis). 
• Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
• Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
 
2.2.1 
Special Notes on Assessment of Progression of Non-Target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
2.2.1.1 
When the patient also has measurable disease 
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare. 


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2.2.1.2 
When the patient has only non-measurable disease 
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 
2.2.2 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not. 
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD). 
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 


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possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
2.3 
Response Assessment 
2.3.1 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement. 
2.3.2 
Time Point Response 
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
 
Table 2.3.2-1: 
Time Point Response: Patients With Target (± Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable 
 
Table 2.3.2-2: 
Time Point Response: Patients with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease and NE = inevaluable 
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
 
2.3.3 
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥ 4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date. 
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified. 
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
 
Table 2.3.3-1: 
Best Overall Response (Confirmation of CR and PR Required) 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD OR PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 


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Table 2.3.3-1: 
Best Overall Response (Confirmation of CR and PR Required) 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
 
 
2.3.4 
Confirmation Scans 
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation. 
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease. 
REFERENCES 
1 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 


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APPENDIX 6 
MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low- 
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 


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Note: Management of Hepatic Adverse Events is modified for HCC participants 
(see below modifications) 


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HEPATIC ADVERSE EVENT MANAGEMENT ALGORITHM 
(MODIFIED FOR HCC PARTICIPANTS) 
The nivolumab program has developed a standardized approach for the management of hepatic events based on cumulative data across 
the program in participants with normal hepatic function. 
Across most nivolumab studies, the eligibility criteria for inclusion are based on a maximum AST or ALT < 3× ULN; therefore, only 
participants with normal to Grade 1 liver function tests have been enrolled. Participants with advanced HCC generally have underlying 
cirrhosis with decreased hepatic function. They may also have a concomitant chronic viral infection. For CA2098KX, the upper limits 
for inclusion were therefore adjusted to account for baseline liver dysfunction. Participants with AST or ALT elevations within the 
CTCAE Grade 2 range are eligible for inclusion. In contrast, the majority of participants included in prior nivolumab studies have had 
no higher than a CTCAE Grade 1 AST or ALT elevation. Criteria for dose delay, resumption, & discontinuation are in Section 7.4.2, 
Section 7.4.3, and Section 8.1.1. The tumor-specific approach for the management of hepatic events is as follows: 
• If AST or ALT levels do not improve with a dose delay of 3-5 days or if the levels worsen, initiate steroid therapy at 0.5-2 mg/kg/day 
methylprednisolone or oral equivalent. 
• For ALT or AST levels > 8× ULN, initiate steroid therapy promptly at 1-2 mg/kg/day methylprednisolone or oral equivalent. 
• For all participants initiating steroids, consult the BMS Medical Monitor within 24 hours after initiation of steroids. Gastroenterology 
consult is recommended. 
• If AST or ALT levels do not improve within 3-5 days or the levels worsen after the start of steroid therapy, discuss with the BMS 
Medical Monitor the possibility of adding mycophenolate mofetil at 1 g BID. 
− If no response to mycophenolate mofetil, consider treatment with tacrolimus or other immuno-suppressants per local guidelines 
and in discussion with the BMS Medical Monitor. Avoid infliximab due to potential risk of liver failure. 
• Tapering of steroids can start once AST or ALT levels have declined by 1 CTCAE grade. Taper steroids slowly over no less than 
1 month. 
 
As outlined in Section 7.4.3, nivolumab therapy may resume when AST or ALT have returned to near baseline unless the criteria for 
permanent discontinuation are reached (Section 8.1.1). 


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28-Sep-2020 


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APPENDIX 7 
PERFORMANCE STATUS SCALES 
 
STATUS 
SCALES 
STATUS 
KARNOFSKY 
ZUBROD-ECOG- 
WHO 
Normal, no complaints 
100 
0 
Normal activity 
Able to carry on normal activities Minor 
signs or symptoms of disease 
90 
0 
Symptoms, but fully 
ambulatory 
Normal activity with effort 
80 
1 
Cares for self. Unable to carry on normal 
activity or to do active work 
70 
1 
Symptomatic, but in 
bed < 50% of the day. 
Requires occasional assistance, but able to 
care for most of his needs 
60 
2 
Requires considerable assistance and 
frequent medical care 
50 
2 
Needs to be in bed 
> 50% of the day, but 
not bedridden 
Disabled. Requires special care and 
assistance 
40 
3 
Severely disabled. Hospitalization 
indicated though death non imminent 
30 
3 
Unable to get out of 
bed 
Very sick. Hospitalization necessary. 
Active supportive treatment necessary 
20 
4 
Moribund 
10 
4 
Dead 
0 
5 
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APPENDIX 8 
COUNTRY SPECIFIC AMENDMENTS 
Criteria for exclusion of HIV-positive subjects in Argentina, and any other countries where 
exclusion of HIV-positive participants is locally mandated 
Protocol Section 
Revised Protocol Text 
 
Table 2-1 Screening Procedural 
Outline (CA2098KX) 
Add “HIV testing” to list of laboratory tests. 
Section 6.2 Exclusion Criteria, 1) 
Medical Conditions g) 
Replace “Known history of testing positive for human immunodeficiency 
virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 
Testing for HIV must be performed at sites mandated by local 
requirements” with “Positive test for HIV” 
Section 
9.4.4 
Clinical 
Safety 
Laboratory Assessments 
Replace “Testing for HIV-1 and HIV-2 must be performed at sites where 
mandated by local requirements” with “Testing for HIV-1 and HIV-2 
must be performed.” 


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APPENDIX 9 
CHILD-PUGH SCORE 
 
Score 
Points 
Child-Pugh A 
5 - 6 
Child-Pugh B 
7 - 9 
Child-Pugh C 
> 9 
 
Scoring 
 
Score 
Measure 
1 Point 
2 Points 
3 Points 
Ascites 
Absent 
Slight 
Moderate 
Serum bilirubin (mg/dl) 
< 2.0 
2.0 - 3.0 
> 3.0 
Serum albumin (g/dl) 
> 3.5 
2.8 - 3.5 
< 2.8 
PT prolongation 
or INR 
< 4 sec 
< 1.7 
4 - 6 sec 
1.7 - 2.3 
> 6 sec 
> 2.3 
Encephalopathy grade 
None 
1 - 2 
3 - 4 
 
Encephalopathy Grading 
 
Encephalopathy 
Grade 
Clinical Definition 
Grade 0 
Normal consciousness, personality, and neurological examination 
Grade 1 
Restless, sleep disturbed, irritable/agitated, tremor, and impaired 
handwriting 
Grade 2 
Lethargic, time-disoriented, inappropriate, asterixis, and ataxia 
Grade 3 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, and 
rigidity 
Grade 4 
Unrousable coma, no personality/behavior, decerebrate 


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APPENDIX 10 
INJECTION SITE SELECTION AND PREPARATION AND 
ADMINISTRATION OF STUDY DRUG 
Subcutaneous Injection Site Selection and Preparation: 
Subcutaneous injections of nivolumab (BMS-986298) alone and nivolumab with rHuPH20 will be 
administered in the abdominal area. An abdominal site that is approximately at the level of the 
navel (as allowed by skin condition) and approximately 15 cm (minimum 10 cm) away from the 
margin of the navel should be selected. The lateral portion of the abdomen is preferred over the 
midline area. The selected site should include fatty tissue. 
Subcutaneous injections of nivolumab (BMS-986298) alone by syringe pump and nivolumab 
(BMS-986298) with rHuPH20 manually by syringe will be administered in the abdominal area. 
An abdominal site that is approximately at the level of the navel (as allowed by skin condition) 
and approximately 15 cm (minimum 10 cm) away from the margin of the navel should be selected. 
The lateral portion of the abdomen is preferred over the midline area. The selected site as 
determined by the Investigator should include fatty tissue and be free of any skin disease, condition 
(including, but not limited to, scarring, tattoos, or stretch marks), or skin pigmentation that could 
interfere with an assessment of the injection site. 
Administration of Subcutaneous Injection: 
The subject should be in a semi-reclined position during the injection (ie, semi-Fowler’s position: 
30-45°) and in a supine position immediately following injection for the evaluation of the injection 
site (ie, laying flat on back). 
After the injection site for subcutaneous administration has been chosen, the total dose of 
nivolumab (BMS-986298) with rHuPH20 will be administered as a single subcutaneous injection, 
while nivolumab (BMS-986298) alone will be administered as 1 to 4 injections as described briefly 
below. 
• Wipe skin with alcohol to cleanse. Allow to dry. 
• Gently pinch and lift the skin of the abdomen (ie, “tenting’). 
• Insert the needle with bevel up close and parallel to the skin or at an angle that is < 20°. Once 
the needle is inserted, gently release the pinched and lifted skin (“untent the skin”). When the 
skin in in its normal state, the needle should have a slight upward angle of 20°-30°. If the 
subject is obese, a steeper angle for needle insertion can be used but it is recommended keeping 
the angle < 45°. In practical terms, the needle placement should resemble the angle of an IV 
needle placement in the arm. The purpose of pinching and lifting the skin is to make sure the 
needle is properly inserted in the SC space and is not intradermal. 
• Release the subcutaneous tissue. 
 
Care should be taken to avoid inadvertent IV or IM injection. 


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APPENDIX 11    PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY 
Overall Rationale for the Protocol Amendment 04, 02-Apr-2021 
Changes were made to the protocol to add a new cohort (Part E) with a 600 mg every 2 weeks 
(Q2W) regimen of subcutaneous (SC) nivolumab coformulated with recombinant human 
hyaluronidase  PH20  (rHuPH20),  administered  manually  by  syringe.  Approximately 
36 participants with advanced/metastatic tumors, including approximately 10 participants with 
metastatic urothelial carcinoma (mUC), will be enrolled in Part E. 
 
For Parts A-D, SC nivolumab and rHuPH20 were mixed at the site pharmacy (coadministration) 
prior to study drug administration. As of Protocol Amendment 04, coformulated drug product 
(SC nivolumab and rHuPH20 solutions pre-mixed in 1 vial with the same dose ratio) will be 
introduced for Part E. In addition, all ongoing participants in Parts C & D may switch to the 
coformulated drug product. 
Additionally, the screening and on-treatment tumor tissue collection is optional in Part E, as these 
samples will be used for exploratory research of translational biomarkers. Biomarker and PK 
assessments have been streamlined for Part E. 
Information was added to address administration and safety monitoring of SC nivolumab in the 
context of the coronavirus disease 2019 (COVID-19) pandemic, including guidance on COVID-19 
 
Other edits, including those pertaining to safety information and contraceptive requirements for 
nivolumab, were added in harmonization with the updated nivolumab Investigator’s 
Brochure (IB). Nivolumab dose modification criteria were updated to align with the latest 
Common Terminology Criteria for Adverse Events (CTCAE) guidelines version 5 (v5). 
Revisions apply to future participants enrolled in the study and, where applicable, to all 
participants currently enrolled. Other edits were made throughout the protocol and the synopsis to 
fix minor errors, to add clarity and for consistency. 
 
Summary of key changes for Revised Protocol 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Title Page 
Added contact information for 
Clinical Scientist. 
Updated key study 
personnel. 
vaccination. 


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Summary of key changes for Revised Protocol 04 
 
Section Number & Title 
Section 2: Schedule of Activities, 
Section 3: Introduction, 
Section 5.1.3: Safety Follow-up 
Period, Section 6.2: Exclusion 
Criteria, Section 6.4.1: Retesting 
During Screening or Lead-In 
Period, Section 7.4.1: Dose 
Modifications, Section 7.7.1: 
Prohibited and/or Restricted 
Treatments, Section 9.2.1: Time 
Period and Frequency for 
Collecting AE and SAE 
Information, Section 9.2.3: 
Follow-up of AEs and SAEs, 
Description of Change 
Added information on safety 
reporting related to SARS-CoV-2 
and COVID-19 eligibility and 
vaccine guidance. 
Brief Rationale 
Added to optimize 
adverse event (AE) 
and serious adverse 
event (SAE) 
collection, safety, 
participant eligibility, 
and vaccination in the 
context of the 
COVID-19 
pandemic. 


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Summary of key changes for Revised Protocol 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 2: Schedule of Activities, 
Section 3.1: Study Rationale, 
Section 3.1.1: Research 
Hypothesis, Section 4: Objectives 
and Endpoints, Section 5.1: 
Overall Design, Section 5.1.1: 
Screening Period, Section 5.1.2: 
Treatment Period, Section 5.2: 
Number of Participants, 
Section 5.4: Scientific Rationale 
for Study Design, Section 5.4.2: 
Rationale for Selection of Tumor 
Types, Section 5.5.4: Protocol 
Amendment 04: Rationale for SC 
Nivolumab Dose Coformulated 
with rHuPH20 in Part E (600 mg 
Q2W), Section 6.1: Inclusion 
Criteria, Section 6.2: Exclusion 
Criteria, Section 7: Treatment, 
Section 7.1: Treatments 
Administered, Section 7.1.3: 
Subcutaneous Administration of 
Nivolumab with rHuPH20, 
Section 7.4.3: Criteria to Resume 
Treatment, Section 9.4.7: 
Assessment of Subcutaneous 
Injection Site, Section 9.5.1: 
Pharmacokinetics and Anti-drug 
Antibody Sample Collection and 
Processing, Section 9.8: 
Biomarkers, Section 9.8.1: Tumor 
Tissue Specimens, 
Section 9.10.1: Patient 
Experience and Preference 
Questionnaire, Section 9.10.2: 
Qualitative Patient Interviews, 
Section 10.3.3: Pharmacokinetic 
Analyses 
Added Table 2-2 to provide a 
screening procedural outline 
specific for Part E and updated 
Table 2-3 and Table 2-4 to add on- 
treatment and follow-up procedures 
for Part E. Added relevant 
information specific to Part E (eg, 
research hypothesis, objectives and 
endpoints, study design, inclusion 
of mUC participants, 
inclusion/exclusion criteria, PK 
sampling, biomarker sampling, 
 
and patient-reported outcomes). 
Described the new coformulated 
drug product (SC nivolumab and 
rHuPH20 pre-mixed in 1 vial with 
the same dose ratio) to be 
introduced to Part E participants. 
Any ongoing participants in Parts C 
or D may also be switched to the 
coformulated drug product. 
Updated to provide 
information for 
Part E cohort 
including study 
design, objectives, 
study population, 
dosing, and 
introduction of 
coformulated drug 
product. 


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Summary of key changes for Revised Protocol 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 3.2.1: Nivolumab 
Mechanism of Action, 
Section 3.2.2: Nivolumab Clinical 
Activity, Section 3.2.3: Clinical 
Pharmacology of Nivolumab, 
Section 5.4.4: Rationale for Two 
Year Duration of Treatment 
Updated background information 
on mechanism of action for 
nivolumab, nivolumab clinical 
activity in several tumor types, 
nivolumab PK information, and 
rationale for two year duration of 
treatment. 
Updated to align with 
the current nivolumab 
IB and to provide 
current background 
information relevant 
to this amendment. 
Section 3.2.4.2: Clinical 
Pharmacology of Recombinant 
Human Hyaluronidase PH20 
Added DARZALEX FASPRO™ 
and PHESGO™ to list of approved 
products in the United States (US) 
and/or European Union (EU) that 
are in combination with rHuPH20. 
Updated to align with 
information in 
updated rHuPH20 IB. 
Section 3.3: Benefit/Risk 
Assessment 
Added updated safety and 
immunogenicity results from Part C 
and Part D. 
Updated for 
completeness since 
last protocol revision. 
Section 4: Objectives and 
Endpoints, Section 10.3.2: Safety 
Analyses 
Updated secondary endpoints to 
include treatment-related adverse 
events (TRAEs), treatment-related 
serious adverse events (TRSAEs), 
and TRAEs leading to 
discontinuation. 
Clarified that safety 
analyses include 
collection of TRAEs 
and TRSAEs. 
Section 6.1: Inclusion Criteria 
Updated inclusion criteria related to 
tumor types, tumor tissue 
collection, tumor programmed 
death ligand 1 (PD-L1) expression, 
and reproductive 
status/contraceptive requirements 
for females. 
Updated for clarity 
and to provide 
inclusion criteria for 
Part E. 


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Summary of key changes for Revised Protocol 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 6.1: Inclusion Criteria, 
Section 9.2.5: Pregnancy, 
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception 
Removed contraception 
requirements for all males. Updated 
duration of pregnancy surveillance 
from at least 5 half-lives to at least 
5 months after study product 
administration. 
Updated to align with 
modified nivolumab 
contraception and 
pregnancy 
requirements. 
Updated male 
contraception 
requirements due to 
no genotoxicity and 
no transmission of 
biologically relevant 
amount to women of 
childbearing potential 
(WOCBP) partner. 
Section 6.2: Exclusion Criteria 
Updated exclusion criteria related 
to brain metastases, leptomeningeal 
metastases, treatment with 
corticosteroids/immunosuppressive 
medications, prior malignancy, 
HIV/AIDs, women who are not 
breastfeeding, serious or 
uncontrolled medical disorders, 
complementary medicines, hepatitis 
B virus (HBV)/hepatitis C virus 
(HCV) and prior radiation therapy. 
Updated for clarity 
and to provide 
exclusion criteria for 
Part E. 
Section 7.4.1: Dose 
Modifications, Section 7.4.2: 
Dose Delay Criteria, 
Section 7.4.3: Criteria to Resume 
Treatment, Section 7.7.4: 
Treatment of Infusion-related 
Reactions, Section 9.2: Adverse 
Events, Appendix 6: Management 
Algorithms 
Modified criteria for dose delay, 
resume, and discontinuation. Added 
Table 7.4.1-1. Updated treatment 
recommendations for 
infusion-related reactions. Replaced 
management algorithms. 
Updated to align with 
CTCAE v5. 
Section 7.4.4.2: 
Recommendations for 
Management of Hepatic Events in 
Nivolumab Participants with 
HCC, Appendix 6: Management 
Algorithms 
Added further guidance if no 
response to mycophenolate mofetil 
in hepatocellular carcinoma (HCC) 
participants. Added specific 
information for HCC participants to 
Hepatic Adverse Event 
Management Algorithm. 
Updated for clarity 
and to provide 
information specific 
to HCC participants. 


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Summary of key changes for Revised Protocol 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 7.7.1: Prohibited and/or 
Restricted Treatments, 
Section 8.1.2: Nivolumab 
Treatment Beyond Disease 
Progression, Section 9: Study 
Assessments and Procedures, 
Section 9.2.1: Time Period and 
Frequency for Collecting AE and 
SAE Information, Section 9.8.4: 
Additional Research Collection 
Updated information on prohibited 
and restricted treatments 
(corticosterioids, radiation therapy, 
and complementary preparations). 
Updated information on treatment 
beyond progression. Updated 
information regarding signs of 
cardiac or pulmonary toxicity. 
Indicated that all nonserious AEs 
should be collected continuously 
during treatment and for a 
minimum of 100 days following 
discontinuation. Updated 
information on additional research 
collection for US sites. 
Updated for clarity. 
Section 7.4.3: Criteria to Resume 
Treatment, Section 8.1: 
Discontinuation from Study 
Treatment, Section 8.1.1: 
Nivolumab Dose Discontinuation 
Added information for resumption 
or discontinuation of treatment after 
events that lead to a prolonged 
delay in dosing (defined in 
protocol, with exceptions listed). 
Updated to align with 
modified nivolumab 
clinical approaches 
for dose delay. 
Section 9.4.4: Clinical Safety 
Laboratory Assessments 
In Table 9.4.4-1, modified 
chemistry laboratory assessment 
panels and removed urinalysis 
laboratory assessment panels at 
screening. 
Updated to align with 
modified nivolumab 
clinical safety 
approaches for 
laboratory 
assessments. 
Section 10.1: Sample Size 
Determination 
Modified for clarity and added 
precision estimates for PK endpoint 
in Part E. 
Updated for clarity 
and to provide 
statistical details on 
calculation of 
precision estimates 
for Part E. 


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Summary of key changes for Revised Protocol 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 10.3.8: Interim Analyses 
Added information about Interim 
Analysis 5, to occur when all 
participants in Part E have 
completed a minimum of 6 months 
of follow-up from first dose date. 
Updated to provide 
details on Interim 
Analysis 5. 
Appendix 2: Study Governance 
Considerations 
In the Monitoring section, removed 
text indicating central review of 
data and scheduling of on-site 
visits. Provided additional details of 
information provided in the 
monitoring plan. 
Updated for clarity 
and to allow 
flexibility for 
monitoring. 
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception 
Updated information on WOCBP 
definition and methods of 
contraception. Removed 
contraception guidance for male 
participants with partners of child 
bearing potential. 
Updated 
contraception 
guidance for 
participants for 
accuracy and clarity. 
 
Overall Rationale for the Revised Protocol 03, 25-Oct-2019 
Actual bioavailability from participants dosed at 720 mg and 960 mg SC nivolumab with rHuPH20 
no clinically meaningful differences in incidence of AEs (regardless of causality or related) of any 
grade or Grade 3, 4, or 5 among dose treatment group, BMS considers a SC dose which provides 
exposures between the doses of 3 mg/kg Q2W and 10 mg/kg Q2W to have an acceptable and 
similar risk/benefit profile across tumors/indications. 
Revised protocol 03 was warranted in order to provide updated data and dose rationale, and 
introduces the 1200 mg dose for Parts C & D. Primary objective of this portion of the study does 
not change. Purpose of Part D is to assess actual PK of 1200 mg across multiple tumors and body 
weight ranges in the context of continuous SC dosing. Body weight (BW) tertiles within the IV 
program represent a wide distribution of participants (up to 65kg, 65-90kg, >90kg), this revised 
(Group 1 & 3) 
Given that there were


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protocol also increases the number of participants in the Part D in order to enroll approximately 
thirty-six participants in total to represent broad range of body weights as seen in IV program 
(approximately ten participants within the lowest BW tertile). 
 
Summary of key changes for Revised Protocol 03 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 2, Table 2-1 Screening 
Procedural Outline; Tumor Tissue 
Sample 
 
- Updated to allow for 
approximately 15 participants in 
Part D who do not meet tissue 
requirements 
- Clarification 
-Updated the number of participants in 
Part D that may not meet tissue 
requirements, as the expected total 
number of participants in Part D has 
been updated. 
Section 2, Table 2-1 Screening 
Procedural Outline, SAE 
Line item for collection of SAE 
added 
Clarification to align table with 
procedures as listed in protocol. 
Section 2, Table 2-2; On- 
Treatment Procedural Outline, 
Study Drug Administration 
- Updated to reflect the cross-over 
of participants from IV dosing in 
Part C to 1200 mg Q4W SC 
nivolumab 
-Clarification of maximum 
treatment duration (regardless of 
IV or SC) 
- Dose has been identified as 1200 mg 
Q4W, and protocol has been updated 
to reflect specific dose to be 
administered 
- Maximum treatment duration has be 
clarified to specify 104 weeks from 
first dose of nivolumab (IV or SC). 
Section 3, Introduction 
General update on nivolumab and 
SC nivolumab 
Updated to reflect the most recent 
understanding of nivolumab and 
immuno-oncology. 
Synopsis, Section 3.1.1, Study 
Rationale 
Updated to reflect the identified 
dose of nivolumab SC 
Dose has been identified as 1200 mg 
Q4W, and protocol has been updated 
to reflect specific dose to be 
administered 
Section 3.2.2 Clinical 
Pharmacology of Nivolumab 
Updated to provide information on 
SC PPK model. 
Updated with data on modeling 
Section 3.3 Benefit/Risk 
Assessment 
Updated to describe results from 
interim analyses of Parts A and B, 
and the expected exposure. 
Updated to include interim data 
Section 4, Table 4-1 Objectives 
and Endpoints 
Endpoint for Part C PK analyses 
separated from Parts A, B, and D. 
This update provides clarification that 
only Ctau will be assessed from Part C 
participants. This update serves to 
clarify in the table, and is not a change 
to endpoints or analyses. 
Section 5.1, Overall Design 
Updated to the anticipated number 
or participants in Part D, and to 
reflect the enrollment of Parts A 
and B. 
To include the updated dose of 
nivolumab SC to be used in Parts 
C and D. 
Updated to reflect Part D updates 


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Summary of key changes for Revised Protocol 03 
Section Number & Title 
Description of Change 
Brief Rationale 
Updated Figure with new numbers 
for Part D, and identified dose 
included. 
Section 5.2 Number of 
Participants 
Updated to reflect new total 
number of participants expected. 
Number of participants for Part D was 
increased to 36 from 10 in the 
previous number. 
Additionally, actual enrollment of 
Parts A and B was reflected in this 
version. 
Section 5.4, Scientific Rationale 
for Study Design 
Updated to reflect the three doses 
under study, and that PK data from 
Parts A and B were used to 
establish the recommended dose of 
1200 mg. 
Updated to include the 1200 mg dose 
to be studied in Part C and D. 
Section 5.5.2, Justification of 
Subcutaneous Doses of 
Nivolumab 
Updated with PK data from 960 
mg dose in Groups 3 and 4. 
Updated with interim data 
Section 5.5.3, Revised Protocol 
03: Selection of SC Nivolumab 
Dose in Part D and D (1200 mg 
Q4W) 
Updated with justification for 1200 
mg Q4W dose 
PK data from participants receiving 
the 720 mg and 960 mg nivolumab SC 
dose in Parts A and B, and historical 
nivolumab IV data across several 
tumor type was used to characterize 
the estimated exposures for the 1200 
mg dose Q4W to be administered in 
Part D. 
Section 6.1 Inclusion Criteria, h) 
Updated to allow enrollment of 
approximately 15 participants who 
do not meet tissue requirements. 
Based on the increased participant 
number planned for D, the permitted 
number of participants not meeting the 
minimum tissue requirement was also 
updated. 
Section 7.1, Treatments 
Administered; Table 7.1-1: 
Selection and Timing of Dose 
Updated with 1200 mg Q4W dose 
for Part D 
Updated to include identified dose. 
Section 7.1.3 Subcutaneous 
Administration of Nivolumab 
with rHuPH20 
Updated to reflect the details of 
1200 mg nivolumab SC + 
rHuPH20 dosing for participants in 
Part C and D. 
Updated for 1200 mg dose. 
Section 7.4.4.1 Program Safety 
Management Algorithms; 
Appendix 6 
Added myocarditis to the list of 
algorithms provided. 
Updated algorithms to align with the 
most recent version of the nivolumab 
IB 
Section 8.1 Discontinuation from 
Study Treatment 
Added Pregnancy to the list of 
reasons requiring discontinuation 
form study treatment 
Updated to specify that treatment 
should be discontinued in the event of 
pregnancy. 
Section 9.3 Overdose 
Updated language and reporting 
requirements 
Updated language is aligned with the 
reporting requirements detailed in 
Appendix 3. 


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Summary of key changes for Revised Protocol 03 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 9.4.7, Assessment of 
Subcutaneous Injection Site 
Assessments for injection site 
reaction following 1200 mg dose 
in Parts C and D have been 
updated. 
Included updated assessment timings 
for Part C and D. 
Section 9.8, Biomarkers 
• 
Description of biomarkers 
of interest and collections 
to be performed have 
been updated. 
• 
Collection of MDSCs has 
been removed. 
• 
Updated tissue 
requirements described 
for Part D. 
Description of biomarkers to be 
studied clarified. 
Removed MDSC collection and 
updated requirements for Part D. 
Section 9.10.1 Patient Experience 
and Preference Questionnaire; 
Section 9.10.2 Qualitative Patient 
Interviews 
Updated to add collections in Part 
D. 
Added Part D. 
Section 10.1 Sample Size 
Determination 
Updated to include rationale for 36 
participants in Part D. 
Updated rationale for the number of 
PK evaluable participants in Part D. 
Section 10.3.3 Pharmacokinetic 
Analyses 
Updated with analyses for PK 
Updated to reflect that Ctau will be 
the primary PK parameter for Part C. 
Section 10.3.8 Interim Analyses 
Updated to contain details of 
Interim Analyses 3 and 4. 
IA 3 will occur when the first 10 
participants in Part D have completed 
1 dose of SC nivolumab. 
IA4 will occur when all participants in 
Part D have completed a single dose 
of nivolumab. 
Appendix 3 Adverse Events and 
Serious Adverse Events; 
Definitions and Procedures for 
Recording, Evaluating, Follow-up 
and Reporting 
Updated. 
Updated to contain the reporting 
language. 
Appendix 6, Management 
Algorithms 
Updated to include the myocarditis 
algorithm. 
Myocarditis algorithm was added to 
align with the most recent nivolumab 
investigator brochure. 
 
Overall Rationale for the Revised Protocol 02, 11-Dec-2018 
Part B of the study will include both assigned and randomized participants; as a result, the study 
design has been updated. In Part B, 30 participants will be dosed. The first 10 participants will be 
assigned to Group 3. The next 20 participants will be randomized 1:1 into Group 2 and Group 4. 
All participants will undergo pre- and on-treatment biopsies on Cycle 1 Day 15 for Part A, Part B, 
and Part D. This is recommended but optional for Part A and mandatory for Part B and Part D. 
Timing, method of collection, and type of tumor tissue specimens from biopsy has been updated. 


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Up to 5 participants from each part of the trial (part A, B and D) who do not meet tissue 
requirements may be allowed treatment after discussion with the Medical Monitor. Other 
exceptions may be provided at the discretion of the Medical Monitor. 
Guidelines and criteria for participants with HCC have been added that take into account the 
anticipated compromise of baseline liver function for these participants. 
Additional changes added to provide clarity around protocol-defined populations and activities. 
Revisions apply to future participants enrolled in the study, and where applicable, to all 
participants currently enrolled. 
 
Summary of key changes for Revised Protocol 02 
Section Number & Title 
Description of Change 
Brief Rationale 
All 
Minor formatting and typographical 
corrections. 
Minor, therefore have not been 
summarized. 
All 
Minor clarifications throughout 
document for consistency across 
sections. 
Minor, therefore have not been 
summarized. 
Synopsis, Number of Participants 
and Treatment Arms and Duration 
Synopsis, Figure 1 
Section 2 Schedule of Activities, 
Table 2-2 
Section 5.1, Figure 5.1-1 
Section 5.1 Overall Design 
Section 5.2 Number of participants 
7.2 Method of Treatment 
Assignment 
In Part B, 30 participants will be 
dosed. The first 10 participants will 
be assigned to Group 3. The next 20 
participants will be randomized 1:1 
into Group 2 and Group 4. 
Change to randomization of 
participants in Part B 
Synopsis Study Treatment Table 
Section 7 Treatment, Table 7-1 
Footnote b 
Deleted text: If needed, rHuPH20 
can be obtained as local commercial 
product in countries if allowed by 
local regulations or through the 
investigating site’s standard 
prescribing procedures. 
 
(rHuPH20) is not commercially 
available. 
Section 2 Schedule of Activities, 
Table 2-1 
Removed text to refer to the DM 
ECG study guidelines. 
Document no longer available. 
Section 2 Schedule of Activities, 
Table 2-2 
Removed Inclusion/Exclusion 
Criteria row under Eligibility 
Assessments. 
Inclusion/Exclusion criteria only 
assessed during screening visit. 
Section 2 Schedule of Activities, 
Table 2-3 
Section 5.1.3 Safety Follow-up 
Period 
Frequency of scans for response and 
survival follow-up changed to every 
12 weeks. 
Prior text reflected continuation of 
on-treatment scan frequency in 
error. 
Section 2 Schedule of Activities, 
Table 2-1 
5.1.1 Screening period 
All participants will undergo pre- 
and on-treatment biopsies on Cycle 
1 Day 15 for Part A, Part B, and 
Part D. This is recommended but 
optional for Part A and mandatory 
Timing, method, and type of tumor 
tissue specimens from biopsy 
defined, including exceptions for 
participants who had a biopsy in the 
preceding 12 months. 


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Summary of key changes for Revised Protocol 02 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 6.1 Inclusion Criteria, 2) 
Type of Participants and Target 
Disease characteristics, h) 
Section 9.8, Table 9.8-1 
Section 9.8.1 Tumor Tissue 
Specimens 
for Part B and Part D. Sufficient, 
recent tumor tissue FFPE block or 
unstained slides 
from a metastatic tumor lesion or 
from an unresectable primary tumor 
lesion, which has not been 
previously irradiated, must be 
submitted. Up to 5 participants from 
each part of the trial (part A, B and 
D) who do not meet tissue 
requirements may be allowed 
treatment after discussion with the 
Medical Monitor. Other exceptions 
may be provided at the discretion of 
the Medical Monitor. 
Section 6.1 Inclusion Criteria, 2) 
Type of Participants and Target 
Disease characteristics, a), iv) 
Added the following inclusion 
criteria for HCC participants: 
(1) lenvatinib added 
(7) Participants with chronic 
hepatitis B virus (HBV) infection 
must be on antiviral therapy and 
must have HBV DNA < 500 IU/mL. 
(8) Platelets ≥ 60 x 103/µL 
The added criteria take into account 
anticipated compromise of baseline 
liver function in participants with 
HCC. Addition of lenvatinib reflects 
newly approved therapy for 
participants with HCC. 
Section 6.1 Inclusion Criteria, 2) 
Type of Participants and Target 
Disease characteristics, a) vi) 
vi) In Part B, other solid tumor 
types may be considered for 
enrollment at the discretion of the 
Medical Monitor. 
Other solid tumor types can be 
enrolled in Part B at the Medical 
Monitor’s discretion in addition to 
those identified in Part A. 
Section 6.1 Inclusion Criteria, 2) 
Type of Participants and Target 
Disease characteristics, f) 
Added text indicating that there 
were separate criteria for screening 
laboratory values for platelets, 
AST/ALT, and total bilirubin for 
HCC participants. 
The added criteria take into account 
anticipated compromise of baseline 
liver function in participants with 
HCC. 
6.2 Exclusion Criteria, 1) Medical 
conditions, p 
Exclusion for positive urine screen 
for drugs of abuse is not applicable 
per this protocol revision. 
Not applicable 
6.2 Exclusion Criteria, 1) Medical 
conditions, q 
q) Participants must not have any 
positive test result for HBV or 
hepatitis C virus (HCV) indicating 
presence of virus, eg, Hepatitis B 
surface antigen (HBsAg, Australia 
antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive 
(except if HCV-RNA negative). For 
HCC, participants with chronic 
HBV infection are permitted and 
must be on antiviral therapy and 
must have HBV DNA < 500 IU/mL. 
Excluding participants with hepatitis 
B/C virus positive test results except 
for HCC participants with chronic 
HBV infection on antiviral therapy 
and HBV DNA < 500 IU/mL. 


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Summary of key changes for Revised Protocol 02 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 7.4.2 Dose Delay Criteria 
Added dose delay criteria for 
participants with HCC. 
The added criteria take into account 
anticipated compromise of baseline 
liver function in participants with 
HCC. 
Section 7.4.3 Criteria to Resume 
Treatment 
Added criteria to resume treatment 
for participants with HCC. 
The added criteria take into account 
anticipated compromise of baseline 
liver function in participants with 
HCC. 
Section 7.4.4.2 Management 
Algorithms for Immuno-Oncology 
Agents 
Section 7.4.4.1 Program Safety 
Management Algorithms 
Section 7.4.4.2 Recommendations 
for Management of Hepatic Events 
in Nivolumab Participants with 
HCC 
Added a subsection for tumor- 
specific recommendations for the 
management of hepatic events in 
nivolumab participants with HCC. 
The added recommendations take 
into account anticipated 
compromise of baseline liver 
function in participants with HCC. 
Section 8.1.1 Nivolumab Dose 
Discontinuation 
Added dose discontinuation criteria 
for participants with HCC 
The added criteria take into account 
anticipated compromise of baseline 
liver function in participants with 
HCC. 
Section 9.2.7 Potential Drug- 
induced Liver Injury (DILI) 
Added definition of DILI for 
participants with HCC. 
The added criteria take into account 
anticipated compromise of baseline 
liver function in participants with 
HCC. 
Section 10.2 Populations for 
Analyses 
The Evaluable PK Participants 
population includes all participants 
in the PK population who 
completed Cycle 1 SC and Cycle 2 
IV and with adequate PK profiles 
for accurate estimation of PK 
parameters. Inadequate PK profiles 
are defined as 3 or more 
missed/unevaluable PK samples out 
of the 9 planned for the 2 first 
cycles in Part A and B and 8 
planned for the 2 first cycles in Part 
D, including 2 or more PK samples 
being from Cycle 1. 
Further described the Evaluable PK 
Participants population and defined 
what is considered an inadequate 
PK profile. 
Section 10.3.3 Pharmacokinetic 
Analyses 
Deleted Endpoint/Statistical 
Analysis Method table 
Redundant to presented text. 
Section 10.3.8 Interim Analyses 
Removed reference to number of 
interim analyses. 
Details regarding interim analyses 
can be found in the Statistical 
Analysis Plan. 
Removed reference to number of 
interim analyses to allow greater 
flexibility to add additional analyses 
if necessary. 


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Summary of key changes for Revised Protocol 02 
Section Number & Title 
Description of Change 
Brief Rationale 
Appendix 03 Adverse Events 
Updates were made to the following 
sections: 
Adverse Events 
Reporting of SAEs to Sponsor or 
Designee 
BMS updated required language for 
the Adverse Events appendix. 
Appendix 06 - Hepatic Adverse 
Event Management Algorithm 
Footnote stating I-O therapy may be 
delayed, rather than discontinued, if 
AST/ALT ≤ 8 x ULN or T.bili ≤ 5 x 
ULN was removed. 
Language was modified to align 
protocol with current Nivolumab 
Investigator’s Brochure and 
nivolumab program safety 
parameters. 
Appendix 06 - Hepatic Adverse 
Event Management Algorithm 
Added a Hepatic Adverse Event 
Management Algorithm for 
Participants with HCC. 
The added algorithm takes into 
account anticipated compromise of 
baseline liver function in 
participants with HCC. 
Appendix 10 - Injection Site 
Selection and Preparation and 
Administration of Study Drug 
Removed reference to figure. 
Nivolumab (BMS-986298) alone 
will be administered as 1 to 4 
injections. 
Figure not located in appendix. 
Added language for subcutaneous 
administration of nivolumab alone. 
 
Overall Rationale for the Revised Protocol 01, 05-Jul-2018 
The study will no longer include SC nivolumab Process D drug substance; as a result, the study 
design has been updated. Participants in Part D will receive SC nivolumab Process C drug 
substance with rHuPH20 manually by syringe beginning at Cycle 1 and will not receive study 
treatment by syringe pump. 
All participants are required to have assessment of pre-treatment tumor PD-L1 expression. Results 
of tumor PD-L1 assessment is not required for enrollment/randomization. PD-L1 status for 
participants in Part A must be available prior to opening Part B for enrollment. Each treatment 
group 
or with microsatellite 
instability-high/mismatch repair deficient (MSI-H/dMMR) status (for participants with colorectal 
cancer). Additional participants may be enrolled to meet this minimum accrual. 
Additional biomarker and pharmacodynamic assessments have been added to the study. 
Revisions apply to future participants enrolled in the study, and where applicable, to all 
participants currently enrolled. 
 
Summary of key changes for Revised Protocol 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Synopsis: Overall Study Design 
Section 2: Schedule of Activities 
Section 5.1: Overall Design 
Table 2.2 On-treatment Procedural 
Outline has been updated in Study 
Drug Administration. 
Change in drug substance and dose 
regimen for study Part D. 


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Summary of key changes for Revised Protocol 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Synopsis: Overall Study Design 
Section 6.1: Inclusion Criteria 
Section 5.1: Overall Design 
Added inclusion criteria 2.j. 
Table 2.1 Screening Procedural 
Outline has been updated in 
Eligibility Assessments. 
Inclusion criteria added to require all 
participants to have tumor PD-L1 
expression measured by IHC or prior 
documented MSI-H/dMMR status (for 
CRC) prior to study treatment. 
Section 5.4 
Removed Section 5.4.2 (Rationale 
for Inclusion of Process C and 
Process D Drug Substance) 
Rationale for use of Process D is not 
needed. 
Section 9.5.1 
Table 2.2 On-treatment Procedural 
Outline has been updated in 
Pharmacokinetic and 
Immunogenicity Assessments. 
Added reference to Part D PK and 
immunogenicity sample collection 
schedule table. 
Section 9.4.4 
Table 2.2 On-treatment Procedural 
Outline has been updated in 
Laboratory Tests. 
Simplified description of clinical 
laboratory tests to be performed in 
Cycle 3 and beyond in Table 2-2. 
Updated list of clinical laboratory tests 
in Section 9.4.4. 
Section 9.8: Biomarkers 
Section 9.8.1: Tumor Tissue 
Specimens 
Added collection of serum 
samples to Table 9.8-1. 
Additional biomarker and 
pharmacodynamic assessments have 
been added to the study. 
Section 3.2.2: Clinical 
Pharmacology of Nivolumab 
Updated pharmacokinetics text. 
Updated pharmacokinetics section. 
All 
Minor formatting and 
typographical corrections 
Minor, therefore have not been 
summarized