Clinical trial NCT04340193
Conditions: Cancer, Hepatocellular
Sponsor: Bristol-Myers Squibb
Start date: 2020-09-14; Completion date: 2023-12-12
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of nivolumab with and without ipilimumab in combination with Trans-arterial ChemoEmbolization (TACE) to TACE alone in participants with intermediate liver cancer.

Detailed description:

Arms: arm 1: TACE (Trans-arterial ChemoEmbolization) arm 2: None arm 3: None
Interventions: intervention 1: nivolumab intervention 2: ipilimumab intervention 3: TACE
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: TACE (Trans-arterial ChemoEmbolization)

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Randomized, Multi-center, Double-blinded, Placebo-controlled Phase 3 Study of Nivolumab 
and Ipilimumab, Nivolumab Monotherapy, or Placebo in Combination With Trans-arterial 
ChemoEmbolization (TACE) in Patients With Intermediate-stage Hepatocellular Carcinoma 
(HCC) 
 
NCT Number: NCT04340193 
Document Date (Date in which document was last revised): 01 December 2021 


Approved v 21.0 
930142607 2.0 
 
Page: 
Protocol Number: 
IND Number: 
EX-US 
1 
CA20974W 
142,795 
Non-IND 
EUDRACT Number: 2019-002790-58 
Date: 05-Aug-2019 
Revised Date: 01-Dec-2021 
 
CLINICAL PROTOCOL CA20974W 
A Randomized, Multi-center, Double-blinded, Placebo-controlled Phase 3 Study of Nivolumab 
and Ipilimumab, Nivolumab Monotherapy, or Placebo in Combination with Trans-arterial 
ChemoEmbolization (TACE) in Patients with Intermediate-stage Hepatocellular Carcinoma 
(HCC) 
(CheckMate 74W: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 74W) 
Short Title: Nivolumab and 
Ipilimumab or Nivolumab or 
Placebo Plus TACE in 
Intermediate-stage Liver Cancer 
Protocol Amendment Number: 01 
Incorporates Administrative Letters 02, 03, and 04 
Monitor 
 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Telephone (office): 
Email: 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Telephone (office): 
Email: 
 
24-hr Emergency Telephone Number 
USA: 
International: 
 
Bristol-Myers Squibb Research and Development 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Avenue de Finlande 4 
B-1420 Braine-l’Alleud, Belgium 
6-5-1 Nishi-Shinjuku, Shinjuku-ku, 
Tokyo, 163-1327, Japan 
 
 
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 
Medical 


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study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
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 01 
01-Dec-2021 
BMS determined 
to stop the study. As a result, the study 
will be unblinded and the procedures for participants in treatment or in 
follow-up simplified. 
Administrative 
Letter 04 
16-Jul-2021 
Updated study personnel information. 
Administrative 
Letter 03 
28-Apr-2021 
Removed the 24-hr Emergency Telephone Number listed for Japan. This 
number will be retired, so Japan should use the provided international 
number instead. 
Administrative 
Letter 02 
26-Jan-2021 
Updated study personnel information. 
Administrative 
Letter 01 
28-Jul-2020 
Updated study personnel information. 
Original Protocol 
05-Aug-2019 
Not applicable 


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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: 
 
Therefore, a decision was made by Bristol-Myers Squibb in September 2021 to stop the study. 
Importantly, there is no change to the understanding of the safety profile of nivolumab in 
combination with ipilimumab and trans-arterial chemoembolization (TACE) for the treatment of 
patients with intermediate-stage hepatocellular carcinoma (HCC). 
Protocol Amendment 01 describes the modification to study procedures. All participants must be 
re-consented upon approval and implementation of Protocol Amendment 01. These changes affect 
all participants and should be implemented when Protocol Amendment 01 is implemented at the 
site. 
Key changes in Protocol Amendment 01 include: 
• Details of closure of the study with provision for participants currently on treatment or in 
the follow-up period to continue in the study as per the current protocol. 
• The study will be unblinded. 
• Removal of placebo infusions for participants in Arms B and C. 
• Removal of pharmacokinetic (PK), immunogenicity (IMG), biomarker, and patient- 
reported outcome (PRO) assessments. Only safety assessments will be conducted. 
• Removal of on-study imaging assessments. Sites should continue imaging assessments as 
per local standard of care. 
• Removal of study-related efficacy assessments. Sites should continue efficacy assessments 
as per local standard of care. 
• Align dose modification criteria and immuno-oncology agent management algorithms with 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
• Add the collection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection-related adverse events (AEs) and serious adverse events (SAEs) to evaluate the 
impact of SARS-CoV-2 on participant safety and add coronavirus disease 2019 (COVID- 
19) vaccination information for study participants. 
• Incorporate country-specific information for France, Czech Republic, and China; 
incorporate additional updates to improve alignment across protocol sections and/or clarify 
expectations for assessments, sample collections, and treatment administration. 
 
This amendment incorporates the changes from the approved Administrative Letter 02, 03 and 04 
that are detailed in the Document History but not listed in the Summary of Key changes below. 


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Additional revisions, including to sections of the Protocol Synopsis, have been made to align the 
protocol with respect to these changes. 
Changes instituted in Protocol Amendment 01 should override any existing protocol requirements 
in the event of any apparent discrepancies. 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
All 
Minor editorial changes. 
Minor, therefore have not 
been summarized. 
All 
Where applicable, “designee” 
was updated to “Clinical 
Scientist” in the text. 
Clinical Scientist will be the 
designee for the Medical 
Monitor. 
Section 2: Schedule of 
Activities 
Section 5.1.2: Treatment 
Period 
Added references to Appendix 
9 where applicable. 
• Table 2-1: Screening 
Procedural Outline 
(CA20974W), Tumor 
Sample Submission Row. 
• Table 2-2: On-treatment 
Procedural Outline 
(CA20974W), Footnote c. 
• Table 2-3: Follow-up 
Procedural Outline 
(CA20974W), Footnote d. 
• Section 6.1, 2), c), ii). 
• Table 9.8-1: CA20974W 
Biomarker Sampling 
Schedule All Participants, 
Footnote d. 
• Text in Sections 5.1.2, 8.1, 
9.2.6, 9.5, 9.6, and 9.8. 
To provide a reference to the 
country-specific requirements 
where applicable. 
Section 6.1: Inclusion 
Criteria, 2) Type of 
Participant and Target 
Disease Characteristics 
Section 8.1: Discontinuation 
from Study Treatment 
Section 9.2.6: Pregnancy 
Section 9.5: 
Pharmacokinetics and 
Immunogenicity 
Section 9.6: 
Pharmacodynamics 
Section 9.8: Biomarkers 
Table 2-1: Screening 
Procedural Outline 
(CA20974W) 
Table 2-2: On-treatment 
Procedural Outline 
(CA20974W) 
Language added to include the 
collection of SARS-CoV-2 
infection-related AEs and 
SAEs. 
To allow for the evaluation of 
the impact of SARS-CoV-2 
infection on participant safety. 
Table 2-3: Follow-up 
Procedural Outline 
(CA20974W) 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 9.2.2: Time Period 
and Frequency for 
Collecting AE and SAE 
Information 
Section 9.2.4: Follow-up of 
AEs and SAEs 
Table 2-1: Screening 
Procedural Outline 
(CA20974W) 
Table 2-2: On-treatment 
Procedural Outline 
(CA20974W) 
Table 2-3: Follow-up 
Procedural Outline 
(CA20974W) 
AE language updated to 
mention CTCAE version 5.0 
grading. 
To identify the NCI CTCAE 
standards used in the study. 
Table 2-2: On-treatment 
Procedural Outline 
(CA20974W) 
Section 5.1.2: Treatment 
Period 
Section 7.1.2: TACE 
Procedure 
TACE timing should be 7 days 
(+ 3 days). Removed the 
minus. 
To clarify the timing of the 
TACE procedure, as it was 
found to cause confusion. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Table 2-2: On-treatment 
Procedural Outline 
(CA20974W) 
1. Updated Column 2 header 
to indicate that ipilimumab 
is administered Q6W. 
2. Pregnancy language 
updated to include a 72- 
hour extension. 
Additionally, “monthly” 
was updated to “every 28 
days.” 
3. Added Urinalysis row. 
4. Language for Efficacy, PK 
and IMG, Biomarker, and 
Outcomes Research 
Assessments, and Clinical 
Drug Supplies updated to 
reflect changes made to on- 
treatment study procedures 
as a result of study 
termination. 
5. Added footnote d. 
1. Correction. 
2. To accommodate 
scenarios in which 
pregnancy test results 
cannot be obtained within 
the standard 24-hour 
window. Clarified the 
time period for monthly 
collection. 
3. To clarify that urinalysis 
is required during on 
treatment as outlined in 
Section 9.4.4. 
4. To describe the 
modifications made to 
study procedures as a 
result of study 
termination. 
5. To clarify timing of 
nivolumab and 
ipilimumab dosing. 
Table 2-3: Follow-up 
Procedural Outline 
(CA20974W) 
Review of Subsequent Cancer 
Therapy; Efficacy, PK and 
IMG, Biomarker, and 
Outcomes Research 
Assessments; Survival Status; 
and Footnote b language 
updated to reflect changes 
made to follow-up study 
procedures as a result of study 
termination. 
To describe the modifications 
made to study procedures as a 
result of study termination. 
Section 3.1: Study Rationale Removed “preliminary” to 
describe CA209040 data. 
Added approval of nivolumab 
with ipilimumab for the 
treatment of HCC in patients 
who previously received 
sorafenib. 
Minor text updates. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 3.1.1: Research 
Hypothesis 
Updated to reflect changes 
made to the research 
hypothesis as a result of study 
termination. 
To describe modifications 
made to the research 
hypothesis as a result of study 
termination. 
Section 3.1.2: Changes Per 
Protocol Amendment 01 
Added Section 3.1.2 to reflect 
changes made to the study 
procedures as a result of study 
termination. 
To describe the modifications 
made to study procedures per 
Protocol Amendment 01 as a 
result of study termination. 
Section 3.2.4: Nivolumab 
Mechanism of Action 
Updated description of 
nivolumab mechanism of 
action. 
Minor text updates. 
Section 3.2.7: Nivolumab 
Combined with Ipilimumab 
Clinical Activity 
Reference to additional 
information and description of 
the nivolumab/ipilimumab 
combination in the 
Investigator’s Brochure (IB). 
Minor text updates. 
Section 3.2.8: Nivolumab 
Combined with Ipilimumab 
in HCC 
Addition of CA2099DW to 
studies for the treatment of 
HCC. 
Minor text updates. 
Section 3.3: Benefit/Risk 
Assessment 
Addition of COVID-19 
vaccination language to the 
benefit/risk section. 
To inform that non-live 
COVID-19 vaccination is 
considered a simple 
concomitant medication 
within the study and that the 
efficacy and safety of non-live 
vaccines in this patient 
population is unknown. 
Section 4: Objectives and 
Endpoints 
Table 4-1: Objectives and 
Endpoints 
Added a description of the 
changes made to the objectives 
and endpoints as a result of 
study termination. 
Removed all objectives and 
endpoints from Table 4-1 
related to efficacy, quality of 
life (QoL), PRO, healthcare 
resource utilization (HCRU), 
PK, IMG, and biomarkers as a 
result of study termination. 
To describe the modifications 
made to the study objectives 
and endpoints as a result of 
study termination. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 5.1: Overall Design 
Figure 5.1-1: Study Design 
Schematic 
Section 7.2: Method of 
Treatment Assignment 
1. Language updated to 
reflect changes made to the 
study design as a result of 
study termination. 
2. Updated description of 
West region in Section 5.1, 
Figure 5.1-1, and Section 
7.2. 
3. Updated figure and added 
Footnote c to reflect 
changes made to the study 
design as a result of study 
termination. 
1. To describe the 
modifications made to the 
study design as a result of 
study termination. 
2. To clarify countries 
grouped under the West 
region. 
3. To visualize and clarify 
the study design 
modifications made as a 
result of study 
termination. 
Section 5.1.2: Treatment 
Period 
Section 5.1.3: Follow-up 
Period 
Section 5.1.4: Treatment 
Beyond Progression 
Section 5.1.5.1: 
Data 
Monitoring Committee 
Section 5.1.5.2: Blinded 
Radiology Review 
Committee 
Section 5.2: Number of 
Participants 
Section 5.4.2: Rationale for 
TTTP as a Dual Primary 
Endpoint 
Section 5.4.3: Rationale for 
OS as a Dual Primary 
Endpoint 
Section 5.4.4: Rationale for 
EFS as a Secondary 
Endpoint 
Section 5.4.5: Rationale for 
PFS as a Secondary 
Endpoint 
Section 7: Treatment 
Language in these sections 
updated to reflect changes 
made as a result of study 
termination. 
To describe the modifications 
made to the study design and 
assessments as a result of 
study termination. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Table 7-1: Study 
Treatments for CA20974W 
Section 7.1.1: Nivolumab 
and Ipilimumab 
Administration 
Section 7.1.2: TACE 
Procedure 
Section 7.2: Method of 
Treatment Assignment 
Section 7.3: Blinding 
Section 7.3.1: Unblinding at 
the Time of Disease 
Recurrence/Progression 
Section 8.1: Discontinuation 
from Study Treatment 
Section 5.4.2: Rationale for 
TTTP as a Dual Primary 
Endpoint 
Added to list of new drug 
options for treatment of 
advanced HCC. 
Minor text update. 
Section 5.4.7: Rationale for 
Shorter Infusion Times (30 
minutes) of Nivolumab and 
Ipilimumab 
Updated with approval of 
shorter infusion time. 
The 30-minute infusion time 
has been approved for 
nivolumab. 
Section 5.4.9: Rationale for 
2 Year Duration of 
Treatment with Nivolumab 
± Ipilimumab 
Removed references to 
Keynote 010 and Keynote 006. 
Based on updated analyses for 
the 2 studies, they have been 
removed from this section. 
Section 5.4.10: Rationale 
for Unblinding 
Added section. 
To continue safety monitoring 
after the decision to terminate 
the study. 
Section 6: Study Population 
Language updated to reflect 
enrollment closing as a result 
of study termination. 
To describe patient enrollment 
closing as a result of study 
termination. 
Section 7.1.1: Nivolumab 
and Ipilimumab 
Administration 
1. Added the word 
“approximately” before 
infusion times. 
2. Updated the text for 
weight-based dosing. 
1. To allow for variations of 
infusion timing. 
2. To clarify weight-based 
dosing calculations. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 7.1.2: TACE 
Procedure 
Added text to reference new 
Appendix 11. 
To align the protocol body 
with changes made to the 
appendices. 
Section 7.4.2: Nivolumab 
and Ipilimumab Dose Delay 
Criteria 
Updated text and added Table 
7.4.2-1 outlining the delay, 
resume, and discontinuation 
criteria for nivolumab and 
ipilimumab. 
To align with NCI CTCAE 
version 5.0 definitions and 
new terms. Tabular format 
done for ease of use. 
Section 7.4.3: Treatment of 
Nivolumab- or Ipilimumab- 
related Infusion Reactions 
Updated text to align with NCI 
CTCAE version 5.0. 
To align with NCI CTCAE 
version 5.0. 
Section 7.7.1: Prohibited 
and/or Restricted 
Treatments 
Updated extensive non- 
palliative radiation therapy to 
palliative or non-palliative 
radiation therapy. 
To prohibit and/or restrict 
palliative therapy during the 
study. 
Section 7.7.3: Permitted 
Therapy 
Added text for COVID-19 
vaccine. 
To include the risk that the 
efficacy and safety of 
COVID-19 vaccination in 
participants who are receiving 
nivolumab and/or ipilimumab 
are unknown. 
Section 8.1: Discontinuation 
from Study Treatment 
Added text about country- 
specific pregnancy 
requirements. 
To clarify that pregnant 
participants must discontinue 
study treatment where locally 
mandated. 
Section 8.1.1.1: Criteria for 
Nivolumab and Ipilimumab 
Treatment Discontinuation 
Modified text to align criteria 
for dose delay, resume, and 
discontinuation with Table 
7.4.2-1. 
To align with NCI CTCAE 
version 5.0 definitions and 
new terms. 
Section 8.1.2: Criteria to 
Resume Treatment 
Removed redundant text and 
added criteria to resume 
treatment for participants with 
a confirmed or suspected 
SARS-CoV-2 infection. 
To reduce redundancy and to 
manage the safety of 
participants with SARS-CoV- 
2 infection. 
Section 8.1.3: Post Study 
Treatment Study Follow-up 
Language updated to reflect 
changes made to follow-up 
study procedures as a result of 
study termination. 
To describe the modifications 
made to study follow-up as a 
result of study termination. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 9.1: Efficacy 
Assessments 
Section 9.1.1: Imaging 
Assessment for the Study 
Section 9.1.1.1: Methods of 
Measurement 
Section 9.1.1.2: Imaging 
and Clinical Assessment 
Section 9.1.1.4: BICR 
Determination of 
Progression or Recurrence 
Section 9.1.2: Efficacy 
Assessments for TTTP 
Section 9.1.2.3: Definition 
of TTTP 
Added language to specify that 
efficacy assessments will be 
conducted per the local 
standard of care. 
To describe the modification 
made to study efficacy 
assessments as a result of 
study termination. 
Section 9.1.1.4: BICR 
Determination of 
Progression or Recurrence 
Section 9.1.2: Efficacy 
Assessments for TTTP 
Section 9.1.2.3: Definition 
of TTTP 
Section 9.1.4: Outcomes 
Research Assessments 
Section 9.1.4.1: EQ-5D-5L 
Section 9.1.4.:2 FACT-Hep 
Section 9.6: 
Pharmacodynamics 
Section 9.8: Biomarkers 
Section 9.8.1: Tumor-based 
Biomarker Measures 
Section 9.8.1.1: 
Characterization of Tumor 
Infiltrating Lymphocytes 
and Tumor Antigens 
Section 9.8.1.2: Tumor 
Genomic Analysis 
Including Tumor Mutational 
Added a statement that this 
section is not applicable per 
Protocol Amendment 01. 
To describe the modifications 
made to efficacy, 
health-related QoL, HCRU, 
pharmacodynamic, and 
biomarkers assessments as a 
result of study termination. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Burden and Gene 
Expression Analysis 
Section 9.8.2.1: Myeloid- 
derived Suppressor Cells 
Section 9.8.2.2: Soluble 
Biomarkers and Other 
Assessments in Serum 
Section 9.8.2.3: Genomic 
Analysis of Circulating 
Tumor DNA in Plasma 
Section 9.8.2.4: Whole 
Blood DNA and RNA 
Analyses 
Section 9.8.3: Microbiome 
Analysis 
Section 9.8.4: Additional 
Research Collection 
Section 9.9: Health 
Economics OR Medical 
Resource Utilization and 
Health Economics 
Section 9.2: Adverse Events 
Added reference to NCI 
CTCAE version 5.0. 
To identify the NCI CTCAE 
standards used in the study. 
Section 9.2.2: Time Period 
and Frequency for 
Collecting AE and SAE 
Information 
Removed reference to Sections 
5.6.1 and 5.6.2 in the IB for 
Reference Safety Information. 
Reference Safety Information 
has been moved from these 
sections in the IB. 
Section 9.2.6: Pregnancy 
Added text about country- 
specific pregnancy 
requirements. 
To clarify that pregnant 
participants must discontinue 
study treatment where locally 
mandated. 
Section 9.5: 
Pharmacokinetics and 
Immunogenicity 
Table 9.5-1: 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for All 
Participants 
Added a statement that 
PK/IMG sample collection is 
no longer necessary per 
Protocol Amendment 01 and if 
these are collected, they do not 
need to be analyzed. Included 
this statement as a note in 
Table 9.5-1. 
To describe the modifications 
made to pharmacokinetic and 
immunogenicity assessments 
as a result of study 
termination. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Included statement that 
original text in Section 9.5 is 
not applicable per Protocol 
Amendment 01. 
Table 9.8-1: CA20974W 
Biomarker Sampling 
Schedule for All 
Participants 
Added footnote d to Table 
9.8-1 clarifying biomarker 
sampling 
. 
To clarify that 
biomarker sample collection 
and analyses will not be 
performed except for PD-L1. 
Section 9.8.1.2: Tumor 
Genomic Analysis 
Including Tumor Mutational 
Burden and Gene 
Expression Analysis 
Updated text describing the 
analyses to be conducted. 
To clarify analyses to be 
conducted. 
Section 9.8.2.2: Soluble 
Biomarkers and Other 
Assessments in Serum 
Title updated to include “and 
Other Assessments.” 
To better reflect content of 
section. 


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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 10: STATISTICAL 
CONSIDERATIONS 
Section 10.1: Sample Size 
Determination 
• Added a statement to 
Section 10 and Section 
10.2 that only safety 
analyses will be conducted 
per Protocol Amendment 
01. 
• Indicated in Section 10 that 
summary tables and 
listings will be provided to 
support the clinical study 
report and listings for 
efficacy data may be 
provided, if requested. 
• Added statement to Section 
10.1 that sample size will 
be limited to participants 
enrolled as of 
22-Sep-2021. 
• Added a statement to 
Sections 10.1.1, 10.1.2, 
10.1.3, 10.3.3, and 10.3.4 
that the section is not 
applicable per Protocol 
Amendment 01. 
• Added a statement in the 
table for PK, IMG, 
biomarker, and PRO that 
the populations are not 
applicable as per Protocol 
Amendment 01. 
• Removed reference to 
primary and secondary 
endpoints in Section 10.3. 
• Added a statement to 
Section 10.3.1 that a 
formal efficacy analyses 
will not be conducted per 
Protocol Amendment 01. 
To describe the modifications 
made to statistical analyses as 
a result of study termination. 
Section 10.1.1: Sample Size 
Justification for Primary 
Endpoint of TTTP 
Section 10.1.2: Sample Size 
Justification for Primary 
Endpoint OS 
Section 10.1.3: Power 
Considerations in 
Nivolumab plus TACE vs 
Placebo plus TACE (Arm B 
vs Arm C) TTTP and OS 
Comparison as Secondary 
Endpoints 
Section 10.2: Populations 
for Analyses 
Table 10.2-1: Populations 
for Analyses 
Section 10.3: Statistical 
Analyses 
Section 10.3.1: Efficacy 
Analyses 
Section 10.3.3: Other 
Analyses 
Section 10.3.4: Interim 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 10.3: Statistical 
Analyses 
Section 10.3.2: Safety 
Analyses 
Section 10.3.3: Other 
Analyses 
Updated sentence to read 
"...before the first database 
lock .... " 
To clarify timing of the 
statistical analysis plan. 
Table 10.3.1-1: Efficacy - 
Statistical Analyses 
Correct a typo (TTTP should 
be OS). 
Correction of a typo. 
Appendix 1: Abbreviations 
and Trademarks 
Added new terms and 
definitions. 
To provide definitions for 
new terms introduced into the 
protocol with Protocol 
Amendment 01. 
Appendix 2: Study 
Governance Considerations 
Updated text under 
Monitoring. 
Added “Dissemination of 
Clinical Study Data” 
subheading. 
To allow for alternative 
monitoring in circumstances 
where on-site monitoring is 
not advised. 
To clarify the dissemination 
of data for clinical trials. 
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception 
Updated the text for the 
“Definitions” and “Methods of 
Contraception” sections of the 
appendix. 
To provide general 
information and definitions 
related to Woman of 
Childbearing Potential and 
methods of contraception that 
can be applied to most clinical 
trials. 
Appendix 6: Management 
Algorithms for Studies 
Under CTCAE Version 5.0 
Updated algorithms, including 
modified criteria for hepatic 
adverse events. 
To be current with NCI 
CTCAE version 5.0 
standards. 
Appendix 9: Country- 
Specific Requirements 
Updated appendix title and 
reformatted the tables. 
Added pregnancy- and 
biomarker-related country- 
specific requirements. 
Reformatted for clarity. 
Inclusion of CA20974W 
country-specific protocol 
amendment changes for China 
(to provide clarity on which 
samples will be collected for 
biomarker analysis) and the 
Czech Republic 
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Section Number & Title 
Description of Change 
Brief Rationale 
Appendix 11: France- 
specific General Guidance 
for Trans-arterial Chemo- 
embolization 
Added France-specific 
appendix to include additional 
guidance on TACE. 
Inclusion of CA20974W 
country-specific protocol 
amendment changes for 
France. The 
additional 
guidance for TACE 
procedure, specifically 
authorized dose or dose 
ranges of anticancer agents 
that will be used in TACE 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
1 
DOCUMENT HISTORY.............................................................................................. 
3 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: ............................ 
4 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01................ 
5 
TABLE OF CONTENTS.............................................................................................. 
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1 SYNOPSIS................................................................................................................. 
23 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
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3 INTRODUCTION ..................................................................................................... 
43 
3.1 Study Rationale ................................................................................................. 
43 
3.1.1 Research Hypothesis ................................................................................ 
43 
3.1.2 Changes Per Protocol Amendment 01 ..................................................... 
43 
3.2 Background ....................................................................................................... 
45 
3.2.1 The Unmet Need in Intermediate-Stage Hepatocellular Carcinoma....... 
45 
3.2.2 Role of Immune Checkpoint Blockade in the Treatment of HCC ............ 
46 
3.2.3 Rationale for Immune Checkpoint Inhibitors Combinations ................... 
48 
3.2.4 Nivolumab Mechanism of Action ............................................................. 
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3.2.5 Ipilimumab Mechanism of Action ............................................................ 
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3.2.6 Nivolumab Monotherapy for Hepatocellular Carcinoma........................ 
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3.2.7 Nivolumab Combined with Ipilimumab Clinical Activity ........................ 
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3.2.8 Nivolumab Combined with Ipilimumab in HCC ...................................... 
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3.2.9 Immunotherapy and Loco-regional Therapy for HCC ............................ 
55 
3.2.9.1 Impact of Loco-regional Therapy on the HCC Immune Environment 
............................................................................................................... 
55 
3.2.9.2 Data on the Combination of Loco-regional Therapy with 
Checkpoint Inhibitors............................................................................ 
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3.2.9.3 Nivolumab in Combination with TACE .......................................... 
56 
3.3 Benefit/Risk Assessment .................................................................................. 
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3.3.1 Nivolumab and Ipilimumab Safety Profile............................................... 
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3.3.2 Clinical Experience with Nivolumab and Ipilimumab in HCC ............... 
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4 OBJECTIVES AND ENDPOINTS ........................................................................... 
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5 STUDY DESIGN....................................................................................................... 
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5.1 Overall Design .................................................................................................. 
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5.1.1 Screening Period...................................................................................... 
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5.1.2 Treatment Period ..................................................................................... 
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5.1.3 Follow-up Period ..................................................................................... 
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5.1.4 Treatment Beyond Progression................................................................ 
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5.1.5 Data Monitoring Committee and Other External Committees ................ 
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5.1.5.1 Data Monitoring Committee ........................................................... 
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5.1.5.2 Blinded Radiology Review Committee............................................ 
66 
5.2 Number of Participants ..................................................................................... 
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5.3 End of Study Definition .................................................................................... 
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5.4 Scientific Rationale for Study Design............................................................... 
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5.4.1 Rationale for Study Population................................................................ 
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5.4.2 Rationale for TTTP as a Dual Primary Endpoint.................................... 
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5.4.3 Rationale for OS as a Dual Primary Endpoint ........................................ 
5.4.4 Rationale for EFS as a Secondary Endpoint ........................................... 
5.4.5 Rationale for PFS as a Secondary Endpoint ........................................... 
5.4.6 Rationale for Nivolumab and Ipilimumab Dose and Schedule................ 
5.4.7 Rationale for Shorter Infusion Times (30 minutes) of Nivolumab and 
Ipilimumab .................................................................................................. 
5.4.8 Rationale for Stratification Factors......................................................... 
5.4.8.1 Region ............................................................................................. 
5.4.8.2 Alpha-fetoprotein ............................................................................ 
5.4.8.3 Albumin-bilirubin Grade ................................................................ 
5.4.9 Rationale for 2 Year Duration of Treatment with Nivolumab ± 
Ipilimumab .................................................................................................. 
5.4.10 Rationale for Unblinding ....................................................................... 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Nivolumab Clinical Pharmacology Summary ......................................... 
5.5.2 Ipilimumab Clinical Pharmacology Summary......................................... 
5.5.3 Justification for Dose of Nivolumab ........................................................ 
5.5.4 Justification for Dose of Ipilimumab ....................................................... 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures.................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered.................................................................................. 
7.1.1 Nivolumab and Ipilimumab Administration............................................. 
7.1.2 TACE Procedure ...................................................................................... 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.3.1 Unblinding at the Time of Disease Recurrence/Progression .................. 
7.4 Dosage Modification......................................................................................... 
7.4.1 Nivolumab and Ipilimumab Dose Modifications ..................................... 
7.4.2 Nivolumab and Ipilimumab Dose Delay Criteria .................................... 
7.4.3 Treatment of Nivolumab- or Ipilimumab-related Infusion Reactions...... 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence / Biocomparability 
..................................................................................................................... 
7.6 Treatment Compliance...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions......................................................... 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
7.7.3 Permitted Therapy ................................................................................... 
7.7.3.1 Antiviral Therapy ............................................................................ 
7.7.3.2 Other Systemic Therapy .................................................................. 
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7.8 Treatment After the End of the Study............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Treatment Discontinuation Criteria ........................................................ 
8.1.1.1 Criteria for Nivolumab and Ipilimumab Treatment Discontinuation 
............................................................................................................... 
8.1.2 Criteria to Resume Treatment.................................................................. 
8.1.3 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES..................................................... 
9.1 Efficacy Assessments........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.1.1 Methods of Measurement ................................................................ 
9.1.1.2 Imaging and Clinical Assessment ................................................... 
9.1.1.3 Assessment of Baseline Disease Status ........................................... 
9.1.1.4 BICR Determination of Progression or Recurrence....................... 
9.1.2 Efficacy Assessments for TTTP ................................................................ 
9.1.2.1 Definition of Baseline Tumor Burden ............................................. 
9.1.2.2 Dynamic Assessment of Tumor Burden .......................................... 
9.1.2.3 Definition of TTTP .......................................................................... 
9.1.3 Efficacy Assessments using mRECIST ..................................................... 
9.1.4 Outcomes Research Assessments ............................................................. 
9.1.4.1 EQ-5D-5L ....................................................................................... 
9.1.4.2 FACT-Hep....................................................................................... 
9.2 Adverse Events ................................................................................................. 
9.2.1 Immune-mediated Adverse Events ........................................................... 
9.2.2 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.3 Method of Detecting AEs and SAEs......................................................... 
9.2.4 Follow-up of AEs and SAEs ..................................................................... 
9.2.5 Regulatory Reporting Requirements for SAEs......................................... 
9.2.6 Pregnancy ................................................................................................ 
9.2.7 Laboratory Test Result Abnormalities ..................................................... 
9.2.8 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.9 Other Safety Considerations .................................................................... 
9.2.10 Management Algorithms for Immuno-oncology Agents ........................ 
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 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetics and Immunogenicity ............................................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
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9.8 Biomarkers ........................................................................................................ 
9.8.1 Tumor-based Biomarker Measures.......................................................... 
9.8.1.1 Characterization of Tumor Infiltrating Lymphocytes and Tumor 
Antigens................................................................................................. 
9.8.1.2 Tumor Genomic Analysis Including Tumor Mutational Burden and 
Gene Expression Analysis..................................................................... 
9.8.2 Peripheral Biomarkers............................................................................. 
9.8.2.1 Myeloid-derived Suppressor Cells .................................................. 
9.8.2.2 Soluble Biomarkers and Other Assessments in Serum ................... 
9.8.2.3 Genomic Analysis of Circulating Tumor DNA in Plasma .............. 
9.8.2.4 Whole Blood DNA and RNA Analyses ............................................ 
9.8.2.5 Viral Safety Biomarkers .................................................................. 
9.8.3 Microbiome Analysis ............................................................................... 
9.8.4 Additional Research Collection ............................................................... 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination............................................................................. 
10.1.1 Sample Size Justification for Primary Endpoint of TTTP...................... 
10.1.2 Sample Size Justification for Primary Endpoint OS .............................. 
10.1.3 Power Considerations in Nivolumab plus TACE vs Placebo plus TACE 
(Arm B vs Arm C) TTTP and OS Comparison as Secondary Endpoints .... 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.4 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 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 6 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0 ......................................................................................................... 
APPENDIX 7 BEYOND MILAN AND UP-TO-7 CRITERIA................................... 
APPENDIX 8 CHILD-PUGH SCORE ........................................................................ 
APPENDIX 9 COUNTRY-SPECIFIC REQUIREMENTS ......................................... 
APPENDIX 10 RESPONSE EVALUATION CRITERIA MODIFIED FOR 
HEPATOCELLULAR CARCINOMA (MRECIST) WITH BMS ADAPTATIONS 
................................................................................................................................. 
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APPENDIX 11 FRANCE-SPECIFIC GENERAL GUIDANCE FOR TRANS- 
ARTERIAL CHEMO-EMBOLIZATION.............................................................. 
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1 
SYNOPSIS 
Protocol Title: A Randomized, Multi-center, Double-blinded, Placebo-controlled Phase 3 Study 
of Nivolumab and Ipilimumab, Nivolumab Monotherapy, or Placebo in Combination with 
Trans-arterial ChemoEmbolization (TACE) in Patients with Intermediate-stage Hepatocellular 
Carcinoma (HCC) 
Short Title: Nivolumab and Ipilimumab or Nivolumab or Placebo Plus TACE in 
Intermediate-stage Liver Cancer 
Study Phase: 3 
Rationale: 
Nivolumab is currently in development and has been registered in a variety of tumors. 
Development of nivolumab for hepatocellular carcinoma (HCC) was initiated in 2012 with 
CA209040, which is a Phase 1/2 clinical trial evaluating the safety and efficacy of nivolumab in 
advanced HCC. Data from the dose-escalation and expansion cohorts of this study led to the 
approval of nivolumab for the second-line (2L) therapy of advanced HCC patients who progressed 
on or were intolerant to sorafenib. 
Combining immunotherapeutic agents with different mechanisms of action offers the possibility 
of an additive to synergistic response, and therefore represents an attractive therapeutic option that 
has proven to be effective in several cancer types. In advanced HCC, data from CA209040 shows 
promising results of the combination nivolumab and ipilimumab as 2L therapy, with durable 
antitumor activity and an acceptable and manageable safety profile and led to the Food and Drug 
Administration accelerated approval of nivolumab in combination with ipilimumab for the 
treatment of HCC patients who have been previously treated with sorafenib. These data provide 
support for evaluation of nivolumab and nivolumab and ipilimumab in an earlier stage of HCC (ie, 
intermediate-stage HCC). 
Chemoembolization is recommended and widely used for the treatment of intermediate-stage HCC 
(Barcelona Clinic Liver Cancer [BCLC] Stage B), with conventional trans-arterial 
chemoembolization (TACE) being the most widely practiced embolotherapy for HCC. However, 
TACE is considered a palliative treatment and variable degrees of liver function impairment are 
observed post-TACE. The most common adverse effects of TACE include signs of liver injury 
and hepatic insufficiency. Elevated aminotransferases and negative changes in liver function tests 
are seen in almost all patients. The impact of treatment on liver function is problematic, particularly 
for patients who undergo repeated TACE sessions. The majority of patients with HCCs have 
underlying cirrhosis and preserving liver function is important. Physicians have to consider the 
risks of TACE and avoid adverse effects that will outweigh survival benefit. These have led to 
efforts to define when continuing TACE will be an ineffective therapeutic option. 
The palliative nature of TACE and the need for a safer alternative for better liver function 
preservation has driven efforts to improve outcomes with TACE in patients with 
intermediate-stage HCC. Over the past decade, significant effort has been focused on clinical trials 


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combining TACE with systemic therapies, including sorafenib, brivanib, and orantinib. To date, 
these studies have been unsuccessful. 
Despite these failures, the research on TACE is still ongoing. In particular, deeper investigation 
into combination strategies is recommended. The avidity with which this effort is pursued is 
reflected in the number of ongoing TACE studies. There are currently over 100 studies registered 
on ClinicalTrials.gov exploring combinations of TACE with systemic agents, including 
immunotherapy. At present, however, TACE remains the sole recommended treatment for 
intermediate-stage HCC. No systemic agent has been successfully developed for this stage of the 
disease. 
Current data support the potential of immunotherapy for HCC therapy. Immune checkpoint 
inhibitors have clinical activity and are tolerable in advanced HCC, supporting their potential for 
use in other stages of the disease. Data on loco-regional therapy indicate that these procedures 
induce changes in the immune environment that suggest a synergistic potential for the combination 
of loco-regional therapy with immunotherapy. The preliminary data from tremelimumab in 
combination with ablation and from nivolumab in combination with TACE indicate that the 
combinations are feasible and tolerable. The combination of TACE with ipilimumab and/or 
nivolumab has the potential to address the need for better therapeutic options for 
intermediate-stage HCC, and support the further investigation of ipilimumab and nivolumab in 
combination with TACE in this setting. 
 
 
Therefore, a 
decision was made by Bristol-Myers Squibb in September 2021 to stop the study. Importantly, 
there is no change to the understanding of the safety profile of nivolumab alone or in combination 
with ipilimumab and TACE for the treatment of patients with intermediate-stage HCC. 
As of 22-Sep-2021, enrollment for new participants was closed. The number of participants 
randomized was 26 as of 14-Oct-2021. Per Protocol Amendment 01, there are no formal 
hypotheses or efficacy objectives for CA20974W. Only safety assessments will be conducted. 
Following unblinding, study participants who are currently receiving nivolumab ± ipilimumab and 
tolerating study treatment may continue to receive study drug; however, placebo infusions will no 
longer be administered. 
Study Population: 
Male or female adults (≥ 18 years or age of majority) with histologically confirmed HCC who 
have intermediate-stage HCC by BCLC staging, have not previously received TACE, and whose 
tumor characteristics exceed the Beyond Milan and Up-to-7 (BMU7) criteria. Participants must 
not have extrahepatic spread (EHS), and disease characteristics must include no regional lymph 
node involvement, no portal vein thrombosis, and no macrovascular invasion (MVI). 


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Objectives and Endpoints: 
Per Protocol Amendment 01, no analyses of efficacy, quality of life/patient-reported 
outcomes, 
healthcare 
resource 
utilization, 
biomarkers, 
pharmacokinetics, 
or 
immunogenicity are planned. Only safety assessments will be conducted. Previously collected 
biomarker samples may be analyzed, but no further biomarker collections are planned with this 
amended protocol. 
 
Objective 
Endpoint 
• 
To evaluate the safety and tolerability of Arm A, 
Arm B, and Arm C in all treated participants. 
• 
Incidence of AEs, SAEs, deaths, AEs leading to 
treatment discontinuation, and laboratory 
abnormalities in all treated participants. 
Abbreviations: AE = adverse event; SAE = serious adverse event. 
 
 
Overall Design: 
This is a double-blind, placebo-controlled, 3-arm, randomized Phase 3 study of nivolumab and 
ipilimumab in combination with TACE and nivolumab in combination with TACE vs placebo in 
combination with TACE in participants with intermediate-stage HCC. Participants must have 
tumor characteristics that exceed the BMU7 criteria, no EHS, no regional lymph node 
involvement, no portal vein thrombosis, and no MVI must be present. As of 22-Sep-2021, 
enrollment for new participants was closed. The number of participants randomized was 26 as of 
14-Oct-2021. Per Protocol Amendment 01, there are no formal hypotheses or efficacy 
objectives for CA20974W. Only safety assessments will be conducted. Following unblinding, 
study participants who are currently receiving nivolumab ± ipilimumab and tolerating study 
treatment may continue to receive study drug; however, placebo infusions will no longer be 
administered. 
The study will consist of 3 periods: Screening, Treatment, and Follow-up. A complete list of study 
required procedures are provided within the Schedule of Activities section in the main protocol. 
After signing an informed consent form, participants who have not previously received TACE will 
be evaluated for eligibility. If participants are eligible for receiving TACE and meet other 
eligibility criteria, they will be randomized in a 1:1:1 ratio to receive nivolumab and ipilimumab 
plus TACE (Arm A), nivolumab and ipilimumab placebo plus TACE (Arm B), or nivolumab 
placebo and ipilimumab placebo plus TACE (Arm C). Since TACE is the only recommended 
standard of care in clinical practice guidelines for the intended population, TACE plus nivolumab 
placebo and ipilimumab placebo will be used as a control. Both conventional TACE and 
TACE with drug-eluding beads (DEB-TACE) are acceptable treatment modalities in this study 
(see the TACE Procedure section within the main protocol for restrictions on TACE use) and first 
TACE will be administered 7 days (+ 3 days) after study drug administration. Stratification will 
occur by albumin-bilirubin (ALBI) grade (Grade 1 vs Grade 2), baseline alpha-fetoprotein (AFP) 
level (< 400 ng/mL vs ≥ 400 ng/mL), and Region (West [Europe, Americas, and Australia] vs 
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Participants will receive blinded treatment with 1 of the following regimens: 
• Arm A: Nivolumab 240 mg every 2 weeks (Q2W) and ipilimumab 1 mg/kg every 6 weeks 
(Q6W) plus TACE 
• Arm B: Nivolumab 240 mg Q2W and ipilimumab placebo Q6W plus TACE 
• Arm C: Nivolumab placebo Q2W and ipilimumab placebo Q6W plus TACE 
 
Per Protocol Amendment 01, this study will be unblinded and participants randomized to 
Arm B and Arm C will no longer receive placebo infusions following unblinding. 
All randomized participants will receive treatment until progression as assessed by investigator, 
unacceptable toxicity, or consent withdrawal, for a maximum duration of treatment of 2 years. 
Participants will also receive on-demand TACE during the trial and can continue to receive TACE 
until they are not eligible for further TACE (see TACE Procedure section in main protocol). 
Participants in any arm may be treated with study therapy beyond progression as assessed by 
investigator under protocol-defined conditions (see Treatment Beyond Progression section in main 
protocol). 
 
The study design schematic is presented in the figure below. 


 
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Study Design Schematic 
 
 
Abbreviations: AFP = alpha-fetoprotein; ALBI = albumin-bilirubin; BMU7 = beyond Milan and up-to-7; ECOG = Eastern Cooperative Oncology Group; 
EHS = extrahepatic spread; EU = Europe; HCC = hepatocellular carcinoma; N0 = no regional lymph node metastasis; PS = performance status; Q2W = every 
2 weeks; Q6W = every 6 weeks; TACE = trans-arterial chemoembolization; VP0 = no portal vein thrombosis; Vv0 = no macrovascular invasion. 
a Number of nodules ≥ 1 cm + diameter of largest nodule in cm = 7. 
b Per Protocol Amendment 01, participants randomized to Arm B and Arm C will no longer receive placebo following unblinding. Participants randomized 
to nivolumab and ipilimumab plus TACE (Arm A), nivolumab plus TACE (Arm B), or TACE alone (Arm C) will receive treatment until progression as assessed 
by investigator (unless treatment beyond progression was allowed), unacceptable toxicity, or consent withdrawal, for a maximum duration of treatment of 2 
years. 
c Per Protocol Amendment 01, all participants randomized will have 30- and 100-day safety follow-up visits. No survival follow-up visits will occur. 
 
 
 
 
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Study Population 
Screening 
Randomize 1:1:1 
Treatment Period b 
Follow-up Periodc 
Key Inclusion Criteria 
• Intermediate-stage HCC 
• No prior TACE 
• Tumor exceeds 
BMU7 criteriaa 
• Child-Pugh score 5-6 
• ECOG PS 0-1 
• No EHS, N0, VP0, Vv0 
Arm C 
TACE 
Arm B 
Nivolumab 240 mg Q2W + 
TACE 
Stratify by: 
• ALBI grade (1 vs 2) 
• AFP level (< vs = 400 ng/mL) 
• Region (West [EU, Americas, and 
Australia] vs Japan vs rest of Asia) 
Arm A 
Nivolumab 240 mg Q2W + 
Ipilimumab 1 mg/kg Q6W + 
TACE 
Safety Follow-up 
30-Day 
100-Day 


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Number of Participants: 
As of 22-Sep-2021, enrollment for new participants was closed. The number of participants 
randomized was 26 as of 14-Oct-2021. 
Treatment Arms and Duration: 
The selection and timing of dose for the study treatments is provided in the table below. 
Selection and Timing of Dose 
 
Study Treatment 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
Dosage Formulation 
Frequency of 
Administration 
Route of Administration 
Nivolumab 
240 mg 
Q2W 
IV 
Ipilimumab 
1 mg/kg 
Q6W 
IV 
0.9% Sodium 
Chloride for 
Injection 
NA 
Q2W or Q6W 
IV 
5% Dextrose for 
Injection 
NA 
Q2W or Q6W 
IV 
TACE 
NA 
NA 
Loco-regional 
Abbreviations: IV = intravenous; kg = kilogram; mg = milligram; NA = not applicable; Q2W = every 2 weeks; 
Q6W = every 6 weeks; TACE = trans-arterial chemoembolization . 
 
 
All participants should begin study treatment with nivolumab and ipilimumab in Arm A, 
nivolumab and ipilimumab placebo in Arm B, or nivolumab placebo and ipilimumab placebo in 
Arm C within 3 days after randomization. After nivolumab and ipilimumab (or placebo[s]) 
administration, first TACE will be administered 7 days (+ 3 days) after study drug administration. 
Per Protocol Amendment 01, this study will be unblinded and participants randomized to 
Arm B and Arm C will no longer receive placebo infusions following unblinding. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
29 
Approved v 21.0 
930142607 2.0 
 
 
Study Treatment: 
Study Drug for CA20974W 
 
Medication 
Potency 
IP/Non-IP 
Nivolumab (BMS-936558-01) 
Solution for Injectiona 
10 mg/mL 
IP 
Ipilimumab Solution for Injection 
5 mg/mL 
IP 
0.9% Sodium Chloride for Injectionb 
NA 
IP 
5% Dextrose for Injectionb 
NA 
IP 
Abbreviations: IP = investigational product; mg = milligram; mL = milliliter; NA = not applicable. 
a Nivolumab is labeled as BMS-936558-01 Solution for Injection. 
b Diluents used for nivolumab and ipilimumab. These will be sourced by the investigative sites if available and 
permitted by local regulations. 
 
Data Monitoring Committee: Yes 
Blinded Independent Central Review (BICR): 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Images will be submitted to a central imaging vendor for BICR on a rolling basis during the study. 
Prior to scanning first participant, sites should be qualified and understand the image acquisition 
guidelines and submission process as outlined in the CA20974W Imaging Manual provided by the 
central imaging vendor. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
30 
Approved v21.0 
930142607 2.0 
 
 
2 
SCHEDULE OF ACTIVITIES 
Table 2-1: 
Screening Procedural Outline (CA20974W) 
 
Procedurea 
Screening 
Visit 
(Days -28 to - 
1) 
Notes 
All windows are based on calendar days. 
Eligibility Assessments 
Informed Consent 
X 
Original informed consent must be obtained before performing any protocol-related procedures 
that are not part of normal patient care. 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. 
Register in IRT system to obtain participant number. 
Inclusion/Exclusion Criteria 
X 
Assessed during Screening Period and re-enrollment, if applicable. Must be confirmed prior to 
randomization. See Section 6 (Study Population). 
Medical History 
X 
All medical history relevant to the disease under study. 
Child-Pugh Score and ALBI score 
X 
Refer to Appendix 8 (Child-Pugh Score) and Section 5.4.8.3 (Albumin-bilirubin Grade) for 
additional details. 
Tumor Sample Submission 
X 
An FFPE tissue block (preferred) or a minimum of 20 unstained slides of tumor tissue obtained 
from core biopsy, punch biopsy, excisional biopsy, or surgical specimen prior to randomization 
(within 3 months of enrollment with no intervening systemic anticancer treatment between time 
of acquisition and randomization, or archival tissue [if above is not available]) must be sent to the 
central laboratory. Fine needle aspirates or other cytology samples are not acceptable. If despite 
best efforts, a minimum of 20 slides are not obtainable, submission of fewer slides may be 
acceptable in some circumstances following discussion with the BMS Medical Monitor or 
Clinical Scientist. Please see Appendix 9 for country-specific criteria for the collection of tumor 
tissue samples in China. 
The tissue submitted will be assessed for quality and only those participants who have met tissue 
quality thresholds can be randomized. Central laboratory must provide IRT with confirmation of 
receipt of evaluable tumor tissue prior to participant randomization. 
See Section 9.8 (Biomarkers) for additional information. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-1: 
Screening Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
31 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Screening 
Visit 
(Days -28 to - 
1) 
Notes 
All windows are based on calendar days. 
Safety Assessments 
Full PE, Physical Measurements, and 
ECOG PS 
X 
Height, weight, blood pressure (BP), heart rate, temperature, and ECOG PS (Appendix 5). Must 
be collected within 14 days prior to randomization. 
Vital Signs 
X 
Obtain vital signs at the screening visit. 
Vital signs include temperature, respiratory rate, seated BP, and heart rate. BP and heart rate 
should be measured after the participant has been resting quietly for at least 5 minutes. Consider 
alternate position(s) for vital sign collection. 
Assessment of Signs and Symptoms 
X 
Must be performed within 14 days prior to randomization. 
Concomitant Medication Use 
X 
Must be collected within 14 days prior to randomization. Vaccine use within 30 days prior to 
randomization. 
SAE Assessment 
X 
SAE collection from the time of consent. 
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection to be collected from 
time of consent. 
AEs will be graded according to the NCI CTCAE version 5.0. 
12-lead ECG 
X 
Within 14 days prior to randomization. 
Body Imaging 
X 
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis, including pre- and 
post-contrast tri-phasic MRI or CT of the liver, and all other known and/or suspected sites of 
disease, within 28 days prior to randomization. See Section 9.1.1 (Imaging Assessment for the 
Study) for further details. Images must be submitted for BICR to confirm eligibility. 
Brain Imaging 
X 
MRI of the brain without and with contrast is required for participants with suspected brain 
metastases, unless participant has completed an imaging study of the brain within 30 days of 
randomization. 
CT of the brain without and with contrast can be performed if MRI is contraindicated. 
See Section 9.1.1 (Imaging Assessment for the Study) for further details. 
Laboratory Tests 
Hematology and Chemistry/Endocrine 
X 
Must be performed locally within 14 days prior to randomization. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-1: 
Screening Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
32 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Screening 
Visit 
(Days -28 to - 
1) 
Notes 
All windows are based on calendar days. 
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for a list of laboratory tests. 
Serology for Hep B, Hep C, Hep D, and 
HIV 
Testing for Viral Hepatitis to be completed at the central laboratory within 28 days prior to 
randomization. In the event the central laboratory is unable to perform Hep D testing, local 
Hep D testing may be allowed until central laboratory testing resumes. Local testing requires 
approval from BMS along with supporting local laboratory documentation. 
Testing for HIV (when required by local regulations [refer to Appendix 9]) must be done at 
local laboratory within 28 days prior to randomization. 
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for a list of laboratory tests. 
Pregnancy Test (WOCBP only) 
X 
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for a list of laboratory tests. 
Urinalysis 
X 
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for a list of laboratory tests. 
IRT 
Register Participant in IRT 
X 
A call must be made to the IRT to register participant after signing informed consent. 
Abbreviations: AE = adverse event; ALBI = albumin-bilirubin; BP = blood pressure; BICR = blinded independent central review; BMS = Bristol-Myers Squibb; 
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; 
FFPE = formalin-fixed, paraffin-embedded; HCG = human chorionic gonadotropin; Hep B = hepatitis B; Hep C = hepatitis C; Hep D = hepatitis D; HIV = human 
immunodeficiency virus; IRT = interactive response technology; IU = international unit; L = liter; MRI = magnetic resonance imaging; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events; PE = physical examination; PS = performance status; RNA = ribonucleic acid; 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 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. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-2: 
On-treatment Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
33 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Nivolumab 
Cycle 1 Day 1 and 
Q2W Thereafter 
( 3 days) 
Ipilimumab 
Cycle 1 Day 1 and 
Q6W Thereafter 
( 3 days) 
(1 Cycle = 2 weeks) 
TACE 
Cycle 1 Day 7 (+3 days) 
and 
On-demand Thereafter 
Notesb 
Safety Assessments 
Targeted PE 
X 
X 
Targeted PE must include, at a minimum, the following body systems, 
performed within 72 hours prior to dosing: cardiovascular, 
gastrointestinal, pulmonary, and skin. 
Physical Measurements and 
ECOG PS 
X 
X 
Physical measurements include weight and ECOG PS (Appendix 5), to 
be collected within 72 hours prior to dosing. 
Vital Signs 
X 
X 
Vital signs include BP, heart rate, temperature, and respiratory rate. 
Obtain vital signs within 72 hours prior to dosing. 
Child-Pugh Score 
X 
X 
Refer to Appendix 8 for further details. 
AEs Assessment 
(including SAEs) 
X 
X 
Record at each visit. Collect continuously throughout the Treatment 
Period and for a minimum of 100 days following discontinuation of 
dosing. SAEs must be collected from the time of consent. 
All AEs (SAEs and non-serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection must be collected from time of consent 
until 100 days following discontinuation of dosing. 
AEs will be graded according to the NCI CTCAE version 5.0. 
Concomitant Medication Use 
X 
X 
Record at each visit. 
Laboratory Tests 
Hematology and 
Chemistry/Endocrine 
X 
X 
Performed locally within 72 hours prior to dosing. See Section 9.4.4 
(Clinical Safety Laboratory Assessments) for a list of laboratory tests. 
TSH, with reflexive fT3 and fT4 if TSH is abnormal, (every third cycle 
[3, 6, 9, etc]). 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-2: 
On-treatment Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
34 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Nivolumab 
Cycle 1 Day 1 and 
Q2W Thereafter 
( 3 days) 
Ipilimumab 
Cycle 1 Day 1 and 
Q6W Thereafter 
( 3 days) 
(1 Cycle = 2 weeks) 
TACE 
Cycle 1 Day 7 (+3 days) 
and 
On-demand Thereafter 
Notesb 
Serology for Viral Status (for 
HCV- and HBV-infected 
participants) 
See Notes. 
Testing to be completed at the central laboratory (see Table 9.4.4-1). 
Results of viral serologies are not required to continue study treatment. 
For HCV-infected participants: HCV RNA Q4W on treatment (every 
other cycle) through cycle 9, then every 6 cycles thereafter. 
For HBV infected participants, HBV DNA Q4W on treatment. 
Pregnancy Test 
(WOCBP only) 
X 
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done within 24 hours prior to first dose, 
and then every 28 days, regardless of dosing schedule. 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. 
Urinalysis 
X 
See Section 9.4.4 (Clinical Safety Laboratory Assessments) for a list of 
laboratory tests. 
Efficacy Assessments 
Per Protocol Amendment 01, efficacy assessments should be 
conducted per the local standard of care. 
Body Imaging Assessments 
See Notes. 
See Notes 
Per Protocol Amendment 01, imaging should continue per local 
standard of care. The following information refers to the original study 
design. 
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, 
including pre- and post-contrast tri-phasic MRI or CT of the liver, and all 
other suspected sites of disease, should be performed. 
Tumor imaging assessments will occur 6 weeks from the date of 
randomization (± 1 week), then every 6 weeks (± 1 week) thereafter up to 
48 weeks, then it will be every 12 weeks (± 1 week) until disease 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-2: 
On-treatment Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
35 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Nivolumab 
Cycle 1 Day 1 and 
Q2W Thereafter 
( 3 days) 
Ipilimumab 
Cycle 1 Day 1 and 
Q6W Thereafter 
( 3 days) 
(1 Cycle = 2 weeks) 
TACE 
Cycle 1 Day 7 (+3 days) 
and 
On-demand Thereafter 
Notesb 
progression (as assessed by investigator) or treatment is discontinued 
(whichever occurs later). 
See Section 9.1.1 (Imaging Assessment for the Study) for further details. 
PK and IMG Assessments 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
See Section 9.5 (Pharmacokinetics and Immunogenicity) and Table 9.5-1 
for PK/IMG sample collection schedule. 
Biomarker Assessmentsc 
Serum Biomarkers, Whole 
Blood DNA and RNA, 
MDSC, Plasma (ctDNA) 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
See Table 9.8-1 for biomarker sample collection schedule. 
Stool Samples for Microbiome 
Analysis 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
See Table 9.8-1 for biomarker sample collection schedule. 
Collection of Tumor Upon 
TTTP or EOT 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
See Table 9.8-1 for biomarker sample collection schedule. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-2: 
On-treatment Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
36 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Nivolumab 
Cycle 1 Day 1 and 
Q2W Thereafter 
( 3 days) 
Ipilimumab 
Cycle 1 Day 1 and 
Q6W Thereafter 
( 3 days) 
(1 Cycle = 2 weeks) 
TACE 
Cycle 1 Day 7 (+3 days) 
and 
On-demand Thereafter 
Notesb 
Outcomes Research 
Assessments 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
Questionnaires should be administered at the start of the visit, before the 
participant sees the physician and before any study-related procedures are 
done (with the exception of procedures completed 72 hours prior to 
visit). In the case of a delay in dosing, completion of the PRO measures 
will also be delayed to coincide with when dosing is resumed. 
EQ-5D-5L 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
Complete prior to treatment on Day 1 of each treatment cycle through 
C13D1, and then every third cycle thereafter. 
FACT-Hep 
See Notes. 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
Complete prior to treatment on Day 1 of each treatment cycle through 
C13D1, and then every third cycle thereafter. 
Healthcare Resource 
Utilization 
X 
Not applicable per Protocol Amendment 01. The following 
information refers to the original study design. 
HCRU to be assessed during clinical visit; must be completed by site 
staff and recorded on the eCRF. See Section 9.9 for additional details. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-2: 
On-treatment Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
37 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedurea 
Nivolumab 
Cycle 1 Day 1 and 
Q2W Thereafter 
( 3 days) 
Ipilimumab 
Cycle 1 Day 1 and 
Q6W Thereafter 
( 3 days) 
(1 Cycle = 2 weeks) 
TACE 
Cycle 1 Day 7 (+3 days) 
and 
On-demand Thereafter 
Notesb 
Clinical Drug Supplies 
Contact Central 
Randomization IRT/Dispense 
Study Drug 
See Notesd 
Per Protocol Amendment 01, after unblinding, participants in Arms 
B and C will no longer receive placebo infusions. 
First dose of study medication to be administered within 3 calendar days 
following randomization. 
Participants will receive nivolumab 240 mg (flat dose) Q2W, ipilimumab 
1 mg/kg (weight-based dosing) Q6W, and on-demand TACE. 
Participants may be dosed no less than 12 days and no more than 18 days 
between nivolumab doses and no less than 36 days and no more than 
60 days between ipilimumab doses. 
Abbreviations: AE = adverse event; BP = blood pressure; C = cycle; CT = computed tomography; ctDNA = circulating tumor DNA; D = day; 
DNA = deoxyribonucleic acid; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EQ-5D-5L = EuroQol-5 Dimensions-5 Levels; 
FACT-Hep = Functional Assessment of Cancer Therapy-Hepatobiliary; HBV = hepatitis B virus; HCRU = healthcare resource utilization; HCG = human chorionic 
gonadotropin; HCV = hepatitis C virus; IMG = immunogenicity; IRT = interactive response technology; IU = international unit; L = liter; MDSC = myeloid- 
derived suppressor cell; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
PE = physical examination; PK = pharmacokinetic; PRO = patient-reported outcome; PS = performance status; Q2W = every 2 weeks; Q4W = every 4 weeks; 
Q6W = every 6 weeks; RNA = ribonucleic acid; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TACE = trans- 
arterial chemoembolization; TSH = thyroid-stimulating hormone; TTTP = time to TACE progression; WOCBP = women of childbearing potential. 
a If a dose is delayed, the procedures schedule for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs. 
b 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. 
c Please see Appendix 9 for country-specific criteria for the collection and analyses of biomarker samples 
. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
38 
Approved v21.0 
930142607 2.0 
 
 
d The ± 3-day window should be used to align nivolumab and ipilimumab dosing for same-day administration and that participants must be dosed no less than 12 
days and no more than 18 days between nivolumab doses and no less than 36 days and no more than 60 days between ipilimumab doses. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-3: 
Follow-up Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
39 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedure 
Safety 
Follow-up 
Visits 1 (FU1) 
and 2 (FU2)a 
Survival 
Follow-up 
Visitsb 
Notesc 
Safety Assessments 
Targeted PE, Physical Measurements, 
Vital Signs, and ECOG PS 
Assessment 
X 
Weight, BP, heart rate, temperature, and ECOG PS. 
Targeted PE must include, at a minimum, the following body systems: 
cardiovascular, gastrointestinal, pulmonary, and skin. 
AEs Assessment (including SAEs) 
X 
X 
Record at each visit. 
All AEs (SAEs and non-serious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection must be collected from the time of 
consent. 
All AEs (SAEs and non-serious AEs), including AEs associated with 
confirmed or suspected SARS-CoV-2 infection, must be collected 
continuously throughout the treatment period and for a minimum of 100 
days following discontinuation of dosing. Participants will be followed for 
all SAEs and all AEs (SAEs and non-serious AEs) associated with 
confirmed or suspected SARS-CoV-2 infection until resolution, the 
condition stabilizes, the event is otherwise explained, the event is deemed 
irreversible, the participant is lost to follow-up (as defined in Section 8.3), 
or for suspected cases, until SARS-CoV-2 infection is ruled out. 
AEs will be graded according to the NCI CTCAE version 5.0. 
Review of Concomitant Medication 
Use 
X 
Record at each visit. 
Review of Subsequent Cancer 
Therapy 
X 
X 
No longer applicable per Protocol Amendment 01. Review and record 
any subsequent therapies received by the participant. 
Laboratory Tests 
Hematology and Chemistry/Endocrine 
X 
To be performed locally. See Section 9.4.4 (Clinical Safety Laboratory 
Assessments) for a list of laboratory tests to conduct. Total T3/T4 are 
acceptable if free T3/T4 are not available. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-3: 
Follow-up Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
40 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedure 
Safety 
Follow-up 
Visits 1 (FU1) 
and 2 (FU2)a 
Survival 
Follow-up 
Visitsb 
Notesc 
Serology for Viral Status (for HCV- 
and HBV-infected participants) 
X 
Testing to be completed at the central laboratory (see Table 9.4.4-1). 
For HCV-infected participants: HCV RNA. 
For HBV-infected participants: HBV DNA. 
Pregnancy Test (WOCBP only) 
X 
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG). 
Efficacy Assessments 
Per Protocol Amendment 01, efficacy assessments should be conducted 
by investigator per local standard of care. 
Body Imaging Assessments 
X 
X 
Per Protocol Amendment 01, imaging should continue per local 
standard of care. The following information refers to the original study 
design. 
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, 
including pre- and post-contrast tri-phasic MRI or CT of the liver, and all 
other suspected sites of disease, should be performed. 
Tumor imaging assessments will occur 6 weeks from the date of 
randomization (± 1 week), then every 6 weeks (± 1 week) thereafter up to 
48 weeks, then it will be every 12 weeks (± 1 week) until disease 
progression (as assessed by investigator) or treatment is discontinued 
(whichever occurs later). 
See Section 9.1.1 (Imaging Assessment for the Study) for further details. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-3: 
Follow-up Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
41 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedure 
Safety 
Follow-up 
Visits 1 (FU1) 
and 2 (FU2)a 
Survival 
Follow-up 
Visitsb 
Notesc 
PK and IMG Assessments 
See Notes. 
Not applicable per Protocol Amendment 01. The following information 
refers to the original study design. 
See Section 9.5 (Pharmacokinetics and Immunogenicity) and Table 9.5-1 
for PK/IMG sample collection schedule. 
Biomarker Assessmentsd 
See Notes. 
Not applicable per Protocol Amendment 01. The following information 
refers to the original study design. 
See Table 9.8-1 for biomarker sample collection schedule. 
Outcomes Research Assessments 
Not applicable per Protocol Amendment 01. The following information 
refers to the original study design. 
The EQ-5D-5L and FACT-Hep should be administered at the start of the 
visit, before the participant sees the physician and before any study-related 
procedures are done. 
EQ-5D-5L 
X 
X 
Not applicable per Protocol Amendment 01. The following information 
refers to the original study design. 
EQ-5D-5L to be assessed during clinical visit or via a phone for survival 
follow-up visits. 
FACT-Hep 
X 
Not applicable per Protocol Amendment 01. 
Healthcare Resource Utilization 
X 
Not applicable per Protocol Amendment 01. The following information 
refers to the original study design. 
HCRU to be assessed during clinical visit; must be completed by site staff 
and recorded on the eCRF. See Section 9.9 for additional details. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 2-3: 
Follow-up Procedural Outline (CA20974W) 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
42 
Approved v21.0 
930142607 2.0 
 
 
 
 
Procedure 
Safety 
Follow-up 
Visits 1 (FU1) 
and 2 (FU2)a 
Survival 
Follow-up 
Visitsb 
Notesc 
Participant Status 
Survival Status 
X 
Per Protocol Amendment 01, survival follow-up will stop after the 
second safety assessment (FU2) at 100 days. 
The following information is no longer applicable per Protocol 
Amendment 01 and refers to the original study design. 
During safety follow-up and every 3 months (may be accomplished by 
clinic visit or by telephone contact) during the survival Follow-up Period. 
Include documentation of subsequent chemotherapy. 
Abbreviations: AE = adverse event; BP = blood pressure; BMS = Bristol-Myers Squibb; CT = computed tomography; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic case report form; EQ-5D-5L = EuroQol-5 Dimensions-5 Levels; FACT-Hep = Functional Assessment of Cancer Therapy-Hepatobiliary; 
FU1 = follow-up visit 1; FU2 = follow-up visit 2; HCG = human chorionic gonadotropin; HCRU = healthcare resource utilization; IMG = immunogenicity; 
IU = international unit; L = liter; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
PE = physical examination; PK = pharmacokinetic; PS = performance status; RNA = ribonucleic acid; SAE = serious adverse event; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2; SOC = standard of care; WOCBP = women of childbearing potential. 
a Participants must be followed for at least 100 days after last dose of study treatment. FU1 should occur 30 days from the last dose (±7 days) or can be performed 
on the date of discontinuation if that date is great than 42 days from the last dose. FU2 occurs approximately 100 days (±7 days) from last dose of study treatment. 
Both follow-up visits should be conducted in person. 
b Not applicable per Protocol Amendment 01. The following information refers to the original study design. Survival Follow-up visits to occur every 12 weeks 
(± 14 days) from FU2. Survival visit may be conducted in person or by telephone. 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. 
c 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. 
d Please see Appendix 9 for country-specific criteria for the collection and analyses of biomarker samples 
. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
43 
Approved v 21.0 
930142607 2.0 
 
 
3 
INTRODUCTION 
3.1 
Study Rationale 
Nivolumab is currently in development and has been registered in a variety of 
tumors.1Development of nivolumab for hepatocellular carcinoma (HCC) was initiated in 2012 
with CA209040, which is a Phase 1/2 clinical trial evaluating the safety and efficacy of nivolumab 
in advanced2Data from the dose-escalation and expansion cohorts of this study led to the approval 
of nivolumab for the second-line (2L) therapy of advanced HCC patients who progressed on or 
were intolerant to sorafenib. 
Combining immunotherapeutic agents with different mechanisms of action offers the possibility 
of an additive to synergistic response, and therefore represents an attractive therapeutic option that 
has proven to be effective in several cancer types1In advanced HCC, data from CA209040 shows 
promising results of the combination nivolumab and ipilimumab as 2L therapy, with durable 
antitumor activity and an acceptable and manageable safety profile and led to the Food and Drug 
Administration (FDA) accelerated approval of nivolumab in combination with ipilimumab for the 
treatment of HCC patients who have been previously treated with sorafenib.3 These data provide 
support for evaluation of nivolumab and nivolumab and ipilimumab in an earlier stage of HCC (ie, 
intermediate-stage HCC). 
3.1.1 
Research Hypothesis 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Treatment with nivolumab and ipilimumab or nivolumab in combination with trans-arterial 
chemoembolization (TACE) will improve time to TACE progression (TTTP) and/or overall 
survival (OS) compared to TACE in participants with intermediate stage HCC. 
3.1.2 
Changes Per Protocol Amendment 01 
 
 
Therefore, a 
decision was made by Bristol-Myers Squibb (BMS) in September 2021 to stop the study. 
Importantly, there is no change to the understanding of the safety profile of nivolumab alone or in 
combination with ipilimumab and TACE for the treatment of patients with intermediate-stage 
HCC. 
As of 22-Sep-2021, the following measures were put into effect: 
• Enrollment of new participants was closed. 
• Participants who signed study consent prior to this notification and were undergoing 
screening were permitted to be randomized to study treatment. 
• Participants currently on treatment were allowed to continue study treatment. 


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• For participants currently in survival follow-up, it is at the discretion of the investigator 
and participant whether to continue follow-up until Protocol Amendment 01 is approved 
by the relevant Health Authorities and Institutional Review Boards (IRBs)/Independent 
Ethics Committees (IECs) at the site. 
 
Protocol Amendment 01 describes the modification to study procedures. All participants must be 
re-consented upon approval and implementation of Protocol Amendment 01. These changes affect 
all participants and should be implemented when Protocol Amendment 01 is implemented at the 
site. 
Key changes in Protocol Amendment 01 include: 
• Details of closure of the study, with provision for participants currently on treatment or in 
the follow-up period to continue in the study per the current protocol amendment. 
• The study will be unblinded. 
• Removal of placebo infusions for participants in Arms B and C. 
• Removal of pharmacokinetic (PK), immunogenicity (IMG), biomarker, and patient- 
reported outcome (PRO) assessments. Only safety assessments will be conducted. 
• Removal of on-study imaging assessments. Sites should continue imaging assessments per 
local standard of care. 
• Removal of study-related efficacy assessments. Sites should continue efficacy assessments 
per local standard of care. 
• Align dose modification criteria and immuno-oncology agent management algorithms with 
the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. 
• Add the collection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection-related adverse events (AEs) and serious adverse events (SAEs) to evaluate the 
impact of SARS-CoV-2 on participant safety and add coronavirus disease 2019 (COVID- 
19) vaccine information for study participants. 
• Incorporate country-specific information for France, Czech Republic, and China; 
incorporate additional updates to improve alignment across protocol sections and/or clarify 
expectations for assessments, sample collections, and treatment administration. 
 
Changes instituted in Protocol Amendment 01 should override any existing protocol requirements 
in the event of any apparent discrepancies. 


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3.2 
Background 
3.2.1 
The Unmet Need in Intermediate-Stage Hepatocellular Carcinoma 
HCC is the seventh most common cancer in the world and the third most common cause of 
cancer-related death. There are more than 800,000 new cases a year and HCC causes 
approximately 700,000 to 800,000 deaths annually. Furthermore, its incidence and prevalence are 
increasing worldwide. The disease shows wide regional variations in incidence rates and etiology. 
HCC is particularly prevalent in Asian countries relative to Western countries. Over 80% of HCC 
cases occur in Africa and Asia. China alone accounts for more than 50% of cases worldwide.4,5 
Age-standardized (world) incidence rates in South-Eastern to Eastern Asia range from 21.0 to 26.8 
per 100,000, distinctly higher than the rates in Northern Europe (EU) and North America, which 
range from 6.6 to 10.1 per 100,000. Age-standardized (world) mortality rates are similarly much 
higher in South and North Eastern Asia (17.2 to 34.0 per 100,000) than in Northern EU and North 
America (3.1 to 4.4 per 100,000).6 
Virtually any cause of liver damage that leads to cirrhosis can predispose an individual to HCC. 
The main risk factors for primary liver cancer (PLC) are chronic infection with hepatitis B 
virus (HBV) or hepatitis C virus (HCV), aflatoxin B1-contaminated foodstuffs, heavy alcohol 
intake, obesity, and type 2 diabetes mellitus.7 Once cirrhosis is established, the annual incidence 
of HCC is 3% to 5% and one-third of these individuals will develop HCC over their lifetime.8 
Most cases of HCC arise in eastern Asia and sub-Saharan Africa, where the dominant risk factor 
is chronic HBV infection, together with exposure to aflatoxin B1.9 In contrast, in North America, 
EU, and Japan, HCV infection is the main risk factor, together with alcohol use.10 
Intermediate-stage HCC patients belong to the Barcelona Clinic Liver Cancer (BCLC) Stage B. 
The stage consists of patients with preserved liver function and performance status who are not 
eligible for curative treatments, such as surgery and liver transplantation. It includes a 
heterogeneous patient population that presents with a wide range of tumor extension and liver 
function (Child-Pugh compensated A5 cirrhosis to decompensated B9).11 
Chemoembolization is recommended for the treatment of intermediate-stage HCC (BCLC 
Stage B). Transcatheter arterial therapies for HCC were first described in the 1970s12 and include 
a variety of techniques (eg, TACE, bland embolization, trans-arterial embolization [TAE]). The 
use of TACE was adopted into practice guidelines based on 2 meta-analyses13,14 and 2 seminal 
placebo-controlled randomized clinical trials (RCTs)15,16 published in 2002. TACE has since been 
widely used, with conventional TACE being the most widely practiced embolotherapy for HCC.12 
The largest global HCC observational study (GIDEON) suggests that nearly half of all HCC 
patients receive TACE at some timepoint in the course of the disease.17 Real-world data and 
clinical experience demonstrate TACE to be the method of choice for the treatment of 
intermediate-stage HCC, applied in about 50% to 60% of patients.18,19 
However, TACE is considered a palliative treatment. Significant tumor response is achieved in 
17-61.9% in individuals administered TACE, but TACE often fails to induce complete necrosis of 
the lesion. Even in cases where complete ablation is achieved, tumors commonly recur post-TACE 


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liver, it may be detrimental in cancer-bearing host, as it might prevent an adequate immune 
response against malignant cells.36,37,38 Moreover, the intrahepatic immunosuppressive 
environment is exacerbated by the chronic inflammation that underlies the development of fibrosis 
and cirrhosis. This chronic inflammation, characterized by the continued expression of different 
cytokines and recruitment of immune cells to the liver, may contribute to HCC carcinogenesis and 
disease progression by further activating immunosuppressive mechanisms, which results in an 
inability to escalate a meaningful antitumor response.36,39 Indeed, immune changes reported in 
HCC, such as tumor-associated antigen-specific CD8+ T-cell immune responses, T-cell infiltration 
after loco-regional therapy, T regulatory cell (Treg) intratumoral accumulation, and 
myeloid-derived suppressor cells (MDSCs) accumulation have been correlated with disease 
progression and poor survival.40,41,42 Overcoming this immune tolerance is thus an important 
challenge in the search for an effective immunotherapy against HCC. 
Given the unique immunosuppressive tumor microenvironment, HCC is an attractive target for 
immunotherapy, particularly immune checkpoint inhibitors. In HCC, the negative regulatory 
target-immune checkpoints, such as CTLA-4, PD-1, and its ligand PD-L1, are often overexpressed 
to escape the host immune surveillance, and thus, treatment with immune checkpoint inhibitors 
can reactivate tumor-specific T cells and develop an antitumor effect by suppressing 
checkpoint-mediated signaling.38,43,44 
The administration of CTLA-4 inhibitor has been demonstrated to increase antitumor immunity in 
a murine HCC model, with a tumor rejection rate of 90% and a curative rate of 50% in metastatic 
HCC.45 Additionally, the clinical benefit of anti-CTLA-4 as a single-agent has been demonstrated 
in a Phase 2, non-controlled, open-label, multicenter trial.46 In this trial, tremelimumab, a 
monoclonal antibody that blocks CTLA-4, was administered at a dose of 15 mg/kg intravenously 
(IV) every 90 days in 20 participants with HCV-associated HCC with Child-Pugh Stage A (57%) 
and Stage B (43%) who failed traditional HCC therapy. In terms of antitumor responses, this study 
reported a partial response (PR) rate of 17.6%, a disease control rate (DCR) of 76.4%, a time to 
progression (TTP) of 6.48 months, and a median OS of 8.2 months. Regarding safety, 
tremelimumab was generally well tolerated, with few participants experiencing Grade 3 disabling 
adverse events (AEs), being the most common side effects observed fatigue and anorexia, which 
occurred in almost one-half of participants. A remarkable rise in serum transaminases was 
observed after the first dose in more than half of the participants (Grade 3 or higher in 45% of 
cases), but with no other signs of liver dysfunction. 
Similar to the role of CTLA-4 pathway inhibition, the role of PD-1/PD-L1 pathway in HCC has 
been investigated. PD-1 expression on effector phase cluster of differentiation (CD) 8-positive (+) 
T cells is increased in patients with HCC compared to cirrhotic patients or healthy controls.47 
Indeed, patients with HCC and higher numbers of tumor infiltrating and circulating PD-1+, CD8+ 
T cells showed earlier and more frequent disease progression after hepatic resection. PD-L1 is also 
highly expressed on peritumoral stromal cells (Kupffer cells, liver sinusoidal endothelial 
cells [LSECs], and monocytes) as well as cancer cells, promoting a PD-L1/PD-1 pathway-driven 
inhibition of antitumor T-cell responses.48 These preclinical findings are further supported by 
results from CA209040, the first trial evaluating the safety and efficacy of an anti-PD-1 agent in 
advanced HCC. This Phase 1/2 study included 262 participants with unselected PD-L1 tumors, 


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including both treatment-naive and pretreated participants. Following confirmation of safety and 
tolerability in the dose-escalation phase, all participants in the dose-expansion phase received IV 
nivolumab 3 mg/kg every 2 weeks (Q2W) until disease progression or limiting toxicity. This trial 
showed convincing signs of efficacy, with objective tumor responses ranging from 15-20% in the 
escalation and expansion cohorts. Notably, responses were observed regardless of PD-L1 
expression and were similar across different etiologies, and both in sorafenib-naive and 
sorafenib-exposed participants. Remarkably, responses were meaningful and durable (lasting for 
a median of 17 months) and the median OS in the sorafenib-treated group was 15.6 months in the 
expansion cohort, which compares favorably with sorafenib historical data (10.7 months)49 and 
with results of the recently approved 2L molecular-targeted agents (median OS ranging from 8.5 to 
10.6 months).50,51,52 Overall, nivolumab was generally well tolerated with a manageable safety 
profile. Hepatic toxicity, consisting primarily of transaminase elevations, was generally mild, with 
Grade 3 or 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations 
observed in 7 (9%) and 7 (4%) of sorafenib-naive and pretreated participants, respectively; 
bilirubin elevations were infrequent (7 participants overall) and mostly mild, with only 1 Grade 3 
or 4 elevation reported. In addition to nivolumab, other immune checkpoint inhibitors as single 
agents are being evaluated in HCC. Durvalumab (an anti-PD-L1 antibody) has shown clinical 
activity in a small Phase 1/2 study (N = 40), with response rates of 10% and a median OS of 
13.2 months.53 Similarly, most recently, pembrolizumab (an anti-PD-1 antibody) has also 
demonstrated clinical activity as 2L therapy with response rates of 17% and a median OS of 
12.9 months in a Phase 1/2 including 104 participants with advanced HCC.54 
Thus, there is a substantial body of scientific evidence that supports the rationale for the use of 
immune-based approaches to treat HCC. This theoretical rationale is further supported by a 
growing amount of clinical evidence, which indicates that immune checkpoint inhibitors are 
effective treatments for patients with advanced HCC.43,44 
3.2.3 
Rationale for Immune Checkpoint Inhibitors Combinations 
While the efficacy of immune checkpoint inhibitors as single agents in HCC is promising, the 
majority of the patients remain refractory, due to the immunosuppressive mechanisms of HCC, 
comprising multiple humoral mediators and suppressive checkpoint molecules. Combination 
therapies may improve antitumor efficacy, and a number of studies evaluating different 
combination strategies are currently ongoing in the HCC field.38,55 
Owing to the multiplicity of mechanisms used by tumors to evade the immune response, 
combining different immunotherapeutic agents with different mechanisms of action is an 
appealing approach to treat HCC, which offers the possibility of an additive to synergistic 
response. The most relevant example is dual CTLA-4 and PD-1/PD-L1 blockade. PD-1 and 
CTLA-4 are both co-inhibitory molecules, but evidence suggests that they use distinct mechanisms 
to limit T cell activation. Preliminary indirect data from peripheral T cell assessments suggest that 
a given T-cell checkpoint inhibitor may modulate host immune cell phenotypes, rendering them 
more susceptible to alternate checkpoint inhibitors and thereby enhancing antitumor 
activity.38,43,55 


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Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade is synergistic 
and may improve antitumor activity: 
• 
In vitro, combinations of nivolumab and ipilimumab increase interferon-gamma (IFN-γ) 
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction (MLR).53 
• Several preclinical syngeneic tumor models showed that combined treatment with anti-murine 
PD-1 and anti-murine CTLA-4 monoclonal antibody resulted in increased antitumor responses 
over either monoclonal antibody alone, which were greatest when the antibodies were given 
together rather than sequentially.53 In some instances, combined treatment resulted in 
tumor-free mice that exhibited long-lived tumor immunity when re-challenged with tumor 
cells.53 
• 
In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies 
increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor-infiltrating 
T effector cells, and dual blockade increased tumor infiltration of T effector cells and decreased 
intratumoral Tregs, as compared to either agent alone, suggesting a synergistic effect.56 
 
In the clinic, combination therapies with monoclonal antibodies blocking PD-1 or PD-L1 and 
CTLA-4 have resulted in higher response rates and improved outcomes over monotherapy in a 
number of solid tumors.1 In HCC, both durvalumab and tremelimumab57 and nivolumab and 
ipilimumab3 combinations were evaluated in Phase 1/2 clinical trials as 2L therapy in advanced 
HCC. While data are still limited, preliminary results demonstrate the antitumoral activity of these 
combinations, and show an acceptable safety profile, providing scientific rationale to further 
evaluate the role of dual checkpoint blockade in the treatment of advanced HCC. 
Please see Section 3.2.7 (Nivolumab Combined with Ipilimumab Clinical Activity) and 
Section 3.2.8 (Nivolumab Combined with Ipilimumab in HCC) for information on the clinical 
activity and safety of the combination nivolumab and ipilimumab. 
3.2.4 
Nivolumab Mechanism of Action 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immunosurveillance 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.58,59,60 
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 (TCR).61 Collectively, these signals govern 
the balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, inducible T cell co-stimulator (ICOS), and B- and T-lymphocyte attenuator (BTLA).62 


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PD-1 signaling has been shown to inhibit CD28-mediated upregulation of interleukin (IL)-2, 
IL-10, IL-13, IFN-γ, and B-cell lymphoma-extra large (Bcl-xL). PD-1 expression also been noted 
to inhibit T cell activation and expansion of previously activated cells. Evidence for a negative 
regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a variety of 
autoimmune phenotypes.63 These results suggest that PD-1 blockade has the potential to activate 
anti-self T-cell responses, but these responses are variable and dependent upon various host genetic 
factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to 
self-antigens. 
Nivolumab (also referred to as BMS-936558) is a human monoclonal antibody (HuMab; 
immunoglobulin G4 [IgG4]-S228P) that targets the PD-1 CD279 cell surface membrane receptor. 
Binding of PD-1 to its ligands, PD-L1 and programmed death-ligand 2 (PD-L2), results in the 
downregulation of lymphocyte activation. 
In vitro, nivolumab binds to PD-1 with high affinity (half-maximal effective concentration [EC50] 
0.39-2.62 nM) and inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (half-maximal 
inhibitory concentration [IC50] ± 1 nM). Nivolumab binds specifically to PD-1 and not to related 
members of the CD28 family such as CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 
pathway by nivolumab results in a reproducible enhancement of both proliferation and IFN-γ 
release in the MLR. Using a cytomegalovirus (CMV) re-stimulation assay with human peripheral 
blood mononuclear cells (PBMCs), the effect of nivolumab on antigen-specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells in a dose- 
dependent manner vs isotype-matched control. In vivo blockade of PD-1 by a murine analog of 
nivolumab enhances the anti-tumor immune response and results in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).64 
3.2.5 
Ipilimumab Mechanism of Action 
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin (Ig) superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses.65 Ipilimumab (BMS-734016) is a fully 
human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from 
human and nonhuman primates. The proposed mechanism of action for ipilimumab is interference 
of the interaction of CTLA-4 with B7 molecules on antigen-presenting cells, with subsequent 
blockade of the inhibitory modulation of T-cell activation promoted by the CTLA-4:B7 
interaction. 
3.2.6 
Nivolumab Monotherapy for Hepatocellular Carcinoma 
Nivolumab is currently being evaluated in 3 settings for HCC in BMS-sponsored studies for HCC 
(refer to the nivolumab Investigator’s Brochure [IB]1 for additional details). CA209040 is a Phase 
1/2 non-comparative study of nivolumab (alone or in combination with ipilimumab or 
cabozantinib) in participants with advanced HCC with or without chronic viral hepatitis. For first- 
line (1L) advanced HCC, CA209459 is a Phase 3 randomized study of nivolumab vs sorafenib as 
1L treatment in participants with advanced HCC. For early-stage HCC, CA2099DX is a Phase 3 


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randomized, double-blind study of adjuvant nivolumab vs placebo for participants with HCC who 
are at high risk of recurrence after curative hepatic resection or ablation. 
CA209040 showed that monotherapy with nivolumab in participants with advanced HCC 
produced durable responses and disease stabilization, irrespective of HCC etiology and regardless 
of prior therapy with sorafenib. Updated data from a 16-Nov-2017 database lock (minimum 
follow-up of 24 months) revealed a blinded independent central review (BICR)-confirmed 
objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
of 14.3% (95% confidence interval [CI]: 9.2, 20.8) in the 154 sorafenib-treated (2L) participants 
who received nivolumab 3 mg/kg IV Q2W. Responses were observed across participants with both 
viral and non-viral HCC. 
despite the longer follow-up, a median DOR was not yet reached (95% CI: 9.69 months, not 
applicable [NA]) with 9 of 22 (41%) participants having an ongoing response. OS in 2L 
participants is promising, with a median OS of 15.15 months (95% CI: 13.04, 18.23). In addition 
to the clinical benefit observed in 2L participants, efficacy data in sorafenib-naive (1L) participants 
(n = 80) are even more compelling: ORR, 20% (95% CI: 11.9, 30.4) by BICR-confirmed 
RECIST v1.1; median DOR, not yet reached (95% CI: 11.1 months, NA); and median OS, 
26.68 months (95% CI: 16.56, 35.48). Safety data support an acceptable and manageable safety 
profile (data on file). 
These data indicate that nivolumab monotherapy has clinically meaningful antitumor activity in 
patients with advanced HCC with an acceptable and manageable safety profile. The observed 
durable responses and substantially longer OS relative to OS data from targeted agents, including 
historical  data  for  sorafenib  (10.7  months),49  regorafenib  (10.6  months),50 
lenvatinib (13.6 months),66 and cabozantinib (10.2 months),67 provide persuasive evidence to 
further evaluate nivolumab in HCC. 
3.2.7 
Nivolumab Combined with Ipilimumab Clinical Activity 
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules. The following information describes the results of initial early phase clinical studies 
that were the basis for the nivolumab plus ipilimumab combination regimens that have been 
explored in late-phase clinical development. Additional information as well as a detailed 
description of the chemistry, pharmacology, efficacy, and safety of nivolumab and ipilimumab is 
provided in the IB.1 
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly 
with ascending doses of ipilimumab in participants with unresectable or metastatic melanoma. In 
each arm in this multi-arm study, ipilimumab was administered once every 3 weeks (Q3W) for 
4 doses with nivolumab administered once Q3W for 8 doses. Starting at week 24, ipilimumab and 
nivolumab were administered once every 12 weeks (Q12W) for 8 doses. The 3 initial 
dose-escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg + ipilimumab 3 mg/kg; 
n = 14), Cohort 2 (nivolumab 1.0 mg/kg + ipilimumab 3 mg/kg; n = 17), and Cohort 3 (nivolumab 
3 mg/kg + ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a which 


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evaluated nivolumab 3 mg/kg + ipilimumab 1 mg/kg (n = 16). The primary objective was to assess 
safety/tolerability; the secondary objective was to assess preliminary efficacy. 
Of the 52 participants evaluable for response as of the 15-Feb-2013 clinical cut-off in CA209004, 
21 participants (40%) had an objective response by modified World Health Organization (mWHO) 
criteria. In an additional 2 participants (4%), there was an unconfirmed objective response. In 
Cohort 1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 14 evaluable participants had an 
objective response by mWHO (21%), including 1 complete response (CR) and 2 PRs. In Cohort 2 
(1 mg/kg nivolumab + 3 mg/kg ipilimumab), 9 out of 17 (53%) evaluable participants had an 
objective response by mWHO, including 3 CRs (18%) and 6 PRs (35%). In Cohort 2a (3 mg/kg 
nivolumab + 1 mg/kg ipilimumab), 6 out of 15 (40%) evaluable participants had an objective 
response by mWHO, including 1 CR (7%) and 5 PRs (33%). In Cohort 3 (3 mg/kg nivolumab + 
3 mg/kg ipilimumab), 3 out of 6 (50%) evaluable participants had an objective response by 
mWHO, all 3 of which were PRs (50%). 
Preliminary analysis revealed 16 of the 52 evaluable participants (31%) had > 80% reduction in 
the size of target tumor lesions by the week 12 evaluation. This is compared to < 2% for 3 mg/kg 
ipilimumab monotherapy based on CA184020 (N = 540) and < 3% for nivolumab monotherapy 
based on CA209003 (N = 94, 0.1-10 mg/kg). 
The following dose-limiting toxicities (DLTs) were observed: in Cohort 1, Grade 3 elevated 
AST/ALT (1 participant); in Cohort 2, Grade 3 uveitis (1 participant) and Grade 3 elevated 
AST/ALT (1 participant) and in Cohort 3, Grade 4 elevated lipase (2 participants), and Grade 3 
elevated lipase (1 participant). Based on these data, Cohort 2 was identified as the maximum 
tolerated dose (MTD) and Cohort 3 exceeded the MTD. 
A total of 53 melanoma participants were treated with nivolumab combined with ipilimumab in 
CA209004 across Cohorts 1, 2, 2a, and 3. At least 1 AE, regardless of causality, has been reported 
in 98% of participants treated. The most common (reported at > 10% incidence) treatment-related 
AEs  (any  Grade  93%;  Grade  3-4  53%)  are  rash  (55%;  4%),  pruritus  (47%;  0%), 
vitiligo (11%; 0%), 
fatigue (38%; 
0%), 
pyrexia (21%; 
0%), 
diarrhea (34%; 
6%), 
nausea (21%; 0%), vomiting (11%; 2%), ALT increased (21%; 11%), AST increased (21%; 13%), 
lipase increased (19%; 13%), amylase increased (15%; 6%), headache (11%; 0%), and cough 
(13%; 0%). 
The majority of AEs leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 participants, 21%). Grade 3 events included lipase increased, ALT increased, 
AST increased, troponin I increased, colitis, diverticular perforation, pancreatitis, tachycardia, 
renal failure acute, choroiditis, autoimmune disorder, and pneumonitis. One participant each 
discontinued due to Grade 4 events of blood creatinine increased and AST increased. No 
drug-related deaths were reported.53 
The combination of nivolumab with ipilimumab is being studied in the Phase 1 study CA209016. 
Participants with metastatic renal cell carcinoma (RCC; Karnofsky performance status ≥ 80%; 
untreated or any number of prior therapies) were randomized to receive nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) 


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IV Q3W for 4 doses followed by nivolumab 3 mg/kg IV Q2W until progression/toxicity. The 
primary objective was to assess safety/tolerability; secondary objective was to assess antitumor 
activity. 
Participants were randomized to N3 + I1 (n = 47) and N1 + I3 (n = 47). Approximately 
half (n = 46; 51%) had prior systemic therapy (N3 + I1: 22; N1 + I3: 26). 
After a median follow-up of 22.3 months, the confirmed ORR per RECIST v1.1 was 40.4% 
(N = 47) in both arms N3 + I1 and N1 + I3; 42.1% (n = 8) and 36.8% (n = 7) had an ongoing 
response,  with  a  median  DOR  of  88.7  weeks  (95%  CI:  37.14,  NA)  and 
85.9 weeks (95% CI: 35.14, NA), respectively. Median progression-free survival (PFS) was 
7.7 months (95% CI: 3.71, 14.29) and 9.4 months (95% CI: 5.62, 18.63) in Arms N3 + I1 and 
N1 + I3, respectively. OS at 12 months was 80.9% and 85.0% in arms N3 + I1 and N1 + I3, 
respectively, and at 24 months was 67.3% and 69.6%, respectively. 
The safety of nivolumab combined with ipilimumab was assessed in study CA209016. 
Treatment-related AEs were seen in 88 of 94 participants (94%), including 43 of 47 (92%) in 
N3 + I1 and 45 of 47 (96%) in N1 + I3. The most frequently reported drug-related AEs in N3 + I1 
included fatigue (66%), cough (53.2%), and arthralgia (51.1%), the majority of which were 
Grade 1-2. The most frequently reported drug-related AEs in N1 + I3 included fatigue (74.5%), 
nausea (55.3%), and diarrhea (53.2%). The majority were Grade 1-2. 
Treatment-related AEs leading to discontinuation (31.9% vs 10.6%), and treatment-related serious 
adverse events (SAEs; 34% vs 23.4%) occurred more commonly in participants in the N1 + I3 arm 
than in the N3 + I1 arm, respectively.3 
CA209012 was a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in 
participants with chemotherapy-naive advanced non-small cell lung cancer (NSCLC), as either a 
monotherapy or in combination with other agents including ipilimumab, at different doses and 
schedules. The primary endpoint of the study was safety with secondary endpoints of ORR per 
RECIST v1.1 and 24-week progression-free survival (PFS). Participants were assigned to receive 
nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q12W (n = 38), nivolumab 3 mg/kg Q2W + 
ipilimumab 1 mg/kg every 6 weeks (Q6W; n = 39) and nivolumab 3 mg/kg Q2W (n = 52). The 
confirmed ORR was 47% (N3 Q2W + I1 Q12W), 39% (N3 Q2W + I1 Q6W), and 23% (N3 Q2W). 
The median DOR was not reached in any of these groups. 
The rate of treatment-related AEs in the Q12W (82%) and Q6W (72%) arms were comparable to 
monotherapy (72%). In the study, Grade 3 to 4 AEs 37%, 33%, and 19% for the Q12W, Q6W, and 
nivolumab monotherapy arms, respectively. Treatment-related Grade 3 to 4 AEs led to 
discontinuation in 5% and 8% of participants in the Q12W and Q6W cohorts, respectively, and 
were similar to nivolumab monotherapy. There were no treatment-related deaths. The 
treatment-related select AEs in participants administered the optimized dosing schedule (3 mg/kg 
of nivolumab Q2W plus 1 mg/kg of ipilimumab Q6W) were skin related (36%), gastrointestinal 
(23%), endocrine (20%), and pulmonary (5%) and there were ≤ 5% treatment related Grade 3 and 
Grade 4 AEs per category.68 Nivolumab in combination with ipilimumab is FDA approved for the 


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treatment of unresectable or metastatic melanoma, advanced RCC, and microsatellite instability 
(MSI)-high metastatic colorectal cancer (CRC).69,70 
3.2.8 
Nivolumab Combined with Ipilimumab in HCC 
Nivolumab and ipilimumab combination is currently being evaluated as 2L therapy for advanced 
HCC in CA209040, a Phase 1/2 non-comparative, multi-cohort study of nivolumab (alone or in 
combination with ipilimumab or cabozantinib) as 1L/2L treatment in participants with advanced 
HCC with or without chronic viral hepatitis and in CA2099DW, a Phase 3 randomized study of 
nivolumab in combination with ipilimumab vs sorafenib or lenvatinib as 1L treatment in 
participants with advanced HCC. 
CA209040 was initially designed as a Phase 1 dose-escalation study to investigate the safety, 
immuno-regulatory activity, pharmacokinetics (PK), and preliminary antitumor activity of 
nivolumab monotherapy in advanced HCC. Dose escalation occurred in 3 parallel cohorts by 
etiology (uninfected, HBV-infected, and HCV-infected). Participants (n = 48) with histologically 
confirmed advanced HCC and Child-Pugh score ≤ 7, who previously failed or were intolerant of 
sorafenib, received nivolumab at doses ranging from 0.1 to 10 mg/kg for up to 2 years. Following 
preliminary data showing responders in all cohorts, the study was expanded to confirm the safety 
and efficacy of nivolumab monotherapy in a diverse group of participants with advanced HCC. 
In this phase (EXP Cohort), 214 participants were enrolled in 4 parallel cohorts (uninfected 
sorafenib-naive/intolerant, uninfected sorafenib progressors, HCV-infected, and HBV-infected), 
and received nivolumab 3 mg/kg IV Q2W.3 Please refer to Section 3.2.6 (Nivolumab Monotherapy 
for Hepatocellular Carcinoma) for information on the clinical activity and safety of nivolumab 
monotherapy in HCC. 
Once the safety and efficacy of nivolumab monotherapy was established, the study was amended 
to add a cohort aimed to evaluate the safety and efficacy of the combination of nivolumab and 
ipilimumab as 2L therapy. A total of 148 participants with histologically confirmed advanced HCC 
(87.8% had vascular invasion [VI] or extrahepatic spread [EHS]; and 43.9% had alpha-fetoprotein 
[AFP] ≥ 400 ng/mL) and Child-Pugh score ≤ 6, who had previously failed or were intolerant of 
sorafenib, were randomized to 1 of the following 3 dose arms: 
• Arm A (N1+I3 Q3W): nivolumab 1 mg/kg and ipilimumab 3 mg/kg Q3W for 4 doses, followed 
by nivolumab 240 mg Q2W (n = 50) 
• Arm B (N3+I1 Q3W): nivolumab 3 mg/kg and ipilimumab 1 mg/kg Q3W for 4 doses, followed 
by nivolumab 240 mg Q2W (n = 49) 
• Arm C (N3 QW2+I1 Q6W): nivolumab 3 mg/kg Q2W and ipilimumab 1 mg/kg Q6W (n = 49) 
 
Results from CA209040 (interim analysis; database lock, 22-Mar-2019)3 show that treatment with 
nivolumab and ipilimumab in participants with advanced HCC produced durable responses and 
prolonged survival, irrespective of HCC etiology. Overall, the confirmed ORR by BICR 
assessment (using RECIST v1.1 criteria) was 31.0%, with response rates fairly comparable, 
regardless of dose arm (32% for Arm A, 31% for Arm B, and 31% for Arm C). However, a higher 


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rate of CR was observed with N1+I3 QW3 (4 [8%] CR for Arm A, 3 [6%] CR for Arm B, and no 
CR for Arm C). An additional 26.4% of participants had PR (24%, 24%, and 31% in Arm A, 
Arm B, and Arm C, respectively). 
Responses were meaningful and durable with a median DOR of 17.5 months (range: 4.6, 30.5) in 
Arm A, 22.2 months (range: 4.2, 29.9) in Arm B, and 16.6 months (range: 4.1, 32.0) in Arm C. 
Of note, responses were observed across all HCC etiologies (overall ORR of 15.2%, 30.7%, and 
39.4% for uninfected [n = 33], HBV-infected [n = 75], and HCV-infected [n = 33], respectively) 
and regardless of dosing arm. Participants who received treatment with N1+I3 Q3W (Arm A) 
showed a more consistent response rate across etiological subgroups (30.8%, 32.1%, and 28.6% 
for uninfected [n = 13], HBV-infected [n = 28], and HCV-infected [n = 7]) but the small size of 
some subgroups in other treatment arms precludes drawing any definitive conclusion. 
With regards to OS, with a minimum follow-up of 28.0 months, participants treated with N1+I3 
Q3W had longer OS (22.80 months [95% CI: 9.4, N.A]) compared to those randomized to Arm B 
(12.48 months [95% CI: 7.6, 16.4]) or Arm C (12.75 months [95% CI: 7.43, 33.0]), with 2-year 
survival rates of 48.2%, 30.2%, and 42.3%, respectively. 
The preliminary safety data from CA209040 (n = 146) indicate that nivolumab and ipilimumab 
was generally well tolerated, with a safety profile similar to the observed in other tumor types in 
terms of type of reported events; no new safety concerns were identified for nivolumab and 
ipilimumab. One death (reported in Arm A) was attributed to study drug by Investigator 
(pneumonitis, which occurred 79 days after last dose of study drug). Overall, as previously 
reported in other tumor types, the frequency of treatment-related AEs for the combination 
nivolumab and ipilimumab was higher compared to nivolumab monotherapy. By dosing arm, a 
higher frequency of treatment-related AEs (any grade or high grade) were reported in 
Arm A (93.9%; 53.1%) compared to Arm B (69.4%; 28.6%) and Arm C (79.2%; 31.0%). 
Similarly, the frequency of AEs leading to discontinuation was slightly higher in 
Arm A (n = 11; 22.0%) relative to Arm B (n = 3; 6.1%) and Arm C (n = 1; 2.1%), with 
diarrhea (n = 2) and liver test abnormalities (n = 2) being the most frequent reasons for 
discontinuation. Across the 3 arms, treatment-related AEs of increased AST (20.4% of participants 
in the N1+I3 Q3W and N3+I1 Q3W arms, and 13.0% in the N3+I1 Q6W arm) and increased 
ALT (16.3%, 14.3%, and 8.3% of participants in the N1+I3 Q3W, N3+I1 Q3W, and N3+I1 Q6W 
arms, respectively) were observed. These AEs were infrequently associated with treatment-related 
increased bilirubin (11.6% of participants across all arms; 6.1%, 0%, and 4.2% of participants in 
Arm A, Arm B, and Arm C, respectively), and infrequently led to treatment 
discontinuation (n = 2), being most of them manageable with established algorithms. 
Therefore, data from CA209040 demonstrate that nivolumab and ipilimumab has clinically 
meaningful antitumor activity with a manageable safety profile. 
3.2.9 
Immunotherapy and Loco-regional Therapy for HCC 
3.2.9.1 
Impact of Loco-regional Therapy on the HCC Immune Environment 
Loco-regional therapy has been shown to modulate the immune environment. Tregs are the 
dominant cells inducing tumor immune tolerance and thus have a significant role in the 


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development of HCC. An increased quantity of circulating Tregs in patients with HCC is 
associated with a high mortality rate and reduced survival.40 Spontaneous regression of untreated 
lesions has been reported after loco-regional treatment of liver tumors (“abscopal effect”). The 
latter is attributed to the induction of antitumor immunity by the loco-regional therapy.71,72,73 Data 
on the effect of TACE on immune function are limited but suggest that TACE results in immune 
environment change. In a study on the impact of TACE on immune function in 47 participants, 
significant increases in CD4+ T cells and decreases in CD8+ T cells were seen post-TACE, with 
a significant change in the ratio of CD4+/CD8+ T cells from 1.03 ± 0.14 vs 1.29 ± 0.14 (p < 0.05). 
The percentage of CD4+, CD25+ Tregs in CD4+ T cells and CD4+, CD25-high T cells post-TACE 
was reduced from 11.12 ± 3.58% prior to TACE to 7.58 ± 2.65% following TACE (p < 0.05) and 
from 3.34 ± 0.79% prior to TACE to 2.11 ± 0.67% following TACE (p < 0.05), respectively. This 
indicates that the proportion of Tregs following TACE treatment decreased with a reduction in its 
immunosuppressive function,74 and suggests a partial restoration of cellular immune function 
post-TACE. In another study in 51 participants, CD4+ cells and CD4/CD8 ratio decreased but 
CD8+ cells increased post-TACE in the subset of participants treated only with TACE (p < 0.05). 
This, in turn, suggested that TACE lowered immunologic function to a certain extent.75 
Despite variable reports, the data suggest immune environment modulation post-TACE and 
support clinical interest in combining loco-regional therapies with immune checkpoint blockade. 
Local tumor destruction via ablation, chemoembolization, or radioembolization all have the 
potential to differentially alter and enhance tumor-specific antigen presentation. Therefore, there 
exists a synergistic potential for immunotherapy and TACE and it will be of critical importance to 
assess how different methods of local tumor destruction and their timing can augment or be 
augmented by checkpoint blockade.76 
3.2.9.2 
Data on the Combination of Loco-regional Therapy with Checkpoint 
Inhibitors 
Preliminary clinical data for loco-regional therapy in combination with checkpoint inhibitors 
demonstrates a good safety profile and promising efficacy. In a study to evaluate whether 
tremelimumab could be combined safely and feasibly with TACE, radiofrequency ablation (RFA), 
or chemoablation in participants with advanced HCC, no DLTs were encountered. Of the 
19 evaluable participants, 5 (26.3% [95% CI: 9.1, 51.2]) achieved a confirmed PR. Six- and 
12-month probabilities of tumor PFS for this refractory HCC population were 57.1% and 33.1%, 
respectively,  with  median TTP of 7.4  months (95%  CI: 4.7, 19.4). Median OS was 
12.3 months (95% CI: 9.3, 15.4). The authors concluded that tremelimumab in combination with 
tumor ablation is a potential new treatment for patients with advanced HCC and leads to the 
accumulation of intratumoral CD8+ T cells.77 
3.2.9.3 
Nivolumab in Combination with TACE 
CA209731 is a multicenter study designed to test the hypothesis that nivolumab is safe in 
combination with TACE with drug-eluding beads (DEB-TACE) in unresectable HCC patients 
(BCLC Stage B) who are not candidates for hepatic transplantation and have Child-Pugh A hepatic 
function (ClinicalTrials.gov: NCT03143270).78 A modified 3 + 3 design sequentially enrolled 


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participants to define the safety and tolerability of nivolumab given at different times related to 
DEB-TACE. DEB-TACE was performed on Day 0. Nivolumab at 240 mg/m2 was administered 
every 14 days, but at 3 different schedules related to DEB-TACE (Cohort 1-sequential; 
Cohort 2-interrupted; and Cohort 3-continuous) for up to 1 year. DLTs were monitored for 4 weeks 
after combination treatment. 
As of 18-July-2019, 10 participants have been accrued on the study: 4 participants to Cohort 1, 
3 participants to Cohort 2, and 3 participants to Cohort 3. One participant was withdrawn from 
study due to the combination of mixed HCC-cholangiocarcinoma on pretreatment biopsy. 
Five participants have been removed from study due to progression of disease, and 2 remain on 
active treatment, while 2 remain on study in surveillance. Evaluable participants (9) were a median 
65 years of age (range: 54-76), male (89%), with a mixture of etiologic factors (viral [44%, 1 HBV, 
3 HCV] and non-viral [55.6%]), and all with Child-Pugh A liver function. HCC substage included 
3 B1 (33%), 4 B2 (44%), and 2 C (22%). Most participants received prior surgery (44%) and/or 
regional therapy (44%), while 3 (33%) were treatment naive. Median AFP for the study population 
was 22.5 (range: 6-5914) ng/mL. No cases of treatment-related liver failure or DLT in the 3 cohorts 
have occurred. There were no Grade 4 or higher AEs. Grade 3 events at least possibly related to 
nivolumab, DEB-TACE, or both, included: transaminases (AST or ALT) elevation (n = 4), 
post-embolization syndrome (PES; n = 1), lipase increase (n = 1), hypothyroidism (n = 1), and 
post-procedural groin hematoma (1). Regarding 4 AEs of Grade 3 increase in AST/ALT, 
2 occurred immediately post-embolization and were attributed to DEB-TACE; the other 2 AEs 
occurred outside the DLT window and were attributed to be possibly related to nivolumab. 
All Grade 3 events resolved with appropriate medical management. The efficacy data is still 
immature at the time of reporting. 
In summary, current data support the potential of immunotherapy for HCC therapy. Immune 
checkpoint inhibitors have clinical activity and are tolerable in advanced HCC, supporting their 
potential for use in other stages of the disease. Data on loco-regional therapy indicate that these 
procedures induce changes in the immune environment that suggest a synergistic potential for the 
combination of loco-regional therapy with immunotherapy. The preliminary data from 
tremelimumab in combination with ablation and from nivolumab in combination with TACE 
indicate that the combinations are feasible and tolerable. The combination of TACE with 
nivolumab and ipilimumab has the potential to address the need for better therapeutic options for 
intermediate-stage HCC and support further investigation of nivolumab and ipilimumab in 
combination with TACE in this setting. 
3.3 
Benefit/Risk Assessment 
The current standard of care (SOC) for intermediate-stage HCC patients, unsuitable for potentially 
curative therapy, is loco-regional therapy with TACE.79,80,81 Although significant tumor response 
can be achieved, TACE often fails to induce complete necrosis of the lesion. Even in cases where 
complete ablation is achieved, tumors commonly recur post-TACE. Thus, TACE is considered a 
palliative treatment and preventing tumor recurrence in this population remains a significant unmet 
medical need, as there are no other established therapeutic options available. 


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The overall benefit-risk of nivolumab and ipilimumab or nivolumab in combination with TACE 
over TACE in patients with intermediate-stage HCC is not yet known. However, in clinical trials, 
nivolumab and ipilimumab and nivolumab alone have demonstrated an acceptable benefit-risk 
ratio with clinical activity and a tolerable AE profile across multiple tumor types including HCC. 
Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of non-live vaccines (including non-live COVID-19 vaccines) in 
participants receiving nivolumab and ipilimumab or nivolumab alone are unknown. 
3.3.1 
Nivolumab and Ipilimumab Safety Profile 
Extensive details on the safety profile of nivolumab and nivolumab in combination with 
ipilimumab in multiple tumors are available in the IBs.1,82 
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level.1 
The recently reported clinical trial CA209040 Cohort 4 characterized the safety and efficacy of 
different doses of nivolumab and ipilimumab in participants with advanced HCC who progressed 
on sorafenib. The overall frequency of AEs (any Grade, Grade 3-4) were similar in all 3 treatment 
arms. Frequencies of drug-related AEs (any Grade, Grade 3-4) were numerically higher in the 
N1+I3 Q3W arm relative to the N3+I1 Q3W, and N3+I1 Q6W arms. The overall frequencies of 
SAEs were consistent between the N1+I3 Q3W, N3+I1 Q3W, and N3+I1 Q6W arms, but a trend 
for higher drug-related SAEs was seen in the N1+I3 Q3W arm. The overall frequencies of 
all-causality AEs leading to discontinuation and drug-related AEs leading to discontinuation were 
also numerically higher in the N1+I3 Q3W arm relative to the N3+I1 Q3W and N3+I1 Q6W arms. 
The most frequent drug-related AEs across the 3 dose arms were in the skin and subcutaneous 
tissue disorders (48-61%), investigations (31-49%), and GI disorders (35-37%) system organ 
classes; however, these infrequently led to discontinuations due to drug-related AEs. Drug-related 
AST/ALT increases were observed in 20.4%/16.3%, 20.4%/14.3%, and 12.5%/8.3%, in the 
N1+I3 Q3W, N3+I1 Q3W, and N3+I1 Q6W arms, respectively. However, drug-related increases 
in bilirubin were typically not associated with aminotransferase increases and occurred in 
6.1%/0%/4.2%, respectively, and were all low-grade. Drug-related hepatic discontinuations within 
30 days of last dose of study drug were infrequent and occurred in 3 of 49 (6.1%), 2 of 49 (4%), 
and 0 of 48 (0%) subjects in the N1+I3 Q3W, N3+I1 Q3W, and N3+I1 Q6W arms, respectively. 
Please refer to Section 3.2.8 (Nivolumab Combined with Ipilimumab in HCC) for further details. 
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 6. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms.1 Additional details on the safety profile of nivolumab and ipilimumab, including 
results from other clinical studies, are also available in the nivolumab and ipilimumab IBs.1,82 


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3.3.2 
Clinical Experience with Nivolumab and Ipilimumab in HCC 
In HCC, the clinical activity of nivolumab monotherapy observed to date includes data from the 
Phase 1/2 study CA209040, which demonstrated clinically meaningful antitumor activity in the 
advanced setting, regardless etiology and prior therapy with sorafenib.3 The observed durable 
responses and substantially longer OS relative to historical data is particularly remarkable 
considering the unfavorable characteristics of the study population. Additionally, safety data 
showed a safety profile similar to that observed in other tumor types, in terms of the type, 
frequency, and severity of reported events, with no new safety concerns. Treatment-related AEs 
most frequently reported (mostly Grade 1 or 2) were fatigue, pruritus, rash, and diarrhea. 
Of particular interest in the context of HCC is the observed hepatic toxicity. Treatment-related 
AST, ALT, and bilirubin elevations were observed at a slightly increased frequency as compared 
to the nivolumab program overall, but were generally mild, manageable with established treatment 
algorithms, and reversible, with very few discontinuations due to hepatic events. In addition, 
AST/ALT increases typically occurred without change in other hepatic parameters and were more 
frequently observed in participants with higher values at baseline. Taken together, these results 
suggest the potential for improved clinical outcomes with nivolumab in the intermediate-stage 
setting, without impacting the overall safety profile. 
Nivolumab and ipilimumab demonstrated clinically meaningful activity in participants with 
advanced HCC in the 2L or higher setting after sorafenib treatment. The ORR was 32%, 30.6%, 
and 30.6% and DOR was 17.48, 22.21, and 16.59 months by BICR for N1+I3 Q3W, N3+I1 Q3W, 
and N3+I1 Q6W arms, respectively. This compares favorably with other approved therapies for 
post-sorafenib 2L advanced HCC: 14.3% with nivolumab monotherapy, 7% with regorafenib, 
5% with ramucirumab, and 4% with cabozantinib. 
In summary, based on the high unmet medical need in this clinical setting, the robust clinical 
activity demonstrated by nivolumab and ipilimumab in advanced HCC, and the manageable safety 
profile, the overall potential benefits of a combination of nivolumab and ipilimumab or nivolumab 
with TACE in this population outweigh the potential clinical risks. Nevertheless, in order to 
mitigate potential risks, a Data Monitoring Committee (DMC) will be involved in the study to 
periodically evaluate the emerging data and trends (see Section 5.1.5.1 [Data Monitoring 
Committee]). 
4 
OBJECTIVES AND ENDPOINTS 
Per Protocol Amendment 01, no analyses of efficacy, quality of life (QoL)/PROs, healthcare 
resource utilization, PK, or IMG are planned. Only safety assessments will be conducted. 
Previously collected biomarker samples may be analyzed, but no further biomarker collections are 
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Table 4-1: 
Objectives and Endpoints 
 
Objective 
Endpoint 
• 
To evaluate the safety and tolerability of Arm A, Arm 
B, and Arm C in all treated participants. 
• 
Incidence of AEs, SAEs, deaths, AEs leading to 
discontinuation, and laboratory abnormalities in 
all treated participants. 
Abbreviations: AE = adverse event; SAE = serious adverse event. 
 
 
5 
STUDY DESIGN 
5.1 
Overall Design 
This is a double-blind, placebo-controlled, 3-arm, randomized Phase 3 study of nivolumab and 
ipilimumab in combination with TACE and nivolumab in combination with TACE vs placebo in 
combination with TACE in patients with intermediate-stage HCC. Participants must have tumor 
characteristics that exceed the Beyond Milan and Up-to-7 (BMU7) criteria, no EHS, no regional 
lymph node involvement, no portal vein thrombosis, and no macrovascular invasion (MVI) must 
be present. As of 22-Sep-2021, enrollment for new participants was closed. The number of 
participants randomized was 26 as of 14-Oct-2021. Per Protocol Amendment 01, there are no 
formal hypotheses or efficacy objectives for CA20974W. Only safety assessments will be 
conducted. Following unblinding, study participants who are currently receiving nivolumab ± 
ipilimumab and tolerating study treatment may continue to receive study drug; however, placebo 
infusions will no longer be administered. 
The study will consist of 3 periods: Screening, Treatment, and Follow-up. For a complete list of 
study required procedures, please see Section 2 (Schedule of Activities). 
After signing an informed consent form (ICF), participants who have not previously received 
TACE will be evaluated for eligibility. If participants are eligible for receiving TACE and meet 
other eligibility criteria, they will be randomized in a 1:1:1 ratio to receive nivolumab and 
ipilimumab plus TACE (Arm A), nivolumab and ipilimumab placebo plus TACE (Arm B), or 
nivolumab placebo and ipilimumab placebo plus TACE (Arm C). Since TACE is the only 
recommended SOC in clinical practice guidelines for the intended population, TACE plus 
nivolumab placebo and ipilimumab placebo will be used as a control. Both conventional TACE 
and DEB-TACE are acceptable treatment modalities in this study (see Section 7.1.2 [TACE 
Procedure] for restrictions on TACE use) and will be administered 7 days (+3 days) after study 
drug administration. Randomization will be stratified by ALBI grade (Grade 1 vs Grade 2), 
baseline AFP level (< 400 ng/mL vs ≥ 400 ng/mL), and Region (West [EU, Americas, and 
Australia] vs Japan vs rest of Asia). 
Participants will receive blinded treatment with 1 of the following regimens: 
• Arm A: Nivolumab 240 mg Q2W and ipilimumab 1 mg/kg Q6W plus TACE 
• Arm B: Nivolumab 240 mg Q2W and ipilimumab placebo Q6W plus TACE 
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Per Protocol Amendment 01, this study will be unblinded and participants randomized to 
Arm B and Arm C will no longer receive placebo infusions following unblinding. 
All randomized participants will receive treatment until progression as assessed by investigator, 
unacceptable toxicity, or consent withdrawal, for a maximum duration of treatment of 2 years. 
Participants will also receive on-demand TACE during the trial and can continue to receive TACE 
until they are not eligible for further TACE (see Section 7.1.2 [TACE Procedure]). Participants in 
any arm may be treated with study therapy beyond progression as assessed by investigator under 
protocol-defined conditions (see Section 5.1.4 [Treatment Beyond Progression]). 
The study design schematic is presented in Figure 5.1-1. 


 
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Figure 5.1-1: 
Study Design Schematic 
 
 
Abbreviations: AFP = alpha-fetoprotein; ALBI = albumin-bilirubin; BMU7 = beyond Milan and up-to-7; ECOG = Eastern Cooperative Oncology Group; 
EHS = extrahepatic spread; EU = Europe; HCC = hepatocellular carcinoma; N0 = no regional lymph node metastasis; PS = performance status; Q2W = every 
2 weeks; Q6W = every 6 weeks; TACE = trans-arterial chemoembolization; VP0 = no portal vein thrombosis; Vv0 = no macrovascular invasion. 
a Number of nodules ≥ 1 cm + diameter of largest nodule in cm = 7. 
b Per Protocol Amendment 01, participants randomized to Arm B and Arm C will no longer receive placebo following unblinding. Participants randomized 
to nivolumab and ipilimumab plus TACE (Arm A), nivolumab plus TACE (Arm B), or TACE alone (Arm C) will receive treatment until progression as assessed 
by investigator (unless treatment beyond progression was allowed), unacceptable toxicity, or consent withdrawal, for a maximum duration of treatment of 2 
years. 
c Per Protocol Amendment 01, all participants randomized will have 30- and 100-day safety follow-up visits. No survival follow-up visits will occur. 
 
 
 
 
 
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Study Population 
Screening 
Randomize 1:1:1 
Treatment Period b 
Follow-up Periodc 
Key Inclusion Criteria 
• Intermediate-stage HCC 
• No prior TACE 
• Tumor exceeds 
BMU7 criteriaa 
• Child-Pugh score 5-6 
• ECOG PS 0-1 
• No EHS, N0, VP0, Vv0 
Arm C 
TACE 
Arm B 
Nivolumab 240 mg Q2W + 
TACE 
Stratify by: 
• ALBI grade (1 vs 2) 
• AFP level (< vs = 400 ng/mL) 
• Region (West [EU, Americas, and 
Australia] vs Japan vs rest of Asia) 
Arm A 
Nivolumab 240 mg Q2W + 
Ipilimumab 1 mg/kg Q6W + 
TACE 
Safety Follow-up 
30-Day 
100-Day 


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5.1.1 
Screening Period 
The screening assessments are shown in Table 2-1. 
• Screening procedures are to occur within 28 days prior to first dose. 
• Screening begins by establishing the participant’s initial eligibility and signing of the ICF. 
• Participant is enrolled using the interactive response technology (IRT) system. 
• Participant is assessed for study eligibility according to the inclusion (Section 6.1) and 
exclusion (Section 6.2) criteria. 
• Sufficient, recent tumor tissue obtained within 3 months prior to randomization from a lesion 
from an unresectable primary tumor lesion that has not been previously irradiated 
(formalin-fixed, paraffin-embedded [FFPE] block or minimum of 20 slides, obtained from core 
biopsy, punch biopsy, excisional biopsy, or surgical specimen) will be submitted to the central 
laboratory. Fine needle aspirates or other cytology samples are not acceptable. If despite best 
efforts, a minimum of 20 slides are not obtainable, submission of fewer slides may be 
acceptable in some circumstances following discussion with BMS Medical Monitor or Clinical 
Scientist. The central laboratory must provide IRT with confirmation of receipt of evaluable 
tumor tissue prior to randomization. Participants should not have received any systemic 
anticancer therapy after the date that the submitted tumor tissue was obtained. Please see 
Appendix 9 for country-specific criteria for the collection of tumor tissue samples in China. 
• Images must be submitted for BICR to confirm eligibility. 
• The Screening Period either ends with confirmation of full eligibility and randomization for 
the participant, or with the confirmation that the participant is a screen failure. 
• This study permits the re-enrollment of a participant that has discontinued the study as a 
pretreatment failure prior to randomization (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be re-consented. A new participant 
identification number will be assigned by IRT at the time of re-enrollment (see Section 6.4.1 
[Retesting During Screening or Lead-in Period]). 
 
5.1.2 
Treatment Period 
The on-treatment procedures are shown in Table 2-2. 
• The Treatment Period begins with the randomization call to the IRT system. The participant is 
randomly assigned to 1 of the 3 treatment arms: 
− Arm A: Nivolumab 240 mg Q2W and ipilimumab 1 mg/kg Q6W plus TACE 
− Arm B: Nivolumab 240 mg Q2W and ipilimumab placebo Q6W plus TACE 
− Arm C: Nivolumab placebo Q2W and ipilimumab placebo Q6W plus TACE 
Note: The study will be unblinded per Protocol Amendment 01. After unblinding, 
participants in Arms B and C will no longer receive placebo. 
• Administration of study treatment must begin within 3 calendar days after randomization. 
• First TACE will be administered 7 days (+3 days) after study drug administration. Participants 
will receive study treatment until progression as defined by investigator (unless treatment 
beyond progression is permitted), unacceptable toxicity, or consent withdrawal for a maximum 
duration of treatment of 2 years. See Section 5.1.4 (Treatment Beyond Progression). 


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• On-demand TACE is allowed and should be given with at least a 7-day window for systemic 
therapy. See Section 7.1.2 (TACE Procedure) for further details on TACE. 
• Specific requirements for participants treated in any arm, including dose delays or interruptions 
and treatment discontinuation criteria, are described in Section 7.4 (Dosage Modification) and 
Section 8.1.1 (Treatment Discontinuation Criteria), respectively. 
• Women of childbearing potential (WOCBP) must have a documented negative pregnancy test 
within 24 hours prior to the start of study treatment. For additional assessments, see Table 2- 
2. 
• On-study vital sign assessments should be performed at each on-treatment visit (see Table 2- 
2). 
• On-study laboratory assessments should be performed at each on-treatment visit and will be 
assessed at the local laboratory (see Table 2-2). 
• Efficacy assessments will occur in accordance with Table 2-2 per local standard of care until 
progression as assessed by investigator (unless treatment beyond progression is permitted) or 
treatment discontinuation (including treatment beyond progression), whichever occurs later. 
• Not applicable per Protocol Amendment 01: Biomarker sample collection will be done 
according to the schedule in Table 9.8-1. Please see Appendix 9 for country-specific criteria 
for the collection of biomarker samples 
. 
• Not applicable per Protocol Amendment 01: PK and immunogenicity (IMG) samples are to 
be collected predose and according to Table 9.5-1. 
• Not applicable per Protocol Amendment 01: Outcomes research assessments instruments 
(EuroQol-5 Dimensions-5 Levels [EQ-5D-5L] and Functional Assessment of Cancer 
Therapy-Hepatobiliary [FACT-Hep]) will be completed prior to treatment at the start of each 
cycle for the first 6 months, and then every third cycle thereafter during the Treatment Period 
(see Table 2-2). 
• The Treatment Period ends when the participant is discontinued from study therapy for any 
reason, or a maximum of 2-years total duration of study medication (if treatment not 
discontinued before). Please see Section 8 (Discontinuation Criteria) for a complete list of 
possible reasons for discontinuation. 
 
5.1.3 
Follow-up Period 
The follow-up procedures are shown in Table 2-3. 
• The Follow-up Period begins when the decision is made to discontinue a participant from study 
therapy (eg, due to toxicity or progression) or after study drug discontinuation (due to toxicity 
or progression) or treatment completion (2-years total duration), whichever comes first. 
• Participants will have 2 follow-up visits, follow-up visit 1 (FU1) and follow-up visit 2 (FU2) 
for safety within approximately 30 and 100 days from the last dose of study treatment, 
respectively. Both follow-up visits should be conducted in person, according to Table 2-3. 
− Follow-up visits include targeted physical examination, laboratory tests, tumor 
assessments (if applicable), and AE and concomitant medication assessments. Additional 
details and requirements are outlined in Table 2-3. 


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• Participants who discontinue study treatment for reasons other than radiographic disease 
progression (as assessed by investigator) will continue to have tumor assessments (if clinically 
feasible), according to the schedule in Table 2-3. 
• After completion of the first 2 follow-up visits, participants will be followed for ongoing 
treatment-related AEs until these events have resolved, returned to baseline, or are deemed 
irreversible. All toxicities will be documented for a minimum of 100 days after the last dose 
of study medication. Please refer to Section 9.2.4 for further details regarding follow-up of 
AEs and SAEs. 
• Not applicable per Protocol Amendment 01: Participants will be followed for survival status 
Q12W (±14 days) until death, withdrawal of consent for any further contact, lost to follow-up, 
or end of study. 
− Survival status may be ascertained by telephone contact if the participant is unable to return 
to the site for a visit. 
− If new antitumor therapy is initiated for disease progression or for a secondary malignancy 
at any time during this period, this and all other pertinent data obtained should be recorded 
on the appropriate electronic case report form (eCRF). 
 
5.1.4 
Treatment Beyond Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease.83 
Participants will be permitted to continue treatment beyond progression (as assessed by 
investigator) up to a maximum of 24 months from the date of randomization, as long as the 
following criteria are considered: 
• Investigator-assessed clinical benefit. 
• Tolerance of study drug(s). 
• Stable performance status. 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases). 
• Participant provides written informed consent prior to receiving additional treatment with the 
study drug regimen. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply. 
• Should be documented in the study records. 
 
Radiographic assessment/scan(s) should continue in accordance with Section 2 (Schedule of 
Activities) for the duration of the treatment beyond progression. 
If the Investigator feels that the study participant continues to achieve clinical benefit by 
continuing treatment, the participant should remain on the trial and continue to receive monitoring 
according to the Section 2 (Schedule of Activities). 


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The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with study therapy. 
5.1.5 
Data Monitoring Committee and Other External Committees 
5.1.5.1 
Data Monitoring Committee 
A DMC will be established to provide oversight and safety and efficacy considerations in the 
CA20974W study. On 22-Sep-2021, enrollment was closed and a total of 26 participants have 
been randomized. The DMC will provide advice to the Sponsor regarding actions the committee 
deems necessary for the continuing protection of participants enrolled/treated in the study. The 
DMC will be charged with assessing such actions in light of an acceptable benefit-risk profile for 
nivolumab and ipilimumab or nivolumab in combination with TACE. A safety review will be 
conducted by the DMC after all participants have been randomized and have been followed for a 
minimum of 6 weeks, unless decided otherwise by the DMC chair. After participants are unblinded 
as per Protocol Amendment 01, the Sponsor will continue safety monitoring of remaining 
participants on the study. No subsequent DMC meeting will occur after the first safety monitoring 
meeting. 
The BMS clinical study leadership will have responsibility for the overall conduct of the study, 
including managing the communication of study data. The group will be responsible for promptly 
reviewing the DMC recommendations, providing guidance regarding the continuation or 
termination of the study, and determining whether amendments to the protocol or changes to the 
study conduct are required. 
Details of the DMC responsibilities and procedures will be specified in the DMC Charter. 
5.1.5.2 
Blinded Radiology Review Committee 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
In addition to local tumor assessments by mRECIST, images from this study will undergo a BICR 
to assess TTTP and to assess response based on the modified RECIST assessment 
criteria (mRECIST) and RECIST v1.1 criteria. The centrally reviewed response data will be used 
in the analyses of TTTP, ORR, PFS, DOR, DCR, and time to response. All final determinations 
on centrally reviewed image-based endpoints will be made based on the independent assessments, 
for a uniform and unbiased assessment of outcome. Details of the procedures and the criteria for 
the central review are defined in a separate Imaging Charter. 
5.2 
Number of Participants 
As of 22-Sep-2021, enrollment for new participants was closed. The number of participants 
randomized was 26 as of 14-Oct-2021. 
5.3 
End of Study Definition 
The start of the trial is defined as the first participant’s first visit. End of trial is defined as the last 
participant’s last study visit or scheduled procedure shown in the Schedule of Activities (Section 2) 


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for the last participant. Study completion is defined as the final date on which data for the primary 
endpoint and survival follow-up was or is expected to be collected, if this is not the same. 
5.4 
Scientific Rationale for Study Design 
5.4.1 
Rationale for Study Population 
In clinical practice, TACE is used not only as a palliative therapy for patients with 
intermediate-stage HCC, but also a preoperative adjuvant therapy in patients with HCC to improve 
survival, and as a bridging therapy for the purposes of downstaging prior to liver transplantation 
or as bridging therapy while on the transplant waiting list.84,85,86,87 In addition, TACE is also used 
in clinical practice for advanced-stage HCC. This is premised on the fact that more than two-thirds 
of patients with advanced HCC die of liver failure or intrahepatic tumor progression, rather than 
from progression of metastatic disease.88,89,90 Investigations on the use of TACE in advanced HCC 
report a survival benefit in patients with vascular involvement or extrahepatic metastasis who 
underwent TACE instead of receiving best supportive care (BSC).90,91,92,93,94 The participant 
inclusion and exclusion criteria (see Section 6 [Study Population]) are intended to specify inclusion 
of only patients whose disease falls into the BCLC B category for intermediate-stage HCC, for 
whom TACE is recommended in treatment guidelines. 
Tumor characteristics must exceed the BMU7 criteria. The Milan criteria identify early-stage 
patients who are eligible for liver transplantation. There are, however, patients who present with 
HCC beyond the Milan criteria and can be downstaged for transplantation using loco-regional 
therapy. The tumor characteristics of the latter patients fulfill the Up-to-7 criteria and are therefore 
currently considered for transplantation and not the subject of this research. 
5.4.2 
Rationale for TTTP as a Dual Primary Endpoint 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Long OS in the TACE setting necessitates the use of a dual primary endpoint for an earlier 
assessment of clinical benefit. 
TACE treatment affords patients with long survivals. A 2016 meta-analysis review of conventional 
TACE in a large sample size of patients with HCC reported survivals in line with those from the 
seminal RCTs. Median OS was 19.4 months (95% CI: 16.2, 22.6).95 A 2017 network meta-analysis 
projected a similar median survival of 18.1 months (95% CI: 15.6, 21.6) for conventional TACE 
and a reduction in the hazard of death in the range of 24%.96 These data are aligned with the 
expected median survival of 20 months quoted in the 2012 European Society for Medical 
Oncology and the European Society of Digestive Oncology (ESMO-ESDO) guidelines.80 
However, a clear trend of progressively improving survival outcomes over the years has been 
observed.97 Various clinical studies and TACE analyses have reported median OS values higher 
than 19.4 months, ranging from 26.1 to 61 months.15,23,98,99,100,101,102 
The long OS poses challenges for demonstrating OS in the intermediate-stage TACE setting. This 
is not an uncommon challenge for earlier-stage cancer studies, given the relatively long survival 


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relative to later disease stages. The evaluation of OS in settings with long baseline survival 
commonly requires very long study durations and large numbers of participants. 
In addition, there has been an advent of new drug options for the treatment of advanced HCC; 
including atezolizumab in combination with bevacizumab, nivolumab in combination with 
ipilimumab, cabozantinib, lenvatinib, nivolumab, pembrolizumab, ramucirumab and regorafenib. 
These options are now available for HCC patients (in clinical studies or in clinical practice) after 
they migrate from an intermediate to an advanced stage. This raises concerns that efficacy of drugs 
administered in conjunction with TACE, as measured by OS, may be confounded by subsequent 
therapy in the advanced setting, thereby underestimating their true clinical benefit.103 Available 
data from studies using TACE in combination with systemic agents reflects the fact that both 
systemic and non-systemic therapies are used after patients discontinue from TACE studies and 
progress to the advanced stage of the disease.23,26 
The situation for TACE is not dissimilar to the challenges faced by earlier-stage cancer studies, 
where demonstration of OS is difficult given the relatively long OS relative to later stages of the 
disease. In the adjuvant setting for early stage HCC, alternative endpoints, such as relapse-free 
survival (RFS) and disease-free survival (DFS), have become increasingly important surrogate 
endpoints that have been broadly used and accepted by Investigators and regulators as meaningful 
primary endpoints.104,105,106,107 In a TACE setting, however, these exact endpoints do not have 
the same relevance and carry fundamental issues. 
Treatment with TACE follows a different paradigm for discontinuation of treatment. For systemic 
therapies, treatment is generally stopped when disease recurs or progresses. TACE treatment, 
however, can continue in the case of tumor progression (ie, in cases where there is regrowth of an 
initially responsive tumor or the appearance of a new lesion). In actual clinical practice, repeated 
TACE sessions are felt to increase the efficacy of TACE. Patients commonly receive multiple 
TACE treatments.25,108,109,110,111,112 The continued use of TACE in the face of progression raises 
the question of the suitability of endpoints such as DFS, RFS, and PFS in a TACE setting. 
Furthermore, the relevance of traditional tumor assessment-based endpoints, such as ORR and 
TTP, is questionable in a TACE setting. The application of RECIST-assessed ORR and TTP in a 
TACE setting is complicated by the nature of the TACE procedure and its continued application 
in the presence of disease progression or recurrence. In RECIST v1.1, target lesions are designated 
at participant entry into a clinical study and a sum of the diameters for all target lesions are 
calculated and reported as the baseline sum of diameters. The baseline sum of diameters then 
serves as the comparator for subsequent measurements. A CR is based on disappearance of all 
target lesions. A PR is based on a ≥ 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum of diameters.113 
This poses a dilemma in a TACE study setting because TACE destroys tumor tissue each time it 
is administered. TACE responses can be complete or partial, and is complete in as many as 
one-third of patients (28.2%).114,115 Pathology studies have shown that palliative trans-arterial 
lipiodol-based treatments may achieve > 90% tumor necrosis in 26-70% of the treated nodules, 
depending on technique, lesion size, and arterial anatomy.116,117 In a TACE setting, therefore, a 


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response soon after TACE (ie, CR or PR) is mainly attributable to the TACE treatment. An 
objective response post-TACE is the norm and the highest quality studies of conventional TACE 
show a clear trend of progressively improving ORRs over a 15-year period.95 In this setting, a 
systemic agent administered concurrently will not have sufficient time to further improve ORR. 
This is particularly true for immunotherapy agents that require time to stimulate the immune 
system and are known for their delayed cure effect.118,119 Even in a setting where immunotherapy 
agents are administered as monotherapy, there are advocates for a change in the established 
paradigm of response assessment and reconsideration of conventional efficacy endpoints for 
monotherapy immuno-oncology (IO) studies.118,119,120,121,122 A traditional RECIST-defined 
response may therefore not capture the effect of a systemic IO treatment appropriately, particularly 
in a TACE setting. 
These challenges have been observed in clinical studies. Two Phase 3 TACE studies in 
intermediate-stage HCC reported no correlation of ORR by RECIST or mRECIST with OS. In the 
exploratory analysis of the brivanib Phase 3 BRISK-TA study, the ORR was 48% in the brivanib 
group and 42% in the placebo group, with an odds ratio favoring brivanib (odds ratio, 
1.28 [95% CI: 0.90, 1.83]).23 Although sorafenib demonstrated improved OS in the 1L setting, in 
the sorafenib Phase 3 TACE-2 study, response assessments by both RECIST v1.1 and mRECIST 
showed no difference in participants treated with TACE + sorafenib vs TACE + placebo. The 
definition of an endpoint needs to have a biological rationale for its use and must take into context 
the setting in which it is applied. The RECIST guidelines for solid tumors were developed in the 
context of the ability of anticancer cytotoxic agents to generate varying degrees of tumor shrinkage 
and that a change in tumor burden was an important feature of the clinical evaluation of these 
drugs.113 In a TACE setting, the TACE treatment destroys tumor and changes the tumor burden 
independent of the effects of a systemic agent. Evaluating the added benefit of systemic agents to 
TACE therefore requires special considerations. In addition, the added benefit of systemic agents 
is best assessed in patients who can receive a series of TACE treatments. 
The relevance of TTP, PFS, and ORR in a TACE setting are not established. While applicable to 
studies using only systemic agents, these endpoints do not take into account the impact of the 
TACE procedure and raise the question of their suitability as an endpoint in a TACE study. This 
is an important consideration because surrogates may fall short in their ability to predict outcomes 
in hard endpoints (eg, OS) for 2 broad categories of reasons: (1) technical factors in measuring the 
surrogate introduce such uncertainty that their association with the hard endpoints becomes weak; 
and (2) factors in the relationship between the surrogate, hard endpoint, and drug weakens a direct 
causal link between the surrogate and the hard endpoint.123 The destructive effects of TACE, 
coupled with continued TACE with tumor regrowth or the appearance of new lesions, challenges 
the conventional approach to assessing ORR, TTP, and PFS. 
This study will utilize TTTP, which is based on the time to tumor progression. The elements of 
the TTTP endpoint take into consideration: (1) the impact of TACE on tumor lesions; and (2) its 
application in a clinical study that includes participants that can receive more than 1 TACE 
treatment. TTTP is defined as the time from randomization to the appearance of evidence of tumor 
progression that is characterized by the first of any of the following: (1) A 20% increase in dynamic 


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tumor burden over baseline scan (see Section 9.1.1 [Imaging Assessment for the Study] for the 
operational elements of a dynamic tumor burden assessment); (2) development of MVI; 
(3) development of EHS; and (4) death. 
TTTP has been retrospectively evaluated in 3 TACE datasets. Arizumi and colleagues evaluated 
592 Japanese participants treated with conventional TACE.124 Correlation analysis showed a 
moderate positive correlation between OS and TTTP for both B1 (R2 = 0.6563; p = 0.0045) and 
B2 (R2 = 0.6433; p = 0.0052) substages. The authors concluded that TTTP showed a moderate 
correlation with OS after TACE therapy, where participants with short TTTP represented short 
OS, indicating that TTTP is a potential alternative parameter for benefit analysis of HCC patients 
undergoing TACE. Izumoto and colleagues subsequently evaluated 192 Japanese participants 
treated with conventional TACE.125 Similarly, their data showed a modest correlation between 
TTTP and OS (r = 0.527; 95% CI: 0.416, 0.622; p < 0.001). The third evaluation was conducted 
on the placebo arm of the brivanib TACE study.23 To evaluate whether TTTP could be used as a 
survival predictor, landmark analyses of TTTP and OS were conducted that showed that TTTP 
was correlated with OS. Notable differences were seen in the probability of survival at 2, 4, 6, 8, 
and 10 months relative to whether or not participants had reached TTTP. Participants who did not 
reach TTTP at the specified timepoints had longer survivals than those who had reached TTTP. In 
addition, participants who took longer to progress by TTTP had longer survivals than those who 
reached TTTP earlier. 
A fourth evaluation is ongoing in collaboration with TARGET-HCC126 to assess TTTP in a 
real-world population. Preliminary data indicate a median TTTP for BCLC Stage B of 366 days. 
A majority (80.9%) of the participants in the TARGET-HCC database achieved TTTP due to an 
increase in tumor burden, as defined by TTTP parameters. The study was started in Dec-2016 and 
the data are currently too immature to provide a correlation with OS. Essentially, only participants 
who had their first TACE around the time of enrollment could be included for an initial OS 
analysis. The study is ongoing and a robust analysis of OS could be possible in another year. 
Improvement in TTTP may also lead to a clinical benefit in these participants, as defined by EFS. 
If study treatment leads to a delay in development of EHS/VI, these participants do not progress 
to advanced stage and start subsequent 1L systemic therapy. In addition, they may require fewer 
TACE procedures, which limits damage to the liver and may prevent hepatic decompensation. 
This could lead to prolongation in EFS, which is a key secondary endpoint of the study. 
In summary, TTTP differs from previous TACE-specific endpoints as it takes into consideration 
the impact of the TACE procedure on tumor lesions, is an endpoint based on tumor lesion changes, 
is applicable to the population of intermediate-stage HCC that can be treated with a series of 
TACE, and can potentially reflect the added effect of a systemic agent. It also differs from previous 
TACE-specific endpoints in that it has been evaluated in different TACE populations and datasets. 
This is in contrast to previous TACE-specific endpoints that were applied in TACE clinical studies 
without prior evaluation of their relevance. Of note, the 3 evaluations presented used varying 
approaches to assess whether there is a correlation of TTTP with survival, and yet the results 
showed similar trends. The data are of special significance in light of the absence of data 


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supporting the relevance of TTP, PFS, and ORR in a TACE setting. The TTTP data provide 
support for the utilization of TTTP as a more relevant endpoint for assessment of tumor burden 
changes in a TACE setting. 
The TTTP endpoint reasonably reflects both the impact of TACE on tumor lesions and the added 
effect of a systemic agent. Based on the evaluation of TTTP in intermediate-stage HCC TACE 
datasets, TTTP can be considered as a reasonable tumor assessment-based endpoint for a TACE 
study. Therefore, TTTP as a dual primary endpoint in the proposed study can provide insight into 
the benefit of ipilimumab and nivolumab or nivolumab alone added to TACE prior to subsequent 
therapies. 
TTTP is defined as the time from randomization to the first occurrence of any of the following: 
• A 20% increase in dynamic tumor burden (see Section 9.1.2.2) over baseline scan 
• Development of MVI 
• Development of EHS 
• Death 
 
5.4.3 
Rationale for OS as a Dual Primary Endpoint 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
OS, defined as the time from randomization to death from any cause, is a dual primary endpoint 
for this study. As an endpoint, OS is easily measured, unambiguous, objective, and unaffected by 
the timing of assessment. It is considered the gold standard among efficacy endpoints (clinically 
and regulatory accepted), and an appropriate measure of treatment benefit for immune checkpoint 
inhibitors. 
5.4.4 
Rationale for EFS as a Secondary Endpoint 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
EFS is defined as the time from randomization to initiation of first-line systemic therapy or the 
date of progression of cirrhosis from Child Pugh A to Child Pugh C score, or death, whichever 
occurs first. Prolongation of EFS may lead to clinical benefit since it takes into consideration liver 
decompensation, as measured by Child-Pugh score, which is a composite of clinical and laboratory 
factors. Delaying start of 1L systemic therapy may also lead to a clinical benefit in a patient, due 
to shorter survival and significant AEs seen with 1L systemic therapy in HCC. 
5.4.5 
Rationale for PFS as a Secondary Endpoint 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
PFS is defined as the time from randomization to the first documented disease progression as 
assessed by BICR, using mRECIST or death due to any cause, whichever occurs first. PFS was 


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chosen as a secondary endpoint in order to support extrapolation of this study with other completed 
and ongoing studies using PFS in the intermediate stage HCC. 
5.4.6 
Rationale for Nivolumab and Ipilimumab Dose and Schedule 
The nivolumab and ipilimumab combination dosing regimen selected for evaluation in this study 
is nivolumab 240 mg (flat dose) Q2W and ipilimumab 1 mg/kg Q6W. The combination dosing 
and schedule was selected based on the overall benefit-risk observed in CA209040, a Phase 1/2 
study evaluating safety and efficacy of nivolumab, alone or in combination with ipilimumab or 
cabozantinib, in participants with advanced HCC.3 
Exposure-response (E-R) analysis of nivolumab monotherapy across dose ranges of 1 mg/kg to 10 
mg/kg revealed similar clinical activity regardless dose, while E-R analysis of different doses of 
ipilimumab monotherapy (0.3 mg/kg, 3 mg/kg, and 10 mg/kg) in the Phase 2 study CA184022 
have demonstrated an increase in antitumoral activity by increasing ipilimumab dose.1,82 The 
combination of dual checkpoint blockade with both of these agents administered together has 
demonstrated an efficacy advantage over either single agent alone. 
In HCC, results from CA209040 demonstrate antitumor activity of the combination of nivolumab 
and ipilimumab as 2L therapy in the advanced setting, with a manageable safety profile. In this 
trial, participants were treated with nivolumab in combination with either high-dose (3 mg/kg) or 
low-dose (1 mg/kg) ipilimumab at different schedules. Efficacy outcomes were mostly similar 
between the different regimens; however, the nivolumab 3-mg/kg Q2W and ipilimumab 1-mg/kg 
Q6W arm was associated with the most favorable safety profile. Treatment-related AEs leading to 
discontinuation, treatment-related elevations in AST and ALT, and the incidence of hepatic 
immune-mediated adverse events (IMAEs) occurred less frequently in the nivolumab 3-mg/kg 
Q2W and ipilimumab 1-mg/kg Q6W arm compared to the other 2 arms. Most of the AEs were 
Grade 1-2 and manageable with treatment algorithms, leading to treatment discontinuation in 2 out 
of 49 participants (~ 4%) randomized to this arm; none of the participants discontinued due to liver 
function abnormalities (AST/ALT elevation).3 
A flat nivolumab dose of 240 mg Q2W was selected for Arm A and Arm B in this trial, based on 
a less than 15% difference in exposures of nivolumab after 3 mg/kg and 240 mg Q2W dosing, 
using simulations conducted in an HCC population that used 80 kg as a reference body weight. 
Taken together, these data suggest that combination therapy with nivolumab 240 mg and 
ipilimumab 1 mg/kg may provide the most appropriate benefit-risk and support the further 
development of this combination in intermediate-stage HCC. 
5.4.7 
Rationale for Shorter Infusion Times (30 minutes) of Nivolumab and 
Ipilimumab 
Nivolumab has been approved for the shorter 30-minute infusion.69,127 
Long infusion times place a burden on patients and treatment centers. Thus, establishing that 
nivolumab and ipilimumab can be safely administered using shorter infusion times of 30-minute 
duration will diminish the burden, provided that there is no change in the safety profile. 


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Establishing that nivolumab and ipilimumab can be safely administered using a shorter infusion 
time (30 minutes) is still under investigation. Previous clinical studies have used a 60-minute 
infusion duration for nivolumab and 90-minute infusion duration for ipilimumab (1-3 mg/kg 
dosing for both). However, both nivolumab and ipilimumab have been safely administered at up 
to 10 mg/kg with the same infusion duration with no safety concerns: 
• Nivolumab has been safely administered up to 10 mg/kg over long treatment periods, and 
infusion reactions, including high-grade hypersensitivity reactions, have been uncommon 
across the nivolumab clinical program. In study CA209010, a dose association was observed 
for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg 
and 18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An infusion 
duration of 30 minutes for 240 mg and 3 mg/kg nivolumab (30% of the dose provided at 
10 mg/kg) or for 480 mg of nivolumab (~ 60% of the dose provided at 10 mg/kg) is not 
expected to present any safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dosing infused over a 60-minute duration. The safety of nivolumab 3 mg/kg 
administered as a 30-minute infusion was assessed in CA209153 in participants (n = 322) with 
previously treated advanced NSCLC. Overall, there were no clinically meaningful differences 
in the frequency of hypersensitivity/infusion-related reactions (of any cause or 
treatment-related) in participants administered nivolumab over a 30-minute infusion compared 
with that reported for participants with the 60-minute infusion. Additionally, preliminary safety 
data from 310 participants who received 480 mg Q4W over a 30-minute infusion have showed 
no substantive differences in the safety profile compared to nivolumab 3 mg/kg or 240 mg 
given IV over 60 minutes, further supporting that nivolumab 3 mg/kg or nivolumab 480 mg 
(flat dose) can be safely infused over 30 minutes. 
• Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In 
participants with advanced Stage II or Stage IV melanoma (CA184022), where ipilimumab 
was administered up to a dose of 10 mg/kg, on-study drug-related hypersensitivity events 
(Grade 1/2) were reported in 1 participant (1.4%) in the 0.3 mg/kg group and in 2 participants 
(2.8%) in the 10 mg/kg group. There were no drug-related hypersensitivity events reported in 
the 3 mg/kg group. Across the 3 treatment groups, no Grade 3/4 drug-related hypersensitivity 
events were reported and there were no reports of infusion reactions. Ipilimumab 10 mg/kg 
monotherapy has also been safely administered as a 90-minute infusion in a large Phase 3 study 
in prostate cancer (CA184043) and as adjuvant therapy for Stage III melanoma (CA184029), 
with infusion reactions occurring in participants. Administering 3 mg/kg of ipilimumab 
represents approximately one-third of the 10 mg/kg dose, and thus, a shortened infusion 
duration of 30 minutes for ipilimumab is not expected to present additional safety concerns. 
 
Overall, infusion reactions, including high-grade hypersensitivity reactions, have been uncommon 
across clinical studies of nivolumab, ipilimumab, and nivolumab/ipilimumab combinations. 
A change in safety profile is not anticipated with 30-minute infusions of nivolumab, ipilimumab, 
or nivolumab and ipilimumab. Furthermore, a 30-minute break after the first infusion for the 
combination will ensure appropriate safety monitoring before the start of the second infusion. 
Similar infusion times are currently being used in trials evaluating nivolumab and ipilimumab at 
similar dosing schedules in several tumor types and no safety concerns have been identified. 


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5.4.8 
Rationale for Stratification Factors 
Not applicable per Protocol Amendment 01, as enrollment has been stopped for the study. 
The following information refers to the original study design. 
5.4.8.1 
Region 
Differences in patient populations and clinical practice patterns in the different regions are well 
known and can impact OS outcomes. The systematic review of the literature on lipiodol TACE for 
HCC reported significantly higher median OS in Japan (31.3 months [95% CI: 22.9, 39.8]) than in 
the West (18.3 months [95% CI: 13.7, 22.9]) or Asia-Pacific (15.6 months [95% CI: 13.7, 22.9]) 
regions (Japan vs West region, p = 0.007; Japan vs Asia-Pacific region, p = 0.0007; West vs 
Asia-Pacific regions: p = 0.3632).95 As such, the impact of differing HCC patient populations and 
different approaches to clinical practice in the different regions is still important to consider. This 
study will therefore stratify by region. 
5.4.8.2 
Alpha-fetoprotein 
Higher AFP levels are related to more aggressive cancer phenotypes and linked with hepatic cancer 
cells that have stem/progenitor features. Depending on the clinical setting, AFP cutoff levels of 
20, 200, 400, and 1000 ng/mL have been examined to assess the prognostic effect of AFP on 
long-term survival, mostly in a retrospective setting. A prospective propensity model study 
analyzed the prognostic ability of 4 different cutoffs of AFP in 2,579 unselected HCC patients. 
The study showed the independent predictive ability of baseline serum AFP levels. Patients with 
baseline AFP levels ≥ 400 ng/mL had notably lower survivals than patients with lower values. 
The researchers recommended AFP cutoff levels of 20 and 400 ng/mL as feasible cutoffs to predict 
long-term survival outcome in unselected patients.128 The lower cut-off of 20 ng/mL is the upper 
limit of normal (ULN) for AFP and is more relevant to studies in early-stage HCC. Patients with 
intermediate-stage disease are more likely to have elevated AFP levels. This study will use a cutoff 
level of 400 ng/mL for stratification. 
5.4.8.3 
Albumin-bilirubin Grade 
Assessment of liver function is particularly important in HCC trials because cirrhosis is a 
competing cause of death. The ALBI grade129 was developed to assess liver function in patients 
with HCC that involved serum bilirubin and albumin levels. Data from a global database of 
3,887 patients demonstrated that objective measures of liver dysfunction, as measured by the 
ALBI grade, influence survival in patients with HCC in the Japan, US/EU, and China cohorts. 
Patients in the US/EU cohort with an ALBI Grade 1 had a median survival of 24.5 months 
compared to 14.7 months for those with ALBI Grade 2 and 4.7 months for those with 
ALBI Grade 3. Similarly, patients with ALBI Grade 1 in the Japan and China cohorts had better 
median survival than those with ALBI Grade 2 and 3.130 These data show that ALBI grade can be 
used to stratify patients with HCC into 3 risk categories. This study will use ALBI Grade 1 and 2 
as a stratification factor. Participants with Grade 3 ALBI are not eligible for TACE and therefore 
these patients are excluded. 


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5.4.9 
Rationale for 2 Year Duration of Treatment with Nivolumab ± Ipilimumab 
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 suggest that benefit can be maintained in the absence of continued 
treatment. A retrospective pooled analysis of two melanoma studies suggests the majority of 
patients who discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the 
absence of further treatment.131 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.132 
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 participants with previously treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 participants were alive > 5 years and remained progression-free without any 
subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, 
with an OS rate of 25% at 2 years and 18% at 3 years.133 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).134 
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, participants 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 participants 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 (HR, 0.42 [95% CI: 0.25, 0.71). 
With a median follow-up of 14.9 months post-randomization, there also was a trend for patients 
on continued treatment to live longer (OS HR, 0.63 [95% CI: 0.33, 1.20]). Of note, the PFS curves 
in both groups plateau approximately 1 year after randomization (ie, 2 years after treatment 
initiation), suggesting that there may be minimal benefit in extending treatment beyond a total of 
2 years.135 
Collectively, these data suggest that there is minimal, if any, benefit derived from continuing IO 
treatment beyond 2 years in advanced tumors. Even though immunotherapy is well tolerated, 


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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. 
5.4.10 
Rationale for Unblinding 
 
 
Therefore, a 
decision was made by BMS in September 2021 to stop the study. 
Upon implementation of Protocol Amendment 01, participants will be unblinded to allow BMS to 
continue safety monitoring the remaining participants on study without blinding while 
streamlining other study procedures. All investigators, ethics committees, and health authorities 
have been informed. 
5.5 
Justification for Dose 
The doses of nivolumab and ipilimumab in this study were based on the overall clinical 
pharmacology profile of nivolumab and ipilimumab and clinical assessment of the combination in 
HCC. 
5.5.1 
Nivolumab Clinical Pharmacology Summary 
The PK of nivolumab were studied in participants over a dose range of 0.1 to 10 mg/kg, 
administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric 
mean (coefficient of variation [%CV], %) CL was 9.5 mL/h (49.7%), geometric mean volume of 
distribution at steady state (Vss) was 8.0 L (30.4%), and geometric mean elimination 
half-life (t1/2) was 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 
12 weeks when administered at 3 mg/kg Q2W, and systemic accumulation was approximately 
3-fold. The exposure to nivolumab increased dose-proportionally over the dose range of 0.1 to 10 
mg/kg administered Q2W. The CL of nivolumab increased with increasing body weight. The PPK 
analysis suggested that the following factors had no clinically important effect on the CL of 
nivolumab: age (29 to 87 years), gender, race, baseline lactate dehydrogenase (LDH), and PD-L1. 
A PPK analysis suggested no difference in CL of nivolumab based on age, gender, race, tumor 
type, baseline tumor size, and hepatic impairment. 
Although ECOG performance status, baseline glomerular filtration rate (GFR), albumin, and body 
weight had an effect on nivolumab CL, the effect was not clinically meaningful. When nivolumab 
was administered in combination with ipilimumab, the CL of nivolumab was increased by 24%, 
whereas there was no effect on the CL of ipilimumab. Additionally, PPK and E-R analyses have 
been performed to support use of 240-mg Q2W dosing in addition to the 3 mg/kg Q2W regimen. 
Using the PPK model, exposure of nivolumab at a 240-mg flat dose was identical to a dose of 
3 mg/kg for participants weighing 80 kg, which was the approximate median body weight in 
nivolumab clinical trials. 
Full details on the clinical pharmacology aspects of nivolumab can be found in the IB.1 


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5.5.2 
Ipilimumab Clinical Pharmacology Summary 
The PPK of ipilimumab, when administered alone or in combination with nivolumab, to 
participants with melanoma, NSCLC, RCC, small cell lung cancer (SCLC), HCC, and CRC has 
been assessed previously. The PK of ipilimumab in combination with nivolumab was well 
described by a linear 2-compartment model with time-varying CL. Ipilimumab CL decreased with 
time and the decrease was ~ 22% in participants receiving ipilimumab in combination with 
nivolumab. The CL of ipilimumab was higher when administered in combination with nivolumab 
1 mg/kg Q2W, 1 mg/kg Q3W, or 3 mg/kg Q2W compared to ipilimumab monotherapy; however, 
the magnitude of these differences are not considered to be clinically relevant (< 20%). Ipilimumab 
CL, when given in combination with nivolumab 0.3 mg/kg or 3 mg/kg Q3W, was not significantly 
different from that seen with ipilimumab monotherapy. The CL of ipilimumab in participants with 
NSCLC, RCC, HCC, and CRC was not significantly different relative to participants with 
melanoma. The CL of ipilimumab was lower in participants with SCLC relative to participants 
with melanoma; however, the magnitude of the difference was not considered to be clinically 
relevant. Ipilimumab CL was not significantly different in the presence of anti-ipilimumab 
antibodies. 
Full details on the clinical pharmacology aspects of ipilimumab can be found in the IB.82 
5.5.3 
Justification for Dose of Nivolumab 
The nivolumab dose of 240 mg Q2W was selected based on clinical data and modeling and 
simulation approaches using population PK (PPK) and E-R analyses of data from studies in 
multiple tumor types (melanoma, NSCLC, and RCC) where body weight normalized 
dosing (mg/kg) has been used. (See Section 5.4.6 [Rationale for Nivolumab and Ipilimumab Dose 
and Schedule] for additional clinical data in HCC for justification of the selected treatments.) 
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and tumor types were 
observed. Nivolumab clearance (CL) and volume of distribution were found to increase as the 
body weight increases, but less than proportionally with increasing weight, indicating that mg/kg 
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK 
model previously developed using data from NSCLC participants has recently been updated, using 
data from 1,544 participants from 7 studies investigating nivolumab in the treatment of melanoma, 
NSCLC, and RCC. In this dataset, the median (minimum - maximum) weight was 
77 kg (35-160 kg), and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg participant, 
nivolumab 240 mg Q2W, was selected for future studies. To predict relevant summary exposures 
of nivolumab 240 mg Q2W, the PPK model was used to simulate nivolumab 3 mg/kg Q2W and 
240 mg Q2W. In the simulations, the simulated patient populations consisted of 1,000 participants 
per treatment arm randomly sampled from the aforementioned pooled database of cancer 
participants. Because no differences in PK were noted across ethnicities and tumor types, these 
simulated melanoma and NSCLC data will be applicable to participants with other tumor types. 
The simulated measure of exposure of interest, steady-state average concentrations (Cavgss) for 


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240 mg Q2W are predicted to be similar for all participants in reference to 80-kg participants 
receiving 3 mg/kg Q2W. 
Nivolumab is safe and well tolerated up to a 10 mg/kg Q2W dose level. AEs have been broadly 
consistent across tumor types following monotherapy and have not demonstrated clear 
dose-response or E-R relationships. Additionally, the simulated median and 95th prediction 
interval of nivolumab summary exposures across body weight range (35-160 kg) are predicted to 
be maintained below the corresponding observed highest exposure experienced in nivolumab 
(ie, 95th percentile following nivolumab 10 mg/kg Q2W from clinical study CA209003). Thus, 
while participants in the lower body weight ranges would have greater exposures than 
80-kg participants, the exposures are predicted to be within the range of observed exposures at 
doses (up to 10 mg/kg Q2W) used in the nivolumab clinical program and are not considered to put 
participants at increased risk. For participants with greater body weights, the simulated ranges of 
exposures are also not expected to affect efficacy, because the exposures predicted following 
administration of a 240 mg Q2W are on the flat part of the E-R curves for previously investigated 
tumors, melanoma and NSCLC. Given the similarity of nivolumab PK across tumor types and the 
similar exposures predicted following administration of 240-mg flat dose compared to 3 mg/kg, it 
is expected that the safety and efficacy profile of 240 mg nivolumab will be similar to that of 
3 mg/kg nivolumab. Thus, nivolumab 240 mg Q2W over 30 minutes will be used in this study. 
5.5.4 
Justification for Dose of Ipilimumab 
The preliminary safety data from CA209040 cohort 4, which evaluated 3 dosing schedules of 
nivolumab + ipilimumab (N1+I3 Q3W, N3+I1 Q3W, and N3+I1 Q6W) in advanced HCC, shows 
a lower rate of drug-related AEs, SAEs, and AEs leading to discontinuation with the N3+I1 Q6W 
dose compared with the N1+I3 Q3W dose.3 The response rate and DOR are similar for all dosing 
arms. Nivolumab 240 mg Q2W and ipilimumab 1 mg/kg Q6W dosing is being chosen for this 
study to be combined with TACE as it has a lower rate of AEs with comparable efficacy. Please 
see Section 5.4.6 (Rationale for Nivolumab and Ipilimumab Dose and Schedule) for further details. 
6 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. As of 22-Sep-2021, enrollment into 
this study was closed. 
6.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Participants must have signed and dated an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved written 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 participant care. In situations where 
the participant is unable to sign the ICF, a legally acceptable representative would be 
expected to sign (according to country-specific guidelines; refer to Appendix 2 and 
Appendix 9). 
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study. 


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c) Participant re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pretreatment failure (ie, participant has not been 
randomized/has not been treated). If re-enrolled, the participant must be re-consented. 
2) Type of Participant and Target Disease Characteristics 
a) Participant has intermediate-stage HCC by BCLC staging criteria11 whose tumor 
characteristics exceed the BMU7 criteria and is eligible for TACE as per disease 
management team. 
i) Up-to-seven criteria, with 7 being the result of the sum of size (in cm) of the largest 
lesion and number of tumors. This includes all combinations of a given HCC disease, 
from 1 nodule up to 6 cm in size (1 + 6 = 7) to many tumors fulfilling 7 as the sum of 
the size plus number (ie, 2 tumors up to 5 cm in size, 3 tumors up to 4 cm in size, etc; 
refer to Appendix 7).136 
b) Participant has no EHS, no regional lymph node involvement, no main, left main, or right 
main portal vein thrombosis, and no MVI. (Segmental bland portal vein thrombosis is 
allowed). 
c) Participant has histologic confirmation of HCC. 
i) Participants with only a radiologic diagnosis of HCC may be enrolled for screening in 
the study but histological confirmation is mandatory prior to the start of study therapy. 
ii) Either a FFPE tissue block (preferred) or a minimum of 20 unstained slides of tumor 
tissue sections obtained within 3 months prior to randomization or archived (if above 
is not available) with an associated pathology report must be submitted to the central 
laboratory for inclusion. The central laboratory must provide IRT with confirmation of 
receipt of evaluable tumor tissue prior to randomization. Biopsy should be excisional, 
incisional or core needle. Fine needle aspiration or other cytology samples are 
unacceptable for submission. If despite best efforts, a minimum of 20 slides are not 
obtainable, submission of fewer slides may be acceptable in some circumstances 
following discussion with BMS Medical Monitor or Clinical Scientist. Please see 
Appendix 9 for country-specific criteria for the collection of tumor tissue samples in 
China. 
d) Participant has cirrhotic status of Child-Pugh Class A (refer to Appendix 8). 
e) Participant has an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 (refer to 
Appendix 5 for ECOG PS scale). 
f) Participants are eligible to enroll if they have non-viral related HCC, or if they have 
HBV-HCC, or HCV-HCC defined as follows: 
i) Non-HBV, non-HCV related HCC 
ii) HBV-HCC 
(1) Resolved HBV infection, as evidenced by detectable HBV surface antibody, 
detectable HBV core antibody, undetectable HBV deoxyribonucleic acid (DNA), 
and undetectable HBV surface antigen [HBsAg]); OR 
(2) Chronic HBV infection, as evidenced by detectable HBsAg or HBV DNA. 
Participants with chronic HBV infection must be on antiviral therapy 
 


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iii) HCV-HCC 
(1) Resolved HCV infection as evidenced by detectable antibody; OR 
(2) Chronic HCV infection as evidenced by detectable HCV ribonucleic acid (RNA). 
3) Age and Reproductive Status 
a) Males and Females, ages ≥ 18 years or age of majority. 
b) 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. 
c) Women must not be breastfeeding. 
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study treatments plus approximately 5 half-lives of the study treatments 
plus 30 days (duration of ovulatory cycle) for a total of 5 months post-treatment 
completion. 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception and fetal protection (Appendix 4) for the duration of treatment 
with study treatments plus approximately 5 half-lives of the study drugs plus 90 days 
(duration of sperm turnover) for a total of 7 months post-treatment completion. In addition, 
male participants must be willing to refrain from sperm donation during this time. 
f) Azoospermic males are not exempt from contraceptive requirements and will be required 
to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, 
anal, oral) with WOCBP, even if the participant has undergone a successful vasectomy or 
if the partner is pregnant. WOCBP who are continuously not heterosexually active are also 
exempt from contraceptive requirements, and still must undergo pregnancy testing as 
described in this section. 
 
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy and 
when applicable, the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. Investigators shall advise on the use of highly effective 
methods of contraception (Appendix 4) which have a failure rate of < 1% when used consistently 
and correctly. 
6.2 
Exclusion Criteria 
1) Medical Conditions 
a) Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 
b) Prior liver transplant or participants who are on the waiting list for liver transplantation. 
c) Prior history of or current hepatic encephalopathy. 
d) Tumor >10 cm in size and other contra-indications for angiography or embolization. 
e) Clinically significant ascites as defined by: 
i) Any ascites by physical examination at screening; OR 
ii) Prior ascites that required treatment and require on-going prophylaxis; OR 


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iii) Current ascites requiring treatment. 
f) Diffuse pattern of disease on computed tomography (CT)/magnetic resonance imaging 
(MRI). 
g) Infections: 
i) Active co-infection with: 
(1) Both hepatitis B and C as evidenced by detectable HBsAg or HBV DNA and HCV 
RNA, OR 
(2) Hepatitis D infection in participants with hepatitis B. 
ii) 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 (refer to Appendix 9). 
iii) Active bacterial or fungal infections requiring systemic treatment within 7 days prior 
to study drug dosing. 
h) Interstitial lung disease that is symptomatic or may interfere with the detection and 
management of suspected drug-related pulmonary toxicity. 
i) Prior organ allograft or allogeneic bone marrow transplantation. 
j) Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the 
normal range with medication. 
k) Participants with an active, known, or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll. 
l) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease, with the exception of those allowed as per exclusion criterion k) 
above. 
m) Prior malignancy active within the previous 3 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 prostate, cervix, or breast. 
n) Participants with serious or uncontrolled medical disorders 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. 
o) WOCBP who are pregnant or breastfeeding. 
p) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication. 
2) Prior/Concomitant Therapy 
a) Any previous TACE or TAE (trans-arterial embolization without instillation of 
chemotherapy agent) procedure for HCC. 


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b) Prior use of systemic agents for HCC, including prior chemotherapy, immune therapy, and 
targeted kinase inhibitors. 
c) Prior treatment with radioactive isotope yttrium (Y90). 
i) RFA, microwave ablation (MWA), including other forms of ablation and resection, are 
permitted, provided TACE is indicated at the time of relapse/recurrence. TACE as 
combination treatment with the above is not permitted. 
d) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways. 
e) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support to treat the disease under study within 
2 weeks prior to randomization. Refer to Section 7.7.1 (Prohibited and/or Restricted 
Treatments for Nivolumab) for prohibited therapies. 
f) Participants who have received a live/attenuated vaccine within 30 days of randomization. 
3) Physical and Laboratory Test Findings 
a) Positive pregnancy test. 
b) Screening laboratory values must not meet the following criteria, and be without 
continuous supportive treatment (such as, growth factor administration, blood transfusion, 
coagulation factors and/or platelet transfusion, or albumin transfusion): 
i) Inadequate hematologic function: 
(1) WBC < 2,000/μL. 
(2) Neutrophils < 1500/μL. 
(3) Platelets < 60  103/μL. 
(4) Hemoglobin < 8.5 g/dL. 
ii) Prothrombin time (PT)-international normalized ratio (INR) ≥ 1.7 or PT ≥ 4 seconds 
above control. 
iii) Inadequate hepatic function as documented by: 
(1) Serum albumin < 2.8 g/dL. 
(2) Total bilirubin > 2 mg/dL. 
(3) AST > 5  institutional ULN. 
(4) ALT > 5  institutional ULN. 
iv) Inadequate renal function, with a serum creatinine > 1.5  ULN, unless creatinine 
CL ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula). 
4) Allergies and Adverse Drug Reaction 
a) Known or suspected allergy to nivolumab, ipilimumab, or any agents given in association 
with this trial. 
b) History of severe hypersensitivity reaction to any monoclonal antibody. 
c) History of allergy or hypersensitivity to study drug components. 
d) Inability to tolerate contrast-enhanced CT and MRI, including, but not limited to, known 
or suspected allergy to both CT and MRI contrasts. 


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5) Other Exclusion Criteria 
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply and BMS 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. 
6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently 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. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs. 
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 
pretreatment failure (ie, participant has not been randomized / has not been treated). If re-enrolled, 
the participant must be re-consented 
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in Period will be permitted (in addition to any parameters that require a confirmatory value). 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state. 
Laboratory parameters and/or assessments that are included in Table 2-1 (Screening Procedural 
Outline) may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant. 
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. 


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Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following: 
• Nivolumab 
• Ipilimumab 
• Nivolumab-Placebo (0.9% Sodium Chloride Injection or 5% Dextrose Injection) 
• Ipilimumab-Placebo (0.9% Sodium Chloride Injection or 5% Dextrose Injection) 
 
The normal saline or dextrose to be used as placebo will not be provided by the Sponsor. 
Per Protocol Amendment 01, participants will no longer receive placebo infusions following 
unblinding. 
An IP, also known as an IMP in some regions, is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) differently 
than the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. 
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as non-IPs. In this 
study, the TACE procedure is not considered to be a study treatment. 
Premedications used to treat infusion reactions should be sourced by the investigative sites if 
available and permitted by local regulations. 


 
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Table 7-1: 
Study Treatments for CA20974W 
 
Product Description/ 
Class and Dosage Form 
Potency 
IP/Non-IMP 
Blinded or 
Open Label 
Packaging/ 
Appearance 
Storage Conditions 
(per label) 
Nivolumab (BMS-936558-01) 
Solution for Injectiona 
10 mg/mL 
IP 
Open Labelb 
Vial 
Refer to the label on container 
and/or Pharmacy Manual 
Ipilimumab Solution for Injection 
5 mg/mL 
IP 
Open Labelb 
Vial 
Refer to the label on container 
and/or Pharmacy Manual 
0.9% Sodium Chloride for Injectionc 
NA 
IP 
Open Labelb 
Various (local 
commercial product) 
As per package insert 
5% Dextrose for Injectionc 
NA 
IP 
Open Labelb 
Various (local 
commercial product) 
As per package insert 
Abbreviations: BMS = Bristol-Myers Squibb; IMP = investigational medicinal product; IP = investigational product; mg = milligram; mL = milliliter; NA = not 
applicable. 
a Nivolumab is labeled as BMS-936558-01 Solution for Injection. 
b The term “open-label” refers to the medication as it is upon receipt at the pharmacy. 
c Diluents used for nivolumab and ipilimumab. These will be sourced by the investigative sites if available and permitted by local regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.1 
Treatments Administered 
The selection and timing of dose for each participant is as follows: 
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 
Nivolumab 
240 mg 
Q2W 
IV 
Ipilimumab 
1 mg/kg 
Q6W 
IV 
0.9% Sodium Chloride 
for Injection 
NA 
Q2W or Q6W 
IV 
5% Dextrose for 
Injection 
NA 
Q2W or Q6W 
IV 
TACE 
NA 
NA 
Loco-regional 
Abbreviations: IV = intravenous; kg = kilogram; mg = milligram; NA = not applicable; Q2W = every 2 weeks; 
Q6W = every 6 weeks; TACE = trans-arterial chemoembolization. 
 
 
7.1.1 
Nivolumab and Ipilimumab Administration 
Per Protocol Amendment 01, participants in Arm B (nivolumab + placebo + TACE) and 
Arm C (placebos + TACE) will no longer receive placebo following unblinding. 
Participants should receive treatment with nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg 
Q6W), or their matching placebos, as an approximately 30-minute infusion on Cycle 1 Day 1 until 
progression as assessed by investigator (unless treatment beyond progression was allowed), 
unacceptable toxicity, withdrawal of consent, completion of 2 years of study medication, or the 
study ends, whichever occurs first. 
Participants should begin study treatment within 3 calendar days after randomization. Dosing 
calculations for ipilimumab should be based on the body weight assessed at baseline. It is not 
necessary to re-calculate subsequent doses if the participant’s weight is within 10% of the baseline 
weight or the weight used to calculate the previous dose. All doses should be rounded to the nearest 
milligram per institutional standard. 
After the first cycle, subsequent dosing should be based on the actual date of administration of the 
previous cycle. Participants may be dosed no less than 12 days and no more than 18 days between 
nivolumab or matching placebo doses and no less than 36 days and no more than 60 days between 
ipilimumab or matching placebo doses. Doses may be administered within 3 days before or after 
the scheduled date, if necessary. All TACE related toxicities must have resolved to baseline or 
Grade 1 before study treatment is resumed. 
When study treatments (nivolumab and ipilimumab or their matching placebos) are to be 
administered on the same day, nivolumab is to be administered first. Nivolumab infusion must be 
promptly followed by a saline flush of diluent to clear the line of nivolumab before starting the 
ipilimumab infusion. The second infusion will always be the ipilimumab study drug and will start 


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after the infusion line has been flushed, filters changed, and participant has been observed to ensure 
no infusion reaction has occurred. The time in between infusions is expected to be approximately 
30 minutes but may be more or less depending on the situation. 
Premedications are not recommended for the first dose of treatment. Participants should be 
carefully monitored for infusion reactions during administration. If an acute infusion reaction is 
noted, participants should be managed according to Section 7.4.2 (Nivolumab and Ipilimumab 
Dose Delay Criteria). 
There will be no dose escalations or reductions of study treatment allowed. Doses of nivolumab 
and/or ipilimumab and their matching placebos may be interrupted, delayed, or discontinued, 
depending on how well the participant tolerates the treatment. Dosing visits are not skipped, only 
delayed. If dosing is delayed, all study treatments planned to be administered on the same day 
should be delayed at the same time. If dosing is resumed after a delay, all study treatments planned 
must be resumed on the same day. For more details, see Section 7.4.2 (Nivolumab and Ipilimumab 
Dose Delay Criteria) and Section 8.1.1.1 (Criteria for Nivolumab and Ipilimumab Treatment 
Discontinuation). 
Nivolumab injection, 10 mg/mL is to be administered as an IV infusion through a 0.2-micron to 
1.2-micron pore size, low-protein binding in-line filter at the protocol-specified doses. It is not to 
be administered as an IV push or bolus injection. Nivolumab infusion must be promptly followed 
by a flush of diluent to clear the line. Instructions for preparation of nivolumab infusion may be 
provided in the Pharmacy Manual or IB. Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent. 
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day. 
Ipilimumab is to be administered as an approximately 30-minute IV infusion and may be infused 
using a volumetric pump with a 0.2-micron to 1.2-micron, low-protein binding in-line filter at the 
protocol-specified dose. Care must be taken to assure sterility of the prepared solutions, since the 
drug product does not contain any antimicrobial preservatives or bacteriostatic agents. At the end 
of the infusion, flush the line with a sufficient quantity of diluent. 
Please refer to the current version of the IBs1,82 and/or Pharmacy Manual for complete preparation, 
storage, and handling information for nivolumab and ipilimumab. 
7.1.2 
TACE Procedure 
No significant differences in efficacy and safety have been observed between conventional TACE 
and DEB-TACE.137,138 This trial allows the use of conventional TACE and DEB-TACE and the 
choice of procedure to use is left to the Investigator’s discretion. However, once the participant 
starts receiving either conventional TACE or DEB-TACE, the same TACE procedure must be 
followed throughout the study for that participant. Switching to conventional TACE for 
participants that started the trial with DEB-TACE and to DEB-TACE for participants who received 
conventional TACE is not permitted. Additionally, once conventional TACE has been 
administered with a select chemotherapy agent, switching to a different chemotherapy agent is not 


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permitted. For participants receiving DEB-TACE or conventional TACE, the TACE technique 
should be maintained consistently throughout the study. 
First TACE should be administered no later than 7 days (+ 3 days) after study drug administration. 
All drug-related toxicities must have resolved to Grade 1 or baseline before TACE is administered. 
TACE sessions can be continued until all the liver lesions are adequately treated. Evaluation for 
additional on-demand TACE will occur at each imaging as per Section 2 (Schedule of Activities). 
In general, imaging is repeated 4-8 weeks after TACE to assess the need for repeat TACE. Since 
scheduled imaging occurs every 6 weeks for the first 48 weeks, imaging on study will fall within 
the 4- to 8-week window. Ad-hoc imaging can be performed if clinically necessary at any time. 
TACE can be repeated if the dynamic tumor burden is at least 50% of the total tumor burden at 
baseline or earlier, as per Investigator discretion, if it is felt to be in the best interest of the 
participant or as per local practice and guidelines (see Figure 7.1.2-1). Once a determination is 
made to perform TACE, it should be performed within 4 weeks. 
Figure 7.1.2-1: 
Criteria to Re-TACE: Tumor Burden > 50% of the Baseline Tumor 
Burden 
 
Abbreviations: mm = millimeter; TACE = trans-arterial chemoembolization. 
 
Once randomized, participants should receive first TACE in 7 days (+3 days) after study drug 
administration and then TACE as needed, until participant is no longer eligible for further TACE, 
unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first. Once 
progression has been met as assessed by the investigator, the participant may continue to receive 


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additional TACE until the participant is no longer eligible for further TACE, per Investigator 
discretion, if it is felt to be in the best interest of the participant. 
TACE should be administered as per local practices and guidelines. TACE should be given with 
at least a 7-day window of systemic therapy. All drug-related toxicities must have resolved to 
Grade 1 or baseline before TACE is administered, and participants must be evaluated as per Table 
2-2 prior to TACE procedure. 
Premedications for TACE, such as analgesics, antiemetics, sedatives, etc, are allowed and are left 
to the discretion of the Investigator; however, the use of corticosteroids for the prophylaxis of PES 
is not permitted (see Section 7.7 [Concomitant Therapy] for additional details). 
France Only: Please refer to Appendix 11 (France-specific General Guidance for Trans-arterial 
Chemo-embolization) for additional information on the TACE procedure. 
7.2 
Method of Treatment Assignment 
CA20974W is a double-blind, placebo-controlled, randomized trial. Participants with 
intermediate-stage HCC whose tumor characteristics exceed the BMU7 criteria will be eligible to 
participate. All participants will be randomized using an IRT system. Before the study is initiated, 
each user will receive log-in information and directions on how to access the IRT. 
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study by calling the IRT to obtain a participant number. Every 
participant that signs the ICF must be assigned a participant number in IRT. Specific instructions 
for using IRT will be provided to the investigational site in a separate document. The Investigator 
or other delegated and trained site personnel will register the participant for enrollment by 
following the enrollment procedures established by BMS. 
The following information is required for enrollment: 
• Date that informed consent was obtained 
• Date of birth, where applicable by local regulations 
• Gender at birth 
 
Once enrolled in IRT, participants who have met all eligibility criteria will be ready to be 
randomized through IRT. The following information is required for participant randomization: 
• Participant number 
• Date of birth, where applicable per local regulations 
• ALBI grade (Grade 1 vs Grade 2) 
• Baseline AFP level (< 400 ng/mL vs ≥ 400 ng/mL) 
• Region (West [EU, Americas, and Australia] vs Japan vs rest of Asia) 
• Confirmation of tumor tissue sample receipt and acceptability at the central laboratory 
• Confirmation of eligibility by BICR 


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Participants meeting all eligibility criteria will be randomized into one of the treatment arms in a 
1:1:1 ratio. Randomization will be stratified by the following factors: 
• ALBI grade (Grade 1 vs Grade 2) 
• Baseline AFP level (< 400 ng/mL vs ≥ 400 ng/mL) 
• Region (West [EU, Americas, and Australia] vs Japan vs rest of Asia) 
 
Blinded study treatment was dispensed at the study visits as listed in Schedule of Activities 
(Section 2). The exact procedures for using the IRT will be detailed in the IRT Manual. 
As of 22-Sep-2021, enrollment for new participants was closed and the study will be unblinded 
per Protocol Amendment 01. 
7.3 
Blinding 
The Sponsor, participants, Investigator, and site staff will be blinded to the study therapy 
administered. Each investigative site must assign an unblinded pharmacist/designee, and an 
unblinded site monitor will be assigned to provide oversight of drug supply and other unblinded 
study documentation. 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
IP is critical to the participant's management, the blind for that participant may be broken by the 
Investigator. The participant’s safety takes priority over any other considerations in determining if 
a treatment assignment should be unblinded. 
Before breaking the blind of an individual participant's treatment, the Investigator should 
determine that the unblinded information is necessary (ie, that it will alter the participant's 
immediate management). In many cases, particularly when the emergency is clearly not related to 
the IP, the problem may be properly managed by assuming that the participant is receiving active 
product. It is highly desirable that the decision to unblind treatment assignment be discussed with 
the BMS Medical Monitor or Clinical Scientist, but the Investigator always has ultimate authority 
for the decision to unblind. The actual task of unblinding can be delegated by the Investigator to a 
designee assigned the task on the Delegation of Authority. The Principal Investigator should only 
call in for emergency unblinding AFTER the decision to discontinue the participant has been made. 
For this study, the method of unblinding for emergency purposes is through the IRT. 
For information on how to unblind in an emergency, consult the IRT Manual. 
In cases of accidental unblinding, contact the BMS Medical Monitor or Clinical Scientist and 
ensure every attempt is made to preserve the blind. 
Any request to unblind a participant for non-emergency purposes should be discussed with the 
BMS Medical Monitor or Clinical Scientist. 
Designated staff of BMS Research & Development (R&D) may be unblinded prior to database 
lock to facilitate the bioanalytical analysis of pharmacokinetic samples and IMG. A bioanalytical 
scientist in the Bioanalytical Sciences department of BMS R&D (or a designee in the external 


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central bioanalytical laboratory) will be unblinded to the randomized treatment assignments in 
order to minimize unnecessary bioanalytical analysis of samples. 
As of 22-Sep-2021, enrollment for new participants was closed. Per Protocol Amendment 01, 
the objectives of this study have been amended to safety only. The study will be unblinded to 
facilitate ongoing safety monitoring. 
7.3.1 
Unblinding at the Time of Disease Recurrence/Progression 
As of 22-Sep-2021, enrollment for new participants was closed. Per Protocol Amendment 01, 
the objectives of this study have been amended to safety only. The study will be unblinded to 
facilitate ongoing safety monitoring. 
If a participant is assessed by the Investigator to have HCC disease recurrence/progression 
(Section 9.1.1 [Imaging Assessment for the Study]), and unblinding is considered necessary to 
inform the appropriate subsequent anti-cancer therapy, the study treatment assignment for the 
participant can be obtained by the Investigator through IRT for non-emergency unblinding. 
The Investigator should follow the procedures outlined in the IRT Manual to obtain the 
participant’s study treatment assignment. The BMS central study team (including, but not limited 
to, clinical, statistics, and data management) will remain blinded to treatment assignment. 
Investigators must wait for confirmation of recurrence/progression from the BICR prior to 
non-emergency unblinding for the purpose of initiating subsequent anti-cancer therapy, unless 
clinical considerations require immediate intervention (eg, symptomatic brain metastases). 
If subsequent anti-cancer therapy (including systemic cancer therapy, radiotherapy, or 
tumor-directed surgery) is planned prior to BICR confirmation of recurrence/progression, the 
Investigator must contact the BMS Medical Monitor or Clinical Scientist to discuss the case prior 
to the start of any of such therapy. 
If a participant is diagnosed with a non-HCC secondary cancer, blinding should be preserved 
unless specific circumstances, to be discussed with the BMS Medical Monitor or Clinical Scientist, 
require that the blind be broken (eg, participant has metastases and could enroll on a clinical trial 
but would be ineligible if he or she had prior checkpoint inhibitor therapy). 
For this study, the method of unblinding for emergency purposes is through the IRT. For 
information on how to unblind in an emergency, please see Section 7.3 (Blinding). 
7.4 
Dosage Modification 
7.4.1 
Nivolumab and Ipilimumab Dose Modifications 
No dose modifications for nivolumab or ipilimumab are allowed. 
7.4.2 
Nivolumab and Ipilimumab Dose Delay Criteria 
Dose delay criteria summarized in Table 7.4.2-1 apply for all drug-related AEs, regardless of 
whether the event is attributed to nivolumab or ipilimumab or both. Delay administration of both 
nivolumab and ipilimumab if any of the delay criteria in Table 7.4.2-1 are met. 


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Delay nivolumab and ipilimumab for any AE, laboratory abnormality, or intercurrent illness 
which, in the judgment of the Investigator, warrants delaying the dose of study medication. Delay 
study therapy also in cases of confirmed or suspected SARS-CoV-2 infection. 
Participants receiving nivolumab plus ipilimumab who have drug-related toxicities that meet the 
criteria for dose delay should have both drugs (nivolumab and ipilimumab) delayed until 
retreatment criteria are met, regardless of whether or not the event is attributed to 1 of the drugs. 
Tumor assessments for all participants should continue as per protocol even if dosing is delayed. 
Participants who require delay of nivolumab and ipilimumab should be re-evaluated weekly, or 
more frequently if clinically indicated, and resume study treatment when re-treatment criteria are 
met (see Section 8.1.3 [Post Study Treatment Study Follow-up]). Please see also Appendix 6 
(IO Management Algorithms) for guidance on appropriate management and follow-up of AEs. 
Table 7.4.2-1 summarizes criteria for delaying, resuming, and discontinuing dose of both 
nivolumab and ipilimumab. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
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Drug-Related 
Adverse 
Event (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 
Permanently discontinue 
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 
Hepatic 
Aspartate aminotransferase 
(AST), alanine 
aminotransferase (ALT), or 
total bilirubin (T.Bili) 
increased 
AST/ALT 
• 
If Baseline AST/ALT is 
within normal limits: 
− 
AST or ALT > 3× 
upper 
limit 
of 
normal (ULN) 
• 
If  Baseline  AST/ALT 
> ULN and up to 3× 
ULN: 
− 
AST or ALT > 5× 
ULN 
Delay dose 
• 
Dosing may resume when AST or ALT values return 
to normal or ≤ 3× ULN 
• 
Exceptions: 
− 
If baseline AST or ALT > 3× and ≤ 5× ULN, 
dosing may resume when AST or ALT values 
return to ≤ 5× ULN 
− 
Participants with AST 
or ALT meeting 
discontinuation criteria should have treatment 
permanently discontinued 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
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Drug-Related 
Adverse 
Event (AE) per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
• 
If  Baseline  AST/ALT 
> 3× and ≤ 5× ULN: 
− AST or ALT 2-fold 
increase OR AST 
or ALT of 8× ULN 
(whichever 
is 
lower) 
Total Bilirubin 
• 
If Baseline T.Bili is 
within normal limits: 
− 
T.Bili > 1.5× ULN 
• 
If 
Baseline 
T 
Bili 
> ULN and up to 1.5× 
ULN: 
− 
T. Bili > 3× ULN 
• 
If 
Baseline 
T.Bili 
> 1.5× and ≤ 3× ULN: 
− 
T.Bili 
2-fold 
increase 
Delay dose 
• 
Dosing may resume when laboratory values return to 
normal or ≤ 1.5× ULN 
• 
Exceptions: 
− 
If baseline T.Bili > 1.5× and ≤ 3× ULN, dosing 
may resume when T.Bili values return to ≤ 3× 
ULN 
− 
Participants with T.Bili meeting discontinuation 
criteria should have treatment permanently 
discontinued 
• 
AST or ALT > 10× 
ULN for > 2 weeks 
• 
AST or ALT > 15× 
ULN irrespective of 
duration 
• 
T.Bili > 5× ULN for 
participants 
with 
normal T.Bili at entry 
OR  >  8×  ULN  for 
participants 
with 
elevated T.Bili at study 
Permanently discontinue 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
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Drug-Related 
Adverse 
Event (AE) per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
entry, irrespective of 
duration 
• 
Potential drug-induced 
liver injury; Concurrent 
ALT > 10× ULN AND 
T.Bili ≥ 2× ULN or 
baseline 
value 
(if 
elevated bilirubin at 
study entry), and no 
other 
immediately 
apparent 
cause 
of 
hepatic 
lab 
abnormalities. 
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 BMS 
Medical Monitor/Clinical Scientist 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. 
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 BMS 
Medical Monitor/Clinical Scientist needed prior to 
resuming therapy. If hyperglycemia resolves, or is 
adequately controlled with glucose-controlling agents, 
participant may not require discontinuation of study drug. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
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Drug-Related 
Adverse 
Event (AE) per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
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 BMS 
Medical Monitor/Clinical Scientist needed prior to 
resuming therapy. If endocrinopathy resolves or is 
adequately controlled with physiologic hormone 
replacement, participant may not require discontinuation 
of study drug. 
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 BMS 
Medical Monitor/Clinical Scientist 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 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
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Approved v21.0 
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Drug-Related 
Adverse 
Event (AE) per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
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 
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 
Myocarditis 
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 


Clinical Protocol 
BMS-936558 
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nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
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Drug-Related 
Adverse 
Event (AE) per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Other Clinical AE 
Pancreatitis: 
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 patient becomes 
asymptomatic. 
Amylase or Lipase increased 
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 patient requires oral 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 Lab abnormalities 
Other Drug-Related lab 
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. 


Clinical Protocol 
BMS-936558 
CA20974W 
nivolumab 
Table 7.4.2-1: 
Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab and Ipilimumab 
Protocol Amendment No.: 01 
Date: 01-Dec-2021 
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Drug-Related 
Adverse 
Event (AE) per CTCAE V5 
Severity 
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
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 
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 
Refer to Section 7.4.3 on Treatment of Related Infusion 
Reactions 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMS = Bristol-Myers Squibb; CTCAE V5 = National 
Cancer Institute Common Terminology Criteria for Adverse Events version 5.0; DRESS = drug reaction with eosinophilia and systemic symptoms; GBS = Guillain- 
Barre syndrome; MG = myasthenia gravis; SJS = Stevens-Johnson syndrome; T.Bili = total bilirubin; TEN = toxic epidermal necrolysis; ULN = upper limit of 
normal. 


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7.4.3 
Treatment of Nivolumab- or Ipilimumab-related Infusion Reactions 
Since nivolumab and ipilimumab contains only human Ig protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the BMS Medical Monitor or Clinical 
Scientist and reported as an SAE if it meets the criteria. Infusion reactions should be graded 
according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 guidelines. 
Treatment recommendations are provided below based on NCI CTCAE version 5.0 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 to 1000 mg at least 30 minutes before 
additional study treatment administrations. 
 
For Grade 2 symptoms (therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, narcotics, IV 
fluids); prophylactic medications indicated for ≤ 24 hours): 
• 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 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 medication 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 to 1000 mg 
should be administered at least 30 minutes before study treatment infusions. 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 other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]. Grade 4: Life threatening consequences; urgent intervention indicated). 


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• 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 subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms. 
 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids). 
7.5 
Preparation/Handling/Storage/Accountability 
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the Investigator to ensure that IP is only dispensed to study Participants. The IP 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 contact BMS immediately. 
Study treatment not supplied by BMS will be stored in accordance with the package insert. 
IP 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). 
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and the CA20974W Pharmacy Manual. 
7.5.1 
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability 
Not applicable. 
7.6 
Treatment Compliance 
Study treatment will be administered in the clinical facility. Treatment compliance will be 
monitored by drug accountability as well as the participant’s medical record and eCRF. 
7.7 
Concomitant Therapy 
Prohibited and/or restricted treatments are outlined below. 


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7.7.1 
Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat drug-related 
AEs): 
• Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella [MMR]), within 30 days prior to randomization, during treatment, 
and until 100 days after the last dose. 
• Immunosuppressive agents. 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.2 
[Exclusion Criteria] criterion 1) subcriterion 1) and Section 7.7.3 [Permitted Therapy]). 
• Any concurrent anti-neoplastic therapy (ie, chemotherapy, molecular targeted therapy, 
locoregional therapy, hormonal therapy, immunotherapy, palliative or non-palliative radiation 
therapy, or standard or investigational agents for treatment of HCC). TACE on demand is 
allowed as per protocol-defined criteria. 
• Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally. 
• Concurrent use of antiviral therapy containing interferon (IFN). 
 
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 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
• Investigators are strongly encouraged to wait for confirmation of recurrence/progression from 
the BICR prior to initiating subsequent systemic cancer therapy, loco-regional therapy, or 
tumor-directed surgery for suspected recurrence/progression unless clinical considerations 
require immediate intervention (eg, symptomatic brain metastases). If subsequent systemic 
cancer therapy, loco-regional therapy, or tumor-directed surgery is planned prior to BICR 
confirmation of recurrence/progression, the Investigator must contact the BMS Medical 
Monitor or Clinical Scientist to discuss the case prior to the start of any of these procedures. 
 
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 per imaging study. Imaging contraindications and contrast risks are to be 
considered in this assessment. Participants with renal insufficiency are to be assessed as to whether 
or not they should receive contrast and if so, which contrast agent and dose is appropriate. 


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Specific to MRI, participants with severe renal insufficiency (ie, eGFR < 30 mL/min/1.73 m2) are 
at increased risk of nephrogenic systemic fibrosis; therefore, MRI contrast is contraindicated. 
In addition, participants may be excluded from MRI if they have tattoos, metallic implants, 
pacemakers, etc. This will be outlined in the Imaging Manual. 
Gentle hydration before and after IV contrast should follow local SOC. The ultimate decision to 
perform MRI in an individual participant in this study rests with the site radiologist, the 
Investigator, and standards set by the local IEC. 
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. 
Immunosuppressive doses (eg, prednisone > 10 mg/day or equivalent) in the context of treating 
AEs are permitted. 
Supportive care for disease-related symptoms may be offered to all participants on the trial. 
COVID-19 vaccines that are NOT live (not replication competent) are permitted during the study 
and after the last dose of IP. No data are available on the response to COVID-19 vaccines. The 
efficacy and safety of vaccination in participants who are receiving nivolumab and ipilimumab or 
nivolumab alone are unknown. Please contact the BMS Medical Monitor or Clinical Scientist with 
any questions related to COVID-19 vaccines. 
7.7.3.1 
Antiviral Therapy 
Participants on antiviral therapy for hepatitis B or C should continue the treatment during the study, 
providing the regimen is IFN-free. Changing of dosage and regimens of antiviral therapy will be 
at the discretion of the Investigator. If a participant has a > 1 log IU/mL increase in HBV DNA, 
then virologic breakthrough should be considered and HBV DNA confirmed. Adherence to current 
antiviral therapy should be assessed, and resistance testing performed according to local practices. 
If a participant has documented virologic breakthrough due to antiviral resistance, then this should 
be managed based on standardized regional guidelines and treatment with study treatment 
temporarily held. The participant may resume study treatment once virologic control is 
reestablished 
. 
For any participant who continues to be HCV RNA positive after receiving study treatment, current 
guidelines for management of chronic HCV infection, including those from American Association 
for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver 
(EASL), or Asian Pacific Association for the Study of the Liver (APASL) may be consulted. 
Initiation of direct-acting antivirals (DAAs) for HCV is allowed at the discretion of the Investigator 
after discussion with the BMS Medical Monitor or Clinical Scientist. 


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7.7.3.2 
Other Systemic Therapy 
• Hormone replacement therapy: participants may continue to receive hormonal replacement 
therapy if initiated prior to randomization. 
 
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 Section 7.1 (Treatments Administered). 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. 
BMS reserves the right to terminate access to BMS-supplied study treatment if any of the following 
occur: 
• The study is terminated due to safety concerns. 
• The development of nivolumab/ipilimumab is terminated for other reasons, including, but not 
limited to, lack of efficacy and/or not meeting the study objectives. 
• 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 IP (and non-IP 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 the 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. 
• 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, and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.) 
• Criteria listed in Section 8.1.1 (Treatment Discontinuation Criteria). 
• Participants meeting progression as assessed by investigator, unless eligible to continue with 
treatment beyond progression (see Section 5.1.4 [Treatment Beyond Progression]). 


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• Disease progression or occurrence of a secondary malignancy which requires systemic therapy 
or radiotherapy for treatment. 
• Pregnancy, if locally mandated (see Appendix 9 for country-specific requirements). 
 
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, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/Clinical Scientist 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). Study treatment must be permanently discontinued where locally 
mandated. See Section 9.2.6 (Pregnancy). 
All participants who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in Section 2 (Schedule of Activities). 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 eCRF page. 
8.1.1 
Treatment Discontinuation Criteria 
8.1.1.1 
Criteria for Nivolumab and Ipilimumab Treatment Discontinuation 
Nivolumab and ipilimumab treatment must be permanently discontinued per criteria in Table 
7.4.2-1 in Section 7.4. Discontinue nivolumab and ipilimumab 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 and ipilimumab dosing. Any 
event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
• Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are allowed. 
• Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related reasons 
may be allowed if approved by the BMS Medical Monitor (or Clinical Scientist). 
 
Tumor assessments should continue as per protocol, even if dosing is delayed. Periodic study visits 
to assess safety and laboratory studies should also continue Q6W, or more frequently if clinically 
indicated during such dosing delays. 


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8.1.2 
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 7.4.2-1. 
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following conditions are met: 
• At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result (eg, reverse transcription-polymerase chain reaction [RT-PCR] or viral 
antigen), and 
• Resolution of acute symptoms (including at least 24 hours have passed since last fever without 
fever-reducing medications), and 
• Evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment 
 
For suspected cases, treatment may also resume if SARS-CoV-2 infection is ruled out and other 
criteria to resume treatment are met. 
When criteria to resume treatment are met, resume both nivolumab and ipilimumab on the same 
day. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the BMS 
Medical Monitor (or designee) must be consulted (see Section 8.1.1.1 [Criteria for Nivolumab and 
Ipilimumab Treatment Discontinuation]). In addition, see Appendix 6 (IO Management 
Algorithms) for guidance on appropriate management and follow-up of AEs. 
8.1.3 
Post Study Treatment Study Follow-up 
Per Protocol Amendment 01, survival follow-up is not required. However, participants in 
the follow-up period at the time of Protocol Amendment 01 implementation are permitted to 
continue in the study. Participants will be followed for assessment of safety through 100 days 
after the last dose of study treatment. Participants will not be followed for survival. 
The following information refers to the original study design: In this study, OS is a key 
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. Participants who discontinue study treatment must 
continue to be followed (in this study or a rollover study) for collection of outcome and/or survival 
follow-up data, as required and in line with Section 5 (Study Design) until death or the conclusion 
of the study. 
BMS may request that survival data be collected on all randomized participants outside of the 
protocol-defined window (see Section 2 [Schedule of Activities]). 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. 


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Participants who discontinue study treatment may continue to be followed. Subsequent therapies 
received by the participant will also be reviewed and recorded. 
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 eCRF 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 the date and cause of death. 
• If the 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 the participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
• The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
• If after all attempts, the 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). 


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• 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 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, 
baseline scans) and obtained before signing of informed consent may be utilized for screening 
or baseline purposes, provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities (Section 2). 
• Additional measures, including non-study-required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug-induced liver enzyme evaluations) will be monitored during the Follow-up Period via 
on-site/local laboratories until all study drug-related toxicities resolve, return to baseline, or 
are deemed irreversible. 
• 
If a participant shows pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, 
cough, fever) consistent with possible pulmonary AEs, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) IB.1 
• 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 
Study evaluations will take place in accordance with the Schedule of Activities in Section 2. Per 
Protocol Amendment 01, efficacy assessments will be conducted per the local standard of 
care. 
9.1.1 
Imaging Assessment for the Study 
Per Protocol Amendment 01, imaging should continue per local standard of care. The 
following information refers to the original study design. 
Images will be submitted to a central imaging vendor for BICR on a rolling basis 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 CA20974W Imaging Manual 
provided by the central imaging vendor. 


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Section 9.1.2.1 [Definition of Baseline Tumor Burden], no EHS [including regional lymph node 
involvement], no portal vein thrombosis, and no VI), prior to randomization. Randomization must 
occur within 4 weeks from screening imaging. 
9.1.1.4 
BICR Determination of Progression or Recurrence 
Not applicable per Protocol Amendment 01. Tumor assessments will be conducted by the 
investigator per local standard of care. The following information refers to the original study 
design. 
Sites should submit all scans to the central imaging vendor on a rolling basis, throughout the 
duration of the study. BICR of scans will occur on a rolling basis, blinded to treatment arm, clinical 
data, and Investigator assessment of submitted scans. The BICR will be completed and the results 
(TTTP reached or not) provided to the site, as specified in the imaging vendor documents, provided 
there are no pending imaging queries to the site. All details on the timelines and associated process 
requirements will be outlined in the Imaging Manual. 
Participants whose progression by TTTP criteria is not determined by the BICR will be required 
to continue tumor assessments (if clinically feasible) according to the protocol-specified schedule, 
or sooner if clinically indicated. Also, if participants discontinue treatment without radiographic 
progression (TTTP as assessed by BICR), tumor assessments will continue according to the 
protocol-specified schedule, as noted in Section 2 (Schedule of Activities), until progression 
(TTTP as assessed by BICR), has been confirmed by BICR. 
9.1.2 
Efficacy Assessments for TTTP 
Not applicable per Protocol Amendment 01. Tumor assessments will be conducted by the 
investigator per local standard of care. The following information refers to the original study 
design. 
9.1.2.1 
Definition of Baseline Tumor Burden 
The baseline tumor burden in this design will be the tumor burden recorded on imaging at the time 
of screening. The 5 largest (arterially enhancing portion measuring at least 10 mm) liver lesions 
will be selected for the calculation of tumor burden at baseline. 
9.1.2.2 
Dynamic Assessment of Tumor Burden 
During screening (see Section 9.1.2.1 [Definition of Baseline Tumor Burden]) and at each 
prescribed imaging timepoint the 5 largest liver lesions will be selected for the calculation of tumor 
burden. These may be lesions exhibiting regrowth or any new (arterially enhancing portion 
measuring at least 10 mm) liver lesions. This assessment of tumor burden is therefore a dynamic 
one and is more clinically relevant in a TACE setting, particularly when compared to a static 
assessment where tumor burden continues to be assessed based on the initial target lesions selected, 
which may no longer be there after a TACE procedure. Figure 9.1.2.2-1 illustrates the concept of 
a dynamic assessment of tumor burden. 


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Figure 9.1.2.2-1: 
Dynamic Tumor Burden Assessment 
 
Abbreviations: SLD = sum of longest diameters; TACE = trans-arterial chemoembolization. 
 
Finally, intermediate-stage HCC does not include patients with lesions outside of the liver. So the 
recorded measurable lesions will be solely defined based on liver lesions. The development of 
lesions outside of the liver will be captured as an EHS. 
9.1.2.3 
Definition of TTTP 
Not applicable per Protocol Amendment 01. Progression will be assessed by the investigator 
per local standard of care. The following information refers to the original study design. 
TTTP by imaging will be defined as a 20% increase in dynamic tumor burden over the baseline 
tumor burden, development of macroscopic evidence of MVI, extrahepatic tumor spread, or death 
(see Figure 9.1.2.3-1). 


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Figure 9.1.2.3-1: 
Criteria to Reach TTTP Based on Tumor Burden 
 
Abbreviations: TACE = trans-arterial chemoembolization; TTTP = time to TACE progression; mm = millimeters. 
 
 
9.1.3 
Efficacy Assessments using mRECIST 
As with traditional tumor assessment-based endpoints, a baseline tumor burden is needed in order 
to have a reference to compare changes in tumor burden during treatment. Tumor burden 
quantification should also follow the basic principles defined by mRECIST (refer to Appendix 10). 
As such, liver lesions will be categorized as “measurable” if the arterially enhancing portion can 
be accurately measured in at least 1 dimension, with a minimum size of 10 mm by CT or MRI 
scan. 
9.1.4 
Outcomes Research Assessments 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
The evaluation of patient-reported outcomes (PROs) is an increasingly important aspect of clinical 
efficacy in oncology trials. Such data provide an understanding of the impact of treatment from 
the participant’s perspective and offer insights into patient experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life (HRQL) measures 
provide data needed for calculating utility values to inform health economic models. 
Participants will be asked to complete the both the EQ-5D-5L and FACT-Hep in the participant’s 
preferred language when available. Participants will complete both measures prior to any other 


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assessments or study procedures when they are being administered during study visits. The PRO 
measures will also be completed at designated timepoints during the follow-up period. In addition, 
the EQ-5D-5L can be captured during survival follow-up visits by telephone administration. There 
exists a standardized guide that can be used to facilitate telephone administration of the EQ-5D-5L. 
See Section 2 (Schedule of Activities) for timing of assessments. 
9.1.4.1 
EQ-5D-5L 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
The EQ-5D-5L is a standardized instrument used to measure self-reports of health status and 
functioning.140 The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels, reflecting 
no problems, slight problems, moderate problems, severe problems, and extreme problems. A 
dimension for which there are no problems is said to be at level 1, while a dimension for which 
there are extreme problems is said to be at level 5. Thus, the vectors 11111 and 55555 represent 
the best health state and the worst health state, respectively, as described by the EQ-5D-5L. 
Altogether, the instrument describes 55 = 3,125 health states. 
Empirically derived weights can be applied to an individual’s responses to the EQ-5D-5L 
descriptive system to generate an index measuring the value to society of his or her current 
health.141 Utility index values range from a 1 (full health) to 0 (dead) with negative values 
indicating a state considered worse than being dead. In addition, the EQ-5D-5L includes a visual 
analog scale (VAS) that allows respondents to rate their own current health on a 0-100 point scale 
ranging from “the worst health you can imagine” to the “best health you can imagine.” 
The EQ-5D-5L uses a recall period of “today.” 
9.1.4.2 
FACT-Hep 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
The FACT-Hep questionnaire will be used to assess the effects of HCC and its treatment HRQL.142 
The FACT-Hep includes the FACT-G generic cancer-related core questionnaire to assess 
symptoms and treatment-related effects impacting physical well-being (PWB; 7 items), 
social/family well-being (SWB; 7 items), emotional well-being (EWB; 6 items), and functional 
well-being (FWB; 7 items). In addition, the FACT-Hep includes an 18-item disease-specific 
hepatobiliary cancer subscale (HCS) that assesses back and stomach pain, gastrointestinal 
symptoms, anorexia, weight loss, and jaundice. A subset of items from the FACT-Hep can also be 
scored as the National Cancer Care Network (NCCN)-FACT Hepatobiliary-Pancreatic Symptom 
Index (FHSI).143 The GP5 item of the FACT-Hep can also be used to assess the bother associated 
with the side effects of treatment. Each item is rated on a 5-point scale ranging from 0 (not at all) 
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Scores for the PWB, FWB, SWB, and EWB subscales can be combined to produce a FACT-G 
total score, which provides an overall indicant of generic HRQL, while the FACT-G and HCS 
scores can be combined to produce a total score for the FACT-Hep, which provides a composite 
measure of general and targeted HRQL. Higher scores indicate better HRQL. Minimally important 
differences (MIDs) have been estimated for the various FACT-Hep subscale and total scores. 
These are as follows: 2-3 points for the PWB, FWB, SWB, and EWB subscales; 5-6 points for the 
HCS subscale; 6-7 points for the FACT-G total score; 8-9 points for the FACT-Hep total score; 
and 2-3 points for the FHSI-8.144 
The FACT-Hep uses a recall period of the “past 7 days”. 
9.2 
Adverse Events 
Use the NCI CTCAE version 5.0 definitions and grading for safety reporting of all AEs and SAEs 
on the CRF. 
The definitions of an AE or 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 that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3. 
9.2.1 
Immune-mediated Adverse Events 
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which non-inflammatory etiologies (eg, infection, tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology that were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s eCRF. 
9.2.2 
Time Period and Frequency for Collecting AE and SAE Information 
All non-serious 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 dosing, at the timepoints specified in Section 2 (Schedule of Activities). 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and for a minimum of 100 days of discontinuation 
of dosing. For participants randomized/assigned to treatment and never treated with study drug, 
SAEs should be collected for 30 days from the date of randomization. 
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection must be collected from the time of signing the consent until 100 days following 
discontinuation of dosing. 


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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). 
• 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 the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
• The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of the updated information 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. 
9.2.3 
Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AEs and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement 
in the context of known AEs, when appropriate for the program or protocol. 
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 CRF. 
9.2.4 
Follow-up of AEs and SAEs 
• Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (refer to Appendix 3). 
• Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment, as appropriate. 
•  All identified non-serious AEs must be recorded and described on the non-serious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study. 
 
All SAEs and AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS- 
CoV-2 infection will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, the event is deemed irreversible, until the participant is lost to follow-up (as 
defined in Section 8.3 [Lost to Follow-up]), or for suspected cases, until SARS-CoV-2 infection 
is ruled out. 
Further information on follow-up procedures is given in Appendix 3. 


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9.2.5 
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 IB 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 suspected, unexpected serious adverse reaction 
(SUSAR) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
Investigators following local and global guidelines and requirements. 
9.2.6 
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 
5 half-lives after product administration, the Investigator must immediately notify the BMS 
Medical Monitor/Clinical Scientist of this event and complete and forward a Pregnancy 
Surveillance Form to the 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 re-initiation of study treatment, a discussion between the Investigator and the 
BMS Medical Monitor/Clinical Scientist must occur. If, for whatever reason, the pregnancy has 
ended, confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks 
and not greater than 6 weeks after the pregnancy has ended), following approvals of 
participant/Sponsor/IRB/EC, as applicable. Study treatment must be permanently discontinued 
where locally mandated; see Appendix 9 for country-specific requirements. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (eg, vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for the 
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the female partner(s) must sign an ICF for disclosure of this information. Information on the 
pregnancy will be collected on the Pregnancy Surveillance Form. 
9.2.7 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the non-serious 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. 
 
9.2.8 
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 2 and Appendix 3 for reporting details). 
Potential DILI is defined as: 
• Concurrent ALT ≥ 10  ULN, AND 
• Total bilirubin ≥ 2  ULN or baseline value (if elevated bilirubin at study entry), AND 
• 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. 
 
9.2.9 
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-ray filming, and any other potential safety assessment required or not 
required by protocol should also be recorded as a non-serious or serious AE, as appropriate, and 
reported accordingly. 
9.2.10 
Management Algorithms for Immuno-oncology Agents 
IO agents are associated with IMAEs that can differ in severity and duration from AEs caused by 
other therapeutic classes. Nivolumab and ipilimumab are considered IO agents in this protocol. 
Early recognition and management of IMAEs associated with IO agents may mitigate severe 
toxicity. Management algorithms have been developed from extensive experience with 
ipilimumab and nivolumab to assist Investigators in assessing and managing the following groups 
of IMAEs: 
• Gastrointestinal 


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• Renal 
• Pulmonary 
• Hepatic 
• Endocrinopathies 
• Skin 
• Neurological 
• Myocarditis 
 
The algorithms recommended for the management of IMAEs in this protocol are in Appendix 6. 
• Checkpoint inhibitor molecules have been uncommonly associated with ocular drug-related 
AEs. Inflammation of components within the eye (eg, episcleritis, uveitis) are uncommon 
events of nivolumab monotherapy (< 1% of cases). These events are usually of low or 
intermediate grade, reversible, detected early in the course of therapy, and manageable with 
topical or systemic steroids. 
− Routine eye examinations should be performed in participants receiving immune 
checkpoint inhibitors (Section 2 [Schedule of Activities]). Upon clinical suspicion of an 
ocular event, consider ophthalmic consult, dose omission, or dose discontinuation. 
− Permanently discontinue for clinically significant or severe immune-mediated adverse 
reactions. Initiate systemic corticosteroids for severe immune-mediated adverse reactions. 
− Permanently discontinue for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy. 
− Administer corticosteroid eye drops to participants who develop uveitis, iritis, or 
episcleritis. 
 
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 (refer to Appendix 3). 
9.4 
Safety 
Planned timepoints for all safety assessments are listed in Section 2 (Schedule of Activities). 
Additional procedures and assessments may be performed as part of SOC; however, data for these 
assessments should remain in the participant’s medical record and should not be provided to BMS, 
unless specifically requested. Both AEs and laboratory tests will be graded according to the 
NCI CTCAE version 5.0. 
9.4.1 
Physical Examinations 
See the Schedule of Activities (Section 2). 
9.4.2 
Vital Signs 
See the Schedule of Activities (Section 2). 


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9.4.3 
Electrocardiograms 
See the Schedule of Activities (Section 2). 
9.4.4 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report. 
A list of the clinical laboratory analyses to be tested is provided in Table 9.4.4-1 below. 


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Table 9.4.4-1: 
Clinical Safety Laboratory Assessments 
 
Hematology - CBC 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Coagulation profile: International normalized ratio (INR). If INR cannot be done by the local laboratory, then PT 
may be provided instead. 
Chemistry/Endocrine 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Creatinine 
Blood Urea Nitrogen (BUN) or serum urea 
Glucose 
Alpha-fetoprotein (AFP) 
Amylase 
Lipase 
Albumin 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphorus 
Magnesium 
TSH, free T3 and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is abnormal - 
on-treatment. For TSH assessments, total T3/T4 are 
acceptable if free T3/T4 are not available. 
Serology 
Hepatitis B/C/D 
Screening: HBsAg, HBV surface antibody, HBV core antibody, HBV DNA vial load [PCR], HCV viral load 
[PCR], HCV antibody or HCV RNA, HDV antibody 
On-treatment: For HCV-infected participants, HCV RNA; for HBV-infected participants, HBV DNA. 
HIV 
Testing for HIV-1 and HIV-2 must be performed at sites where mandated by local requirements. 
Other Analyses 
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG) 
FSH screening - only required to confirm menopause in women < age 55 
Urinalysis 
Protein 
Glucose 
Blood 
Leukocyte esterase 
Specific gravity 
pH 
Microscopic examination of the sediment if blood, protein, or leukocytes esterase are positive on the dipstick. 
Abbreviations: CBC = complete blood count; DNA = deoxyribonucleic acid; FSH = follicle stimulating hormone; 
HBsAg = hepatitis B surface antigen; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HDV = hepatitis D virus; HIV = human immunodeficiency virus; IU = international unit; L = liter; PCR = polymerase 
chain reaction; PT = prothrombin time; RNA = ribonucleic acid; TSH = thyroid-stimulating hormone; 
WOCBP = women of childbearing potential. 
 
 
9.4.5 
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. 


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9.5 
Pharmacokinetics and Immunogenicity 
Upon implementation of Protocol Amendment 01, PK and immunogenicity sample collection 
is no longer necessary for any participant who is on study treatment. In the event samples 
are collected following implementation of Protocol Amendment 01, samples do not need to 
be analyzed. 
The following information refers to the original study design and is not applicable per 
Protocol Amendment 01. 
Samples for PK and IMG assessments will be collected for all participants, as described in Table 
9.5-1. Only samples collected from nivolumab- and ipilimumab-treated participants will be 
analyzed; samples collected from placebo participants will not be analyzed. All timepoints are 
relative to the start of study treatment administration. All on-treatment timepoints are intended to 
align with days on which study treatment is administered. If it is known that a dose is going to be 
delayed, then the predose sample should be collected just prior to the delayed dose. However, if a 
predose sample is collected but the dose is subsequently delayed, an additional predose sample 
should not be collected. Further details of sample collection, processing, and shipment will be 
provided in the Laboratory Procedures Manual. 
Serum concentration analyses for nivolumab will be performed by a validated immunoassay 
bioanalytical method for participants treated with nivolumab. Samples collected from participants 
treated with nivolumab will be evaluated for the development of anti-drug antibody (ADA) to 
nivolumab by validated immunoassays. Samples with a positive ADA response may also be 
analyzed for nivolumab neutralizing ADA characterization by a validated cell-based assay. 
Serum concentration analyses for ipilimumab will be performed by a validated immunoassay 
bioanalytical method for participants treated with ipilimumab. Samples collected from participants 
treated with ipilimumab will be evaluated for the development of ADA to ipilimumab by validated 
immunoassays. Samples with a positive ADA response may also be analyzed for ipilimumab 
neutralizing ADA characterization by a validated cell-based assay. 
In addition, selected serum samples may be analyzed by exploratory methods that measure 
nivolumab or ipilimumab, or detect ADAs for technology exploration purposes; exploratory 
results will not be reported. The corresponding serum samples designated for either PK, IMG, 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 suspected IMG-related AE). 
Please see Appendix 9 for country-specific criteria for the collection and analyses of biomarker 
samples 
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Table 9.5-1: 
Pharmacokinetic and Immunogenicity Sampling Schedule for All Participants 
 
Study Day of Sample 
Collection 
(1 Cycle = 2 weeks) 
Event 
Time Relative to 
Start of Nivolumab 
Infusion (hr:min) 
Nivolumab 
Pharmacokinetic 
Serum Sample 
Ipilimumab 
Pharmacokinetics 
Serum Sample 
Nivolumab 
Immunogenicity 
Serum Sample 
Ipilimumab 
Immunogenicity 
Serum Sample 
Cycle 1 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
End of infusionb 
See note.c 
X 
X 
Cycle 2 Day 1 
Predosea,d 
00:00 
X 
X 
X 
X 
Cycle 4 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
Cycle 5 Day 1 
Predosea,d 
00:00 
X 
X 
X 
X 
Cycle 9 Day 1 
Predosea,d 
00:00 
X 
X 
X 
X 
Cycle 13 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
Cycle 19 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
Cycle 25 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
Cycle 29 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
Cycle 37 Day 1 
Predosea,d 
00:00 
X 
X 
X 
X 
Cycle 45 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
Abbreviations: hr = hour; min = minute; PK = pharmacokinetic. 
Note: Upon implementation of Protocol Amendment 01, PK and immunogenicity sample collection is no longer necessary for any participant who is on 
study treatment. In the event samples are collected following implementation of Protocol Amendment 01, samples do not need to be analyzed. 
a Predose: All pre-dose samples for nivolumab and ipilimumab should be taken just before the start of nivolumab infusion (preferably within 30 minutes). If it is 
known that a dose is going to be delayed, then the predose sample should be collected just prior to the delayed dose. However, if a predose sample is collected 
but the dose is subsequently delayed, an additional predose sample should not be collected. 
b End of infusion samples for both nivolumab and ipilimumab should be collected at the end of (preferably within 2 minutes prior to the end of) ipilimumab 
infusion. 
c On days where nivolumab and ipilimumab will be administered sequentially, the End of infusion sample collection for both nivolumab and ipilimumab at the 
end of ipilimumab infusion is 1:30, (0:30 for nivolumab infusion + 0:30 break + 0:30 ipilimumab infusion). 


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d Ipilimumab pharmacokinetics/immunogenicity samples will be collected, even though ipilimumab infusion will not be administered at these visits. 


 
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Pharmacodynamics 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Pharmacodynamic parameters will be evaluated in this study. Systemic immune monitoring of 
MDSCs, cytokines/chemokines, and other related soluble factors to investigate the 
immunomodulatory properties of nivolumab, ipilimumab, and TACE will be assessed. 
See Section 9.8 (Biomarkers) for a detailed description of the analyses and Table 9.8-1 for the 
sample collection schedule. 
Please see Appendix 9 for country-specific criteria for the collection and analyses of samples in 
China. 
9.7 
Pharmacogenomics 
Not applicable. 
9.8 
Biomarkers 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
A variety of factors that could potentially predict clinical response to nivolumab, ipilimumab, 
and/or TACE will be investigated in tumor specimens, peripheral blood, and stool taken from all 
participants as described below. Data from these investigations will be evaluated for association 
with efficacy endpoints. In addition, analyses of markers in all 3 treatment arms will provide the 
necessary data to identify and validate biomarkers with predictive vs prognostic value. 
A detailed description of each biomarker analysis is described below and a schedule of biomarker 
sample collections is provided in Table 9.8-1. Tumor tissue, peripheral blood, and a stool sample 
will be collected prior to therapy. Peripheral blood samples and a stool sample will also be 
collected at selected timepoints on-treatment. If a biopsy or surgical resection is performed at the 
time of TTTP by BICR or end of treatment, tumor sample (block or slides) should also be 
submitted for analysis. If biomarker samples are drawn but study treatment(s) are not administered, 
samples will be retained. Detailed instructions of the obtaining, processing, labeling, handling, 
storage and shipment of specimens will be provided in a separate Procedure Manual at the time of 
study initiation. 
Please see Appendix 9 for country-specific criteria for the collection and analyses of samples in 
China. 
 
 
 
 
 
 
 
 
 
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Table 9.8-1: 
CA20974W Biomarker Sampling Schedule All Participants 
 
Study Day of Sample 
Collection 
(1 Cycle = 2 weeks) 
Serum 
Biomarkersa 
Whole Blood 
DNAa 
Whole Blood 
RNAa 
MDSCa 
Plasma 
(ctDNA)a 
Stoolb 
Tumorc,d 
Screening 
X 
Cycle 1 Day 1 
X 
X 
X 
X 
X 
X 
Cycle 3 Day 1 
X 
X 
X 
X 
X 
Cycle 7 Day 1 
X 
X 
X 
Cycle 13 Day 1 
X 
Cycle 19 Day 1 
X 
Cycle 25 Day 1 
X 
Cycle 31 Day 1 
X 
Cycle 37 Day 1 
X 
Cycle 43 Day 1 
X 
Cycle 49 Day 1 
X 
Upon TTTP by BICR 
or EOT 
X 
X 
X 
X 
Abbreviations: BICR = blinded independent central review; ctDNA = circulating tumor DNA; DNA = deoxyribonucleic acid; EOT = end of treatment; 
MDSC = myeloid-derived suppressor cells; RNA = ribonucleic acid; TACE = trans-arterial chemoembolization; TTTP = time to TACE progression. 
a Prior to dosing (when applicable). 
b Stool collection is optional and should be collected within 7 days prior to dosing. Stool should not be collected in China and in other geographies if restricted 
by local requirements. 
c Tumor tissue submission during screening is required for randomization. Upon TTTP by BICR or end of treatment, tumor tissue submission is highly 
recommended if clinically feasible 
d Biomarker samples will not be collected 
 except for tumor samples during Screening. See Appendix 9. 
 
 
 
 
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9.8.1 
Tumor-based Biomarker Measures 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Tumor tissue will be obtained at baseline and upon TTTP by BICR or end of treatment (if clinically 
feasible) to characterize immune cell populations, expression of selected tumor markers, 
expression of inflammatory genes, and genetic analyses mentioned below in detail. Tumor block 
(preferred) or slides must be sent to the central laboratory prior to randomization. Biopsy samples 
should be excisional, incisional, or core needle. Fine needle aspirates or other cytology samples 
are not acceptable. A tumor block is preferred, but if a block is not feasible, a minimum of 
20 unstained slides is required. Slides should be unstained, have a recommended tissue section 
thickness of 4 microns, and must be positively charged. Tumor tissue must contain adequate tumor 
content (≥ 100 tumor cells), as determined by hematoxylin and eosin (H&E) review at the central 
laboratory. If the initial tumor sample submission does not meet this criterion, an additional tissue 
submission (if available) is allowed. Participants must have an evaluable tumor tissue specimen to 
be eligible for randomization. A tumor biopsy upon TTTP by BICR or end of treatment is also 
highly recommended, if clinically feasible. 
Tumor samples may be used for the assessments described below. Please see Appendix 9 for 
country-specific criteria for the collection and analyses of tumor-tissue samples in China. 
9.8.1.1 
Characterization of Tumor Infiltrating Lymphocytes and Tumor 
Antigens 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Immunohistochemistry (IHC) may be used to assess tumor markers as well as the number and 
composition of immune infiltrates in order to define the immune cell subsets present within FFPE 
tumor tissue before therapy and upon TTTP by BICR or end of treatment. IHC analyses may 
include, but not necessarily be limited to, the following markers: major histocompatibility complex 
(MHC) class I/II, CD8, PD-1, PD-L1, PD-L2, and lymphocyte activating 3 (LAG3). 
9.8.1.2 
Tumor Genomic Analysis Including Tumor Mutational Burden and Gene 
Expression Analysis 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
DNA from tumor samples will be analyzed using platforms, including, but not limited to, whole- 
exome sequencing to identify and quantify somatic mutations by using the whole blood DNA 
sample as a germline reference. Mutations that are detected may be analyzed for their ability to 
bind the MHC class I and MHC class II proteins using prediction algorithms. Evaluating the ability 
of tumor mutations to bind MHC molecules may provide evidence that these mutations are serving 
as antigens that are recognized by the immune system and are potential rejection antigens. MSI or 
MSI status may be derived from whole-exome sequencing data if MSI status is not already known. 
Lastly, RNA expression within tumor biopsies may be examined using RNAseq, whole- 


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transcriptome sequencing, or other next-generation sequencing technologies to detect expression 
of all genes. 
9.8.2 
Peripheral Biomarkers 
9.8.2.1 
Myeloid-derived Suppressor Cells 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
MDSCs are an immune cell population capable of suppressing T cell activation and proliferation. 
MDSCs will be measured prior to dosing on Cycle 1 Day 1, on-treatment, and upon TTTP by 
BICR or end of treatment to assess pharmacodynamic changes as well as associations with 
outcome. 
9.8.2.2 
Soluble Biomarkers and Other Assessments in Serum 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Serum will be collected prior to dosing on Cycle 1 Day 1, on-treatment, and upon TTTP by BICR 
or end of treatment to measure levels of cytokines, chemokines, other immune mediators, and 
extracellular matrix fragments. These factors will be assessed by techniques that may include, but 
are not limited to, enzyme-linked immunosorbent assay (ELISA) or multiplex assays. Analyses 
may include, but are not limited to, IFN-, C-X-C motif chemokine ligand (CXCL) 9, CXCL10, 
soluble PD-L1, collagen, and other extracellular matrix fragments. These analyses may identify 
potential biomarkers with prognostic and predictive value for outcomes. 
9.8.2.3 
Genomic Analysis of Circulating Tumor DNA in Plasma 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Plasma will be collected prior to dosing on Cycle 1 Day 1, on-treatment, and upon TTTP by BICR 
or end of treatment to enable genomic analysis of circulating tumor DNA (ctDNA). 
9.8.2.4 
Whole Blood DNA and RNA Analyses 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
DNA in the whole blood samples may be used to examine germline (predisposing) characteristics 
as well as to help identify genetic information specific to the participant’s tumor, such as somatic 
DNA alterations. RNA in the whole blood sample may be used to assess the expression of genes 
associated with inflammation. These blood samples will be obtained prior to dosing on 
Cycle 1 Day 1 (whole blood DNA and whole blood RNA) and on-treatment (whole blood RNA 
only) unless restricted by local requirements. 
9.8.2.5 
Viral Safety Biomarkers 
At screening, HBV DNA, qualitative and quantitative hepatitis B surface antigen (qHBsAg), 
hepatitis B e-antigen (qHBeAg),  hepatitis B  surface antibody (HBsAb),  HCV RNA, 


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HCV antibody, and hepatitis D antibody (if chronic HBV infection) samples will be collected for 
all participants. On-treatment and during follow-up visits FU1 and FU2, HBV DNA will only be 
collected for HBV chronic-infected participants, and HCV RNA will only be collected for 
HCV chronic-infected participants. Details regarding sample collection timepoints can be found 
in Section 2 (Schedule of Activities). These analyses will be performed at the central laboratory. 
Results of HBV DNA and HCV RNA will be provided to sites for management of virologic 
breakthrough (see Section 7.7.3.1 [Antiviral Therapy]). 
9.8.3 
Microbiome Analysis 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
An optional stool sample will be collected prior to dosing and while on-treatment to assess 
microbiome diversity and composition, unless restricted by local requirements. 
9.8.4 
Additional Research Collection 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
This protocol will include residual sample storage for additional research (AR). 
For All US sites: 
AR is required for all study participants, except where prohibited by IRBs/ethics committees, or 
academic/institutional requirements. Where 1 or more of these exceptions occurs, participation in 
the AR should be encouraged but will not be a condition of overall study participation. 
• If the IRB/ethics committees and site agree to the mandatory AR retention and/or collection, 
then the study participant must agree to the mandatory AR 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 AR and/or collection. 
 
For non-US Sites 
AR 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 AR 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 patients. This 
may also include genetic/genomic exploration aimed at exploring disease pathways, progression 
and response to treatment, etc. 


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Sample Collection and Storage 
All requests for access to samples or data for AR will be vetted through a diverse committee of the 
study Sponsor’s senior leaders in R&D (or designee) to ensure the research supports appropriate 
and well-defined scientific research activities. 
• Residual PK/IMG, tumor tissue, and serum, plasma, whole blood, and stool samples from 
collections (see Table 9.8.4-1 [Residual Sample Retention for Additional Research Schedule]) 
will also be retained for AR purposes. 
 
Samples kept for future research will be stored at the BMS Biorepository in 
or 
an independent, BMS-approved storage vendor. 
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law. 
Transfers of samples by the research Sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures. 
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 
 
Sample Type 
Timepoints for Which Residual Samples will be Retained 
PK/IMG 
All 
Tumor tissue 
All 
Serum biomarkers 
All 
Plasma for ctDNA 
All 
Whole blood DNA 
C1D1 
Whole blood RNA 
C1D1 
Stool 
All 
Abbreviations: C = cycle; ctDNA = circulating tumor DNA; D = day; DNA = deoxyribonucleic acid; 
IMG = immunogenicity; PK = pharmacokinetics; RNA = ribonucleic acid. 
 
9.9 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 


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Healthcare resource utilization (HCRU) data will be collected for all randomized participants using 
an internal CRF developed for use in previous trials. The form, which is completed by study staff, 
records information about hospital admissions, including number of days spent in various wards 
and discharge diagnosis, as well as non-protocol specified visits related to study therapy, including 
date of visit, reason for visit, and type of visit. The HCRU data will be used to support subsequent 
economic evaluations. 
10 
STATISTICAL CONSIDERATIONS 
Per Protocol Amendment 01, only safety analyses will be conducted. Summary tables and 
listings for baseline, disposition, and safety data will be provided to support the Clinical Study 
Report (CSR) and study data disclosure. Listings for efficacy data may be provided, if requested, 
per regional data disclosure requirement. Details of the analysis and outputs will be provided in 
the SAP. 
10.1 
Sample Size Determination 
Per Protocol Amendment 01, sample size will be limited to the participants randomized as 
of 22-Sep-2021. The following information refers to the original study design. 
For the comparison of nivolumab and ipilimumab plus TACE (Arm A) vs nivolumab placebo and 
ipilimumab placebo plus TACE (Arm C), both TTTP and OS are primary endpoints. For sample 
size determination purpose, the family-wise error rate of 5% will be controlled using Bonferroni 
split: comparison of TTTP with alpha of 1% and comparion of OS with alpha of 4%. 
Approximately 765 participants will be randomized to 3 treatment arms in a 1:1:1 ratio in 
approximately 36 months. Approximately 94% and 89% power will be achieved for TTTP and 
OS, respectively, under the detailed assumptions described in following subsections. EAST v6.4.1 
was used to conduct simulations for sample size calculation. 
10.1.1 
Sample Size Justification for Primary Endpoint of TTTP 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Assumpations for sample size justification for TTTP include: 
• Exponential distribution in Arm C, with a median of 
. 
• Piecewise-exponential distribution in Arm A as determined by a 2-piece HR with a delay effect 
of HR of 1 in the first 
, followed by a constant HR of  (see Table 10.1.1-1). 
This results in an averaged target HR of 
 at the TTTP final analysis. 
• Anticipated dropout rate of    by month 3 and 
by month 24. 


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Table 10.1.1-1: 
TTTP Hazard Rates and HRs (Arm A vs Arm C) 
 
Starting at 
Time (month) 
Hazard Rates for TACE (Arm C) 
Hazard Rates for Nivolumab and 
Ipilimumab plus TACE (Arm A) 
HR 
Abbreviations: HR = hazard ratio; TACE = trans-arterial chemoembolization. 
 
Based on simulation under the assumptions stated above, approximately 510 participants will be 
randomized to Arm A and Arm C and followed until at least 418 TTTP events are observed, in 
order to provide 94% power for an average HR of 
 with a 2-sided type I error of 1%. 
The number of events is expected to be reached after approximately 55 months from the first 
participant randomized (see Table 10.1.1-2). 
 
Table 10.1.1-2: 
Summary of Sample Size Parameters and Schedule of Analyses for 
TTTP (Arm A vs Arm C) 
 
Parameter 
Value 
Number of randomized participants 
510 
Hypothesized delayed period 
Hypothesized HR after delayed period 
Hypothesized median in control arm 
Significance level (2-sided) 
0.01 
Enrollment perioda 
36 months 
Number of events 
418 
Projected TTTP analysis timea 
55 months 
Power 
94% 
Average HR 
Median in experimental arm time 
14.9 months 
Abbreviations: HR = hazard ratio; TACE = trans-arterial chemoembolization; TTTP = time to TACE progression. 
a Time is calculated from the time the first participant is randomized. 
 
It is projected that an observed HR of 
 or less would results in a statistically significant 
improvement of nivolumab and ipilimumab plus TACE at the final analysis of TTTP. 
10.1.2 
Sample Size Justification for Primary Endpoint OS 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Assumptions for sample size justification for OS include: 


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• Piecewise-exponential distribution in both control and experimental arms. 
• When viewing the OS data from the BRISK-TA study, the TACE arm was considered as the 
most relevant to this study’s control arm, Arm C. Based on such data, a 
exponential 
distribution is assumed for OS of Arm C. The assumed piecewise-exponential model fits the 
OS data of TACE in the BRISK-TA study up to  months. Starting from month 26, the tail 
of the control OS curve rose to have higher OS rates, with a 5-year OS of  (see Figure 
10.1.2-1). The flattened tail of the OS curve intends to indicate that the longer-term OS should 
be improved with current and future available 1L, 2L, and later lines of therapies. 
• The median OS of the control arm is 
 based on above assumptions. 
• Anticipated dropout rate of 
 by month 3 and 
 by month 
 
 
The target average HR of 
is assumed for Arm A vs Arm C and is modeled as an 
HR 
with a delay effect of HR of in the first 
months, followed by multiple pieces of HR. These HRs 
start with 
 after separation, and HRs are gradually increased thereafter to reflect the belief that 
the overall treatment effect will be compromised when participants who progress in the control 
arm have a higher chance to select immunotherapies as their subsequent therapies (see Table 
10.1.2-1). 
Figure 10.1.2-1: 
OS for TACE from External Data (BRISK-TA study) and Assumed 
Probability of OS for Placebo plus TACE (Arm C) 
 
Abbreviations: ctr = control; m = months; mOS = median overall survival; OS = overall survival; 
TACE = trans-arterial chemoembolization. 


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Table 10.1.2-1: 
OS Hazard Rates and HRs (Arm A vs Arm C) 
 
Starting at Time 
(month) 
Hazard Rates for 
TACE (Arm C) 
Hazard Rates for Nivolumab and 
Ipilimumab plus TACE (Arm A) 
HR 
 
 
 
Abbreviations: HR = hazard ratio; OS = overall survival; TACE = trans-arterial chemoembolization. 
 
Based on simulation under the assumptions stated above, approximately 510 participants will be 
randomized to the nivolumab and ipilimumab plus TACE and placebo plus TACE arms and 
followed until at least 371 OS events are observed, in order to provide 89% power for an average 
HR of 
 with a 2-side type I error of 4%. This accounts for a group sequential testing procedure 
with 2 interim analyses and 1 final analysis. The first OS interim analysis will be conducted at the 
time of TTTP final analysis, when approximately 72% of OS events (267 events) are expected. 
The second OS interim analysis will be conducted when 88% of OS events (326 events) are 
expected. The alpha allocation for the interim and final analyses is based on Lan-DeMets alpha 
spending function approach using an O’Brien-Fleming stopping boundary, controlling for a 
2-sided overall type I error of 4%. The stopping boundary will depend on the actual number of 
deaths at the time of the interim analyses and the final analysis (see Table 10.1.2-2). 


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Table 10.1.2-2: 
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Arm A vs Arm C) 
 
Parameter 
Value 
Number of randomized participants 
510 
Hypothesized delayed period 
Hypothesized HR after delayed period 
Hypothesized median in control arm 
Significance level (2-sided) 
0.04 
Enrollment perioda 
36 months 
Interim Analysis #1 for OS 
Number of events 
267 
Projected analysis timea 
55 months 
Interim Analysis #2 for OS 
Number of events 
326 
Projected analysis timea 
68 months 
Final Analysis 
Number of events 
371 
Projected analysis timea 
87 months 
Power 
89% 
Average HR 
Median in experimental arm 
37.7 months 
Abbreviations: HR = hazard ratio; OS = overall survival. 
a Time is calculated from the time the first participant is randomized. 
 
It is projected that an observed HR of 0.74/
 or less would result in a statistically significant 
improvement of nivolumab and ipilimumab plus TACE at the first/second interim analyses of OS, 
and an observed HR of 0.8 or less would result in a statistically significant improvment of 
nivolumab and ipilimumab plus TACE at the final analysis of OS. 
10.1.3 
Power Considerations in Nivolumab plus TACE vs Placebo plus TACE 
(Arm B vs Arm C) TTTP and OS Comparison as Secondary Endpoints 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
TTTP between nivolumab plus TACE (Arm B) vs placebo plus TACE (Arm C) will be tested 
following a hierachical procedure. This comparison will be tested when the primary objective of 
TTTP of nivolumab and ipilimumab plus TACE vs placebo plus TACE meets statistical 


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significance. The testing will be conduced at the same significance level of 1%. The TTTP 
comparison in Arm B vs Arm C will be conducted at the same time of TTTP comparison of Arm A 
vs Arm C. At the time of the TTTP analysis for Arm A and Arm C, it is projected 421 events will 
be observed in Arm B and Arm C. Under the piecewise HR assumption for Arm B (see Table 
10.1.3-1), the comparison will have approximately 86% power (see Table 10.1.3-2). 
Table 10.1.3-1: 
TTTP Hazard Rates and HRs (Arm B vs Arm C) 
 
Starting at 
Time (month) 
Hazard Rates for TACE (Arm C) 
Hazard Rates for Nivolumab 
plus TACE (Arm B) 
HR 
Abbreviations: HR = hazard ratio; TACE = trans-arterial chemoembolization; TTTP = time to TACE progression. 
 
 
Table 10.1.3-2: 
Summary of Design Parameters and Schedule of Analyses for TTTP 
(Arm B vs Arm C) 
 
Parameter 
Value 
Number of randomized participants 
510 
Hypothesized delayed period 
Hypothesized HR after delayed period 
Hypothesized median in control arm 
Significance level (2-sided) 
0.01 
Enrollment perioda 
36 months 
Number of events 
421 
Projected TTTP analysis timea 
55 months 
Power 
86% 
Average HR 
Median in experimental arm 
14.3 months 
Abbreviations: HR = hazard ratio; TACE = trans-arterial chemoembolization; TTTP = time to TACE progression. 
a Time is calculated from the time the first participant is randomized. 
 
OS between nivolumab plus TACE (Arm B) vs placebo plus TACE (Arm C) will be tested 
following a hierarchical procedure. This comparison will be tested when the primary objective of 
OS of Arm A vs Arm C meets statistical significance. The testing will be conduced at the same 
significance level of 4%. At the time of OS final analysis for Arm A and Arm C, it is projected 
376 events will be observed in Arm B and Arm C. Under the piecewise HR assumption for Arm B 
(see Table 10.1.3-3), the comparison will have approximately 83% (see Table 10.1.3-4). 
A graphical approach will be used to control the overall alpha of 4% among the primary endpoint 


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of OS, secondary endpoint of OS, and their interim and final analyses. Detailed will be documented 
in the statistical analysis plan (SAP). 
Table 10.1.3-3: 
OS Hazard Rates and HRs (Arm B vs Arm C) 
 
Starting at Time 
(month) 
Hazard Rates for 
TACE (Arm C) 
Hazard Rates for Nivolumab plus 
TACE (Arm B) 
HR 
Abbreviations: HR = hazard ratio; OS = overall survival; TACE = trans-arterial chemoembolization. 
 
 
Table 10.1.3-4: 
Summary of Design Parameters and Schedule of Analyses for OS 
(Arm B vs Arm C) 
 
Parameter 
Value 
Number of randomized participants 
510 
Hypothesized delayed period 
Hypothesized HR after delayed period 
Hypothesized median in control arm 
Significance level (2-sided) 
0.04 
Enrollment perioda 
36 months 
Interim Analysis #1 for OS 
Number of events 
271 
Projected analysis timea 
55 months 
Interim Analysis #2 for OS 
Number of events 
327 
Projected analysis timea 
68 months 


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Table 10.1.3-4: 
Summary of Design Parameters and Schedule of Analyses for OS 
(Arm B vs Arm C) 
 
Parameter 
Value 
Final Analysis 
Number of events 
376 
Projected analysis timea 
87 months 
Power 
83% 
Average HR 
Median in experimental arm 
36.2 month 
Abbreviations: HR = hazard ratio; OS = overall survival. 
a Time is calculated from the time the first participant is randomized. 
 
10.2 
Populations for Analyses 
Per Protocol Amendment 01, only safety assessments wll be conducted. 
For purposes of analysis, the following populations are defined in Table 10.2-1. 
Table 10.2-1: 
Populations for Analyses 
 
Population 
Description 
All Enrolled 
All participants who signed an ICF and were registered into the IRT. 
All Randomized 
All participants who were randomized to any treatment arm in the study. Participants 
are grouped within the All Randomized population by the treatment to which they 
were randomized. 
This is the primary analysis set for demography, protocol deviations, and baseline 
characteristics. 
All Treated 
All enrolled participants who receive at least 1 dose of study drug. Participants are 
grouped within the All Treated population according to the treatment they actually 
received. This is the analysis set for all safety analyses and study drug administration. 
PK 
Not applicable per Protocol Amendment 01. All participants who receive at least 1 
dose of nivolumab or ipilimumab and have available serum concentration data that allow 
for computation of meaningful PK parameter values. 
IMG 
Not applicable per Protocol Amendment 01. All nivolumab- or ipilimumab-treated 
participants with baseline and at least 1 post-baseline IMG assessment. 
Biomarker 
Not applicable per Protocol Amendment 01. All Treated participants who have 
available biomarker data. 
For predictive biomarkers, biomarker population includes all randomized participants 
who have biomarker data available at baseline. For pharmacodynamic biomarkers, the 
biomarker population includes all randomized participants who have baseline and at 
least 1 post-baseline biomarker data available. 


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Table 10.2-1: 
Populations for Analyses 
 
Population 
Description 
PRO Analysis 
Not applicable per Protocol Amendment 01. All Treated participants who have a 
valid baseline assessment (prior to treatment on Cycle 1 Day 1) and at least 1 post- 
baseline assessment during the treatment period. 
Abbreviations: ICF = informed consent form; IMG = immunogenicity; IRT = interactive response technology; 
PK = pharmacokinetics; PRO = patient-reported outcome. 


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10.3 
Statistical Analyses 
The SAP will be developed and finalized before the first database lock and will describe the 
selection of participants to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. 
10.3.1 
Efficacy Analyses 
Per Protocol Amendment 01, formal efficacy analyses will not be conducted. Descriptive 
summary statistics may be provided for internal dissemination only. 
A Bonferroni-based graphical approach145 will be used for primary and key secondary endpoint 
analyses. Details will be provided in the SAP. The following secondary endpoints will be tested 
sequentially in the following order at the allocated alpha inherited from the primary endpoint of 
TTTP: 
• TTTP in Arm B vs Arm C 
• EFS in Arm A vs Arm C 
• EFS in Arm B vs Arm C 
• PFS in Arm A vs Arm C 
• PFS in Arm B vs Arm C 
 
Statistical analyses for efficacy are shown in Table 10.3.1-1. 
Table 10.3.1-1: 
Efficacy - Statistical Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
TTTP nivolumab and ipilimumab 
plus TACE vs placebo plus TACE 
TTTP is defined as the time from the date of randomization to appearance 
of any of the following: a 20% increase in dynamic tumor burden over 
baseline scan; development of MVI; development of EHS; or death. 
Participants who are alive and with no HCC tumor progression by TTTP 
will be censored at the last tumor assessment date prior to or on first 
subsequent therapy date. 
The distribution of TTTP of nivolumab and ipilimumab plus TACE and 
placebo plus TACE will be compared via a 2-sided, log-rank test stratified 
by the stratification factors. The HR and corresponding 99% CI will be 
estimated in a stratified Cox proportional hazards model using randomized 
arm as a single covariate. The TTTP curves for each arm will be estimated 
using the Kaplan-Meier produce limit method. The 2-sided 95% CIs for 
median TTTP will be computed by Brookmeyer and Crowley method 
(using log-log transformation). 


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Endpoint 
Statistical Analysis Methods 
OS nivolumab and ipilimumab 
plus TACE vs placebo plus TACE 
OS is defined as the time from the date of randomization to the date of 
death due to any cause in all randomized participants. Participants who are 
alive will be censored at the last known alive dates. 
The distribution of OS of nivolumab and ipilimumab plus TACE and 
placebo plus TACE will be compared via a 2-sided, log-rank test stratified 
by the stratification factors. The HR and corresponding 100(1-adjusted 
alpha)% CI will be estimated in a stratified Cox proportional hazards model 
using randomized arm as a single covariate. The OS curves for each arm 
will be estimated using the Kaplan-Meier produce limit method. The 
2-sided 95% CIs for median OS will be computed by Brookmeyer and 
Crowley method (using log-log transformation). In addition, survival rates 
at select milestones will be computed as well as the corresponding 2-sided 
95% CIs using the log-log transformation. 
Secondary 
TTTP nivolumab plus TACE vs 
placebo plus TACE 
Similar to primary endpoint analysis. 
Hierarchical testing of TTTP in nivolumab plus TACE and placebo plus 
TACE will be performed upon demonstration of superiority in TTTP in 
nivolumab and ipilimumab plus TACE and placebo plus TACE. 
Descriptive analysis will be performed if superiority is not demonstrated. 
OS nivolumab plus TACE vs 
placebo plus TACE 
Similar to primary endpoint analysis. 
Hierarchical testing of OS in nivolumab plus TACE and placebo plus 
TACE will be performed upon demonstration of superiority in OS in 
nivolumab and ipilimumab plus TACE and TACE plus placebo. 
Descriptive analysis will be performed if superiority is not demonstrated. 


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Endpoint 
Statistical Analysis Methods 
EFS nivolumab and ipilimumab 
plus TACE vs placebo plus TACE 
and nivolumab plus TACE vs 
placebo plus TACE 
EFS is defined as the time from randomization to initiation of first-line 
systemic therapy or the date of progression of cirrhosis from Child Pugh A 
to Child Pugh C score, or death, whichever occurs first. Participants who 
are alive and received no first-line systemic therapy or are not progressed to 
Child Pugh C will be censored at the last Child-Pugh score assessment date. 
The distribution of EFS in randomized arms will be compared via a 
2-sided, log-rank test stratified by the stratification factors. The HR and 
corresponding 99% CI will be estimated in a stratified Cox proportional 
hazards model using randomized arm as a single covariate. The EFS curves 
for each arm will be estimated using the Kaplan-Meier produce limit 
method. The 2-sided 95% CIs for median EFS will be computed by 
Brookmeyer and Crowley method (using log-log transformation). 
Hierarchical testing of EFS will be performed upon demonstration of 
superiority in TTTP. Descriptive analysis will be performed if superiority is 
not demonstrated in TTTP. 
PFS nivolumab and ipilimumab 
plus TACE vs placebo plus TACE 
and nivolumab plus TACE vs 
placebo plus TACE 
PFS is defined as the time from the randomization date to the first 
documented disease progression as assessed by BICR using mRECIST or 
death due to any cause, whichever occurs first. Participant who are alive 
and not progressed will be censored on the date of last tumor assessment 
prior to or on first subsequent therapy date. 
The distribution of PFS in randomized arms will be compared via a 2-sided, 
log-rank test stratified by the stratification factors. The HR and 
corresponding 100(1-adjusted alpha)% CI will be estimated in a stratified 
Cox proportional hazards model using randomized arm as a single 
covariate. The PFS curves for each arm will be estimated using the 
Kaplan-Meier produce limit method. The 2-sided 95% CIs for median PFS 
will be computed by Brookmeyer and Crowley method (using log-log 
transformation). 
Hierarchical testing of PFS will be performed upon demonstration of 
superiority in TTTP and EFS. Descriptive analysis will be performed if 
superiority is not demonstrated in TTTP and EFS. 
Exploratory 
All exploratory endpoints 
The exploratory endpoints and their analyses will be described in the SAP 
finalized prior to database lock. 
Abbreviations: BICR = blinded independent central review; CI = confidence interval; EFS = event-free survival; 
EHS = extrahepatic spread; HCC = hepatocellular carcinoma; HR = hazard ratio; mRECIST = modified Response 
Evaluation Criteria in Solid Tumors; MVI = macrovascular invasion; OS = overall survival; PFS = progression-free 
survival; SAP = statistical analysis plan; TACE = trans-arterial chemoembolization; TTTP = time to TACE 
progression. 
 
 
10.3.2 
Safety Analyses 
Safety analyses will be described in the SAP finalized before the first database lock. 


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10.3.3 
Other Analyses 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
PK, pharmacodynamic, biomarker, IMG, and outcomes research exploratory analyses will be 
described in the SAP finalized before the first database lock. 
10.3.4 
Interim Analyses 
Not applicable per Protocol Amendment 01. The following information refers to the original 
study design. 
Two interim analyses and 1 final analysis of OS are planned for this study. The first interim 
analysis of OS is planned at the time of final TTTP analysis (with approximately 267 OS events 
expected in Arm A and Arm C). TTTP final analysis is expected to occur when there are 
418 events (approximately 55 months after the first participant’s randomization date) in Arm A 
and Arm C. First OS interim analysis will be conducted at the same time (with approximately 
267 OS events expected in Arm A and Arm C). The second OS interim analysis is expected to 
occur when there are 326 OS events in Arm A and Arm C (approximately 68 months after the first 
participant’s randomization date). These formal comparisons of OS will allow for early stopping 
for superiority. Lan-DeMets alpha spending function with O’Brien and Fleming type of boundary 
will be used. The stopping boundary will depend on the actual number of deaths at the time of the 
interim analyses. An independent statistical group supporting the DMC, external to BMS, will 
perform the analyses. Formal interim analyses for OS and final analysis for TTTP in Arm B and 
Arm C will be performed at the same time of TTTP and OS analysis in Arm A and Arm C. EFS and 
PFS analysis will also be conducted at the TTTP final analysis if TTTP is superior in both Arm A 
and Arm B. 
The SAP will further describe the planned interim analyses. 


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11 
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randomized, open-label study of nivolumab vs sorafenib in advanced hepatocellular carcinoma 
subjects who are naive to systemic therapy. Addendum 03. Bristol-Myers Squibb Company, 
2018. Document Control Number 930128330. 
4 GLOBOCAN 2019. Available from: URL: http://gco.iarc.fr/today/home. Accessed July 7, 
2019. 
5 Yang JD, Roberts LR. Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol 
Hepatol 2010;7(8):448-458. 
6  Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates 
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Patients With Advanced Melanoma (MEL) Who Discontinued Treatment With Nivolumab 
(NIVO) Plus Ipilimumab (IPI) Due to Toxicity in a Phase III Trial (CheckMate 067). 2016 
Annual Meeting of the European Association of Dermato-Oncology; August 31-September 3, 
2016. Vienna, Austria. 
132 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. Journal 
of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 
2015;33(17):1889-94. 
133 Brahmer J, Horn L, Jackman D, et al. Five-year Follow-up From the CA209-003 Study of 
Nivolumab in Previously Treated Advanced Non-small Cell Lung Cancer: Clinical 
Characteristics of Long-term Survivors. Oral presentation presented at: American Association 
for Cancer Research (AACR) Annual Meeting; April 1-5, 2017. Washington, DC, USA. 
134 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 presentation at the European Society of Medical 
Oncology Annual Meeting. September 8-12, 2017. Madrid, Spain. Poster 1301PD. 
135 Spigel DR, et al. Randomized Results of Continuous vs 1-year Fixed-duration in Patients With 
Advanced Non-small Cell Lung Cancer. Oral presentation at the European Society of Medical 
Oncology Annual Meeting. September 8-12, 2017. Madrid, Spain. 
136 Mazzaferro V, Llovet JM, Miceli R, et al. redicting survival after liver transplantation in 
patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory 
analysis. Lancet Oncol 2009;10(1):35-43. 


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137 Kloeckner R, Weinmann A, et al. Conventional transarterial chemoembolization versus drug- 
eluting bead transarterial chemoembolization for the treatment of hepatocellular carcinoma. 
BMC Cancer 2015;15:465. 
138 Song JE, Kim DY. Conventional vs drug-eluting beads transarterial chemoembolization for 
hepatocellular carcinoma. World J Hepatol 2017;9(18):808-814. 
139 Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in 
hepatocellular carcinoma. J Natl Cancer Inst 2008;100(10):698-710. 
140 Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20(10):1727-1736. 
141 van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value Health 2012;15(5):708-715. 
142 Heffernan N, Cella D, Webster K, et al. Measuring health-related quality of life in patients 
with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary 
questionnaire. J Clin Oncol 2002;20(9):2229-2239. 
143 Butt Z, Parikh ND, Beaumont JL, et al. Development and validation of a symptom index for 
advanced hepatobiliary and pancreatic cancers: the National Comprehensive Cancer Network 
Functional Assessment of Cancer Therapy (NCCN-FACT) Hepatobiliary-Pancreatic 
Symptom Index (NFHSI). Cancer 2012;118(23):5997-6004. 
144 Steel JL, Eton DT, Cella D, et al. Clinically meaningful changes in health-related quality of 
life in patients diagnosed with hepatobiliary carcinoma. Ann Oncol 2006;17(2):304-312. 
145 Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective multiple 
test procedures. Stat Med 2009;28(4):586-604. 


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12 
APPENDICES 


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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
 
Term 
Definition 
C 
degrees Celsius 
L 
microliter 
+ 
positive 
1L 
first line 
2L 
second line 
AASLD 
American Association for the Study of Liver Diseases 
AC 
anthracycline + cyclophosphamide 
ADA 
anti-drug antibody 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
AFP 
alpha-fetoprotein 
ALBI 
albumin-bilirubin 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APASL 
Asian Pacific Association for the Study of the Liver 
AR 
additional research 
AST 
aspartate aminotransferase 
BCLC 
Barcelona Clinic Liver Cancer 
Bcl-xL 
B-cell lymphoma-extra large 
BICR 
blinded independent central review 
BMS 
Bristol-Myers Squibb 
BMU7 
Beyond Milan and Up-to-7 
BOR 
best overall response 
BP 
blood pressure 
BSC 
best supportive care 
BTLA 
B- and T-lymphocyte attenuator 
BUN 
blood urea nitrogen 
C 
cycle 
Cavgss 
steady-state average concentration 


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Term 
Definition 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
clearance 
cm 
centimeter 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTAg 
clinical trial agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
ctl 
control 
CTLA-4 
cytotoxic T-lymphocyte-associated protein-4 
CV 
coefficient of variation 
CXCL 
C-X-C motif chemokine ligand 
D 
day 
DAA 
direct-acting antiviral 
DCR 
disease control rate 
DEB-TACE 
trans-arterial chemoembolization with drug-eluding beads 
DFS 
disease-free survival 
DILI 
drug-induced liver injury 


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Term 
Definition 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
E-R 
exposure-response 
EASL 
European Association for the Study of the Liver 
EC 
ethics committee 
EC50 
half-maximal effective concentration 
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 
EHR 
electronic health record 
EHS 
extrahepatic spreading 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EMR 
electronic medical record 
EOI 
end of infusion 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol-5 Dimensions-5 Levels 
ESMO-ESDO 
European Society for Medical Oncology and the European Society of 
Digestive Oncology 
etc 
et cetera 
EU 
Europe 
EWB 
emotional well-being 
FACT-Hep 
Functional Assessment of Cancer Therapy-Hepatobiliary 


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Term 
Definition 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FHSI 
FACT Hepatobiliary-Pancreatic Symptom Index 
FSH 
follicle-stimulating hormone 
FU1 
follow-up visit 1 
FU2 
follow-up visit 2 
FWB 
functional well-being 
g 
gram 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
H&E 
hematoxylin and eosin 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCG 
human chorionic gonadotropin 
HCRU 
healthcare resource utilization 
HCS 
hepatobiliary cancer subscale 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
Hep B 
hepatitis B 
Hep C 
hepatitis C 
Hep D 
hepatitis D 
HIV 
human immunodeficiency virus 
hr 
hour 
HR 
hazard ratio 
HRQL 
health-related quality of life 
HuMab 
human monoclonal antibody 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 


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Term 
Definition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICOS 
inducible T cell co-stimulator 
ie 
id est (that is) 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IFN-γ 
interferon-gamma 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IL 
interleukin 
IMAE 
immune-mediated adverse event 
IMG 
immunogenicity 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IO 
immuno-oncologic 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IU 
international unit 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IVRS 
interactive voice response system 
kg 
kilogram 
L 
liter 
LAG3 
lymphocyte activating 3 
LAM 
lactation amenorrhea method 
LDH 
lactate dehydrogenase 


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Term 
Definition 
LFT 
liver function test 
LSEC 
liver sinusoidal endothelial cell 
m 
month 
m2 
meters squared 
MD 
medical doctor 
MDSC 
myeloid-derived suppressor cell 
mg 
milligram 
MHC 
major histocompatibility complex 
MID 
minimally important difference 
min 
minute 
mL 
milliliter 
MLR 
mixed lymphocyte reaction 
MMR 
measles, mumps, rubella 
mOS 
median overall survival 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
MVI 
macrovascular invasion 
MWA 
microwave ablation 
mWHO 
modified World Health Organization 
N 
number of subjects or observations 
N0 
no regional lymph node metastasis 
NA 
not applicable 
NCCN 
National Cancer Care Network 
NCI 
National Cancer Institute 
nM 
nanomolar 
NSCLC 
non-small cell lung cancer 


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Term 
Definition 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-1+ 
programmed cell death-1-positive 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PE 
physical examination 
PES 
post-embolization syndrome 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFS2 
progression-free survival 2 
PK 
pharmacokinetic 
PLC 
primary liver cancer 
PPK 
population pharmacokinetics 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
performance status 
PT 
prothrombin time 
PWB 
physical well-being 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q6W 
every 6 weeks 
Q12W 
every 12 weeks 
qHBeAg 
qualitative and quantitative hepatitis B e-antigen 
qHBsAg 
qualitative and quantitative hepatitis B surface antigen 
QoL 
quality of life 


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Term 
Definition 
R&D 
research and development 
RCC 
renal cell carcinoma 
RCT 
randomized clinical trial 
RECICL 
Response Evaluation Criteria in Cancer of the Liver 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFA 
radiofrequency ablation 
RFS 
relapse-free survival 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription-polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small cell lung cancer 
SD 
stable disease 
SLD 
sum of longest diameters 
SOC 
standard of care 
SOP 
standard operating procedures 
SUSAR 
suspected, unexpected serious adverse reaction 
SWB 
social/family well-being 
t1/2 
half-life 
TACE 
trans-arterial chemoembolization 
TAE 
trans-arterial embolization 
TM 
trademark 
Treg 
T regulatory cell 
TSH 
thyroid-stimulating hormone 
TTP 
time to progression 
TTDP 
time to disease progression 
TTTP 
time to TACE progression 
TTUP 
time to unTACEable progression 


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Term 
Definition 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
visual analog scale 
VI 
vascular invasion 
VP0 
no portal vein thrombosis 
vs 
versus 
Vss 
mean volume of distribution at steady state 
Vv0 
no vascular invasion 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WNOCBP 
women not of childbearing potential 
Y90 
radioactive isotope yttrium 


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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 CRF 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 the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s). 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
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/participants. 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/participants 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/participants. 
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/participants currently enrolled in the study if they are affected by the amendment; and 
(3) the new form must be used to obtain consent from new subjects/participants 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/participants 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 by subjects/participants, 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/participants, 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/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization. 
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects/participants unable to give their written consent (eg, stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The participant must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this participant become capable, he or she 
should personally sign and date the consent form as soon as possible. The explicit wish of a 
participant who is unable to give his or her written consent, but who is capable of forming an 
opinion and assessing information to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the investigator. 
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society. 


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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). 
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 treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority. 


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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 (eg, lost, wasted) 
• amount destroyed at study site, if applicable 
• amount returned to BMS 
• retain samples for 
bioavailability/bioequivalence/biocomparability, 
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. 
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 


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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. 
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 


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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 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy) 
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures. 
 
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 


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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. 
DISSEMINATION OF CLINICAL STUDY DATA 
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases. 
CLINICAL STUDY REPORT AND PUBLICATIONS 
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator: 
• Participant recruitment (eg, among the top quartile of enrollers) 
• Involvement in trial design 
• Other criteria (as determined by the study team) 
 
SCIENTIFIC PUBLICATIONS 
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. 
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor. 


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Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship: 
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
 
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered. 
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions. 


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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). 


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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. 
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 
(eg, routine colonoscopy) 
• medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason) 
• admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 


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Is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.8 for the definition of potential DILI.) 
 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.2.6 for reporting pregnancies). 
 
EVALUATING AES AND SAES 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 


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Follow-up of AEs and SAEs 
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. 
 
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. 
− The required method for SAE data reporting is through the eCRF. 
− The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee). 
 In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission 
 When paper forms are used, the original paper forms are to remain on site 
• Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list. 
SAE Facsimile Number: Refer to Contact Information list. 
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list 


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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 post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause. 
 
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. The duration of 
the washout period below are suggested guidelines and the 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 
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.* 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctly.a 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b 
− oral (birth control pills) 
− intravaginal (vaginal birth control suppositories, rings, creams, gels) 
− transdermal 
• 
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. 
Highly Effective Methods That Are User Independent 


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• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)b 
• 
Intrauterine device (IUD)c 
• 
Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b,c 
• Bilateral tubal occlusion 
• 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 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. 
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 participating 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 Intrauterine devices and 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. 


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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 
• Lactation amenorrhea method (LAM) 
 
*Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator. 
• Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment. 
• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
study treatment in the male participant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
• Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment. 


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COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.6 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting. 


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APPENDIX 5 
ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUSa 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655. 


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APPENDIX 6 
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0 
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 
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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APPENDIX 7 
BEYOND MILAN AND UP-TO-7 CRITERIA 
 
 
Up-to-7 Criteria 
7 being the result of the sum of size (in cm) and number of tumors for 
any given hepatocellular carcinoma. For example: 1 nodule up to 6 cm 
in size (1 + 6 = 7) to many tumors fulfilling 7 as the sum of the size of 
the largest lesion plus the number (ie, 2 tumors up to 5 cm in size, 3 
tumors up to 4 cm in size, 4 tumors up to 3 cm in size, and 5 tumors up 
to 2 cm in size). Liver lesions must have an arterially enhancing lesion 
measuring at least 10 mm in size to be counted as a tumor. 


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APPENDIX 8 
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 9 
COUNTRY-SPECIFIC REQUIREMENTS 
Criteria for exclusion of HIV-positive participants in Argentina, Czech Republic, Germany, Italy, 
Spain, and any other countries where exclusion of HIV-positive participants is locally mandated. 
 
Protocol Section 
Current Protocol Text 
Revised Protocol Text 
Table 2-1: Screening 
Procedural Outline 
(CA20974W) 
Testing for HIV (when required by local 
regulations [refer to Appendix 9]) must be 
done at local laboratory within 28 days 
prior to randomization. 
Testing for HIV must be done at local 
laboratory within 28 days prior to 
randomization. 
Section 6.2: Exclusion 
Criteria, 1) Medical 
Conditions, g) 
Infections ii) 
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 
(refer to Appendix 9). 
Positive test for HIV. 
Table 9.4.4-1: Clinical 
Safety Laboratory 
Assessments 
Testing for HIV-1 and HIV-2 must be 
performed at sites where mandated by local 
requirements. 
Testing for HIV-1 and HIV-2 must be 
performed. 
Criteria for discontinuation of treatment due to pregnancy in the Czech Republic and any other 
countries where discontinuation of pregnancy participants is locally mandated. 
 
Protocol Section 
Current Protocol Text 
Revised Protocol Text 
Section 8.1: 
Discontinuation from 
Study Treatment 
Pregnancy, if locally mandated (see 
Appendix 
9 
for 
country-specific 
requirements). 
Pregnancy 
Section 9.2.6 
If the Investigator determines a possible 
Remove this text 
Pregnancy 
favorable benefit-risk ratio that warrants 
continuation of study treatment, or re- 
initiation of study treatment, a discussion 
between the Investigator and the BMS 
Medical Monitor/Clinical Scientist must 
occur.  If,  for 
whatever  reason,  the 
pregnancy  has  ended, 
confirmed 
by 
negative serum pregnancy test, treatment 
may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy 
has 
ended), 
following 
approvals 
of 
participant/Sponsor/IRB/EC, as applicable. 
Study  treatment must  be permanently 
discontinued where locally mandated; see 
Appendix 
9 
for 
country-specific 
requirements. 


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Criteria for collection and analyses of biomarker samples 
and any other countries where 
applicable. 
 
Protocol Section 
Current Protocol Text 
Revised Protocol Text 
Section 2 Schedule of 
Activities, Table 2-1 
Screening Procedural 
Outline (CA20974W), 
Tumor Sample 
Submission notes 
An FFPE tissue block (preferred) or a minimum 
of 20 unstained slides of tumor tissue obtained 
from core biopsy, punch biopsy, excisional 
biopsy, 
or 
surgical 
specimen 
prior 
to 
randomization (within 3 months of enrollment 
with 
no 
intervening 
systemic 
anticancer 
treatment between time of acquisition and 
randomization, or archival tissue [if above is not 
available]) must be sent to the central laboratory. 
Fine needle aspirates or other cytology samples 
are not acceptable. If despite best efforts, a 
minimum of 20 slides are not obtainable, 
submission of fewer slides may be acceptable in 
some circumstances following discussion with 
the BMS Medical Monitor or Clinical Scientist. 
Please see Appendix 9 for country-specific 
criteria for the collection of tumor tissue samples 
in China. 
An FFPE tissue block (preferred) or 
a minimum of 5 unstained slides of 
tumor tissue obtained from core 
biopsy, punch biopsy, excisional 
biopsy, or surgical specimen prior to 
randomization (within 3 months of 
enrollment with no intervening 
systemic anticancer treatment 
between time of acquisition and 
randomization, or archival tissue [if 
above is not available]) must be sent 
to the central laboratory. Fine needle 
aspirates or other cytology samples 
are not acceptable. 
Section 2 Schedule of 
Activities, Table 2-2 
On-treatment 
Procedural Outline 
(CA20974W) and 
Table 2-3 Follow-up 
Procedural Outline 
(CA20974W) 
Table 2.2 
Biomarker Assessments, including 
procedures for Serum Biomarkers, Whole 
Blood DNA and RNA, MDSC, Plasma 
(ctDNA); Stool Samples for Microbiome 
Analysis; Collection of Tumor Upon TTTP 
or EOT; and SARS-CoV-2 serology 
Table 2-3 
Biomarker Assessments 
Remove 
Biomarker 
Assessments 
from table. 
Section 4 Objectives 
and Endpoints 
Removed in Protocol Amendment 01 
Objective: To analyze biomarkers in tumor, 
peripheral blood, and stool to evaluate 
association with clinical efficacy and/or 
incidence of AEs in all randomized 
participants. 
Endpoint: Correlation of selected biomarkers 
with efficacy (TTTP, OS, EFS, PFS) and safety 
(incidence of AEs) endpoints. 
Objective: To analyze PD-L1 to 
evaluate association with clinical 
efficacy in all randomized 
participants. 
Endpoint: Correlation of PD-L1 with 
efficacy (TTTP, OS, EFS, PFS) 
endpoints. 
Section 4 Objectives 
and Endpoints 
Removed in Protocol Amendment 01 
Objective: To investigate the association 
between tumor inflammation and clinical 
efficacy measures, including OS, in all 
randomized participants. 
Endpoint: 
Correlation 
of 
inflammatory 
biomarkers with efficacy (TTTP, OS, EFS, PFS) 
endpoints 
Remove objective and endpoint. 
Section 5.1.1 
Screening Period 
Sufficient, recent tumor tissue obtained within 3 
months prior to randomization from a lesion 
from an unresectable primary tumor lesion that 
Sufficient, 
recent 
tumor 
tissue 
obtained within 3 months prior to 
randomization from a lesion from an 


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has not been previously irradiated (formalin 
fixed, paraffin-embedded [FFPE] block or 
minimum of 20 slides, obtained from core 
biopsy, punch biopsy, excisional biopsy, or 
surgical specimen) will be submitted to the 
central laboratory. Fine needle aspirates or other 
cytology samples are not acceptable. If despite 
best efforts, a minimum of 20 slides are not 
obtainable, submission of fewer slides may be 
acceptable in some circumstances following 
discussion with BMS Medical Monitor or 
Clinical Scientist. The central laboratory must 
provide IRT with confirmation of receipt of 
evaluable tumor tissue prior to randomization. 
Participants should not have received any 
systemic anticancer therapy after the date that 
the submitted tumor tissue was obtained. Please 
see Appendix 9 for country-specific criteria for 
the collection of tumor tissue samples in China. 
unresectable primary tumor lesion 
that has not been previously irradiated 
(formalin-fixed, 
paraffin-embedded 
[FFPE] block or minimum of 5 slides, 
obtained from core biopsy, punch 
biopsy, excisional biopsy, or surgical 
specimen) will be submitted to the 
central 
laboratory. 
Fine 
needle 
aspirates or other cytology samples 
are not acceptable. The central 
laboratory must provide IRT with 
confirmation of receipt of evaluable 
tumor tissue prior to randomization. 
Participants should not have received 
any systemic anticancer therapy after 
the date that the submitted tumor 
tissue was obtained. 
Section 5.1.2 
Treatment Period 
Biomarker sample collection will be done 
according to the schedule in Table 9.8-1. Please 
see Appendix 9 for country-specific criteria for 
the collection of biomarker samples 
. 
Remove this text. 
Section 6.1 Inclusion 
Criteria – 2, c, ii) 
Either a FFPE tissue block (preferred) or a 
minimum of 20 unstained slides of tumor tissue 
sections obtained within 3 months prior to 
randomization or archived (if above is not 
available) with an associated pathology report 
must be submitted to the central laboratory for 
inclusion. The central laboratory must provide 
IRT with confirmation of receipt of evaluable 
tumor tissue prior to randomization. Biopsy 
should be excisional, incisional or core needle. 
Fine needle aspiration or other cytology samples 
are unacceptable for submission. If despite best 
efforts, a minimum of 20 slides are not 
obtainable, submission of fewer slides may be 
acceptable in some circumstances following 
discussion with BMS Medical Monitor or 
Clinical Scientist. Please see Appendix 9 for 
country-specific criteria for the collection of 
tumor tissue samples in China. 
Either a FFPE tissue block (preferred) 
or a minimum of 5 unstained slides of 
tumor tissue sections obtained within 
3 months prior to randomization or 
archived (if above is not available) 
with an associated pathology report 
must be submitted to the central 
laboratory for inclusion. The central 
laboratory must provide IRT with 
confirmation of receipt of evaluable 
tumor tissue prior to randomization. 
Biopsy 
should 
be 
excisional, 
incisional or core needle. Fine needle 
aspiration or other cytology samples 
are unacceptable for submission. 


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Section 9.5 
Pharmacokinetics and 
Immunogenicity 
In addition, selected serum samples may be 
analyzed by exploratory methods that measure 
nivolumab or ipilimumab, or detect ADAs for 
technology exploration purposes; exploratory 
results will not be reported. The corresponding 
serum samples designated for either PK, IMG, 
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 suspected IMG-related AE). 
Please see Appendix 9 for country-specific 
criteria for the collection and analyses of 
biomarker samples 
. 
In addition, selected serum samples 
may be analyzed by exploratory 
methods that measure nivolumab or 
ipilimumab, or detected ADAs for 
technology 
exploration 
purposes; 
exploratory results will not be 
reported. The corresponding serum 
samples designated for either PK or 
IMG may also be used for any of 
those analyses, if required (eg, 
insufficient 
sample 
volume 
to 
complete testing or to follow-up on 
suspected IMG-related AE). 
Section 9.6 
Pharmacodyamics 
Not applicable per Protocol Amendment 01. The 
following information refers to the original 
study design. 
Pharmacodynamic parameters will be evaluated 
in this study. Systemic immune monitoring of 
MDSCs, 
cytokines/chemokines, 
and 
other 
related soluble factors to investigate the 
immunomodulatory properties of nivolumab, 
ipilimumab, and TACE will be assessed. See 
Section 9.8 (Biomarkers) for a detailed 
description of the analyses and Table 9.8-1 for 
the sample collection schedule. 
Please see Appendix 9 for country-specific 
criteria for the collection and analyses of 
samples in China. 
Not applicable. 
Section 9.8 
Biomarkers 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
A variety of factors that could potentially predict 
clinical response to nivolumab, ipilimumab, 
and/or TACE will be investigated in tumor 
specimens, peripheral blood, and stool taken 
from all participants as described below. Data 
from these investigations will be evaluated for 
association with efficacy endpoints. In addition, 
analyses of markers in all 3 treatment arms will 
provide the necessary data to identify and 
validate 
biomarkers 
with 
predictive 
vs 
prognostic value. 
A detailed description of each biomarker 
analysis is described below and a schedule of 
biomarker sample collections is provided in 
Table 9.8-1. Tumor tissue, peripheral blood, and 
a stool sample will be collected prior to therapy. 
Peripheral blood samples and a stool sample will 
also be collected at selected timepoints on- 
treatment. If a biopsy or surgical resection is 
performed at the time of TTTP by BICR or end 
of treatment, tumor sample (block or slides) 
Remove text and table. Leave Level 
2 header. 


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should also be submitted for analysis. If 
biomarker samples are drawn but study 
treatment(s) are not administered, samples will 
be retained. Detailed instructions of the 
obtaining, 
processing, 
labeling, 
handling, 
storage and shipment of specimens will be 
provided in a separate Procedure Manual at the 
time of study initiation. 
Please see Appendix 9 for country-specific 
criteria for the collection and analyses of 
samples in China. 
Table 9.8-1: CA20974W Biomarker Sampling 
Schedule All Participants. 
Section 9.8.1 Tumor- 
based Biomarker 
Measures 
9.8.1 
Tumor-based Biomarker Measures 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
Tumor tissue will be obtained at baseline and 
upon TTTP by BICR or end of treatment (if 
clinically feasible) to characterize immune cell 
populations, expression of selected tumor 
markers, expression of inflammatory genes, and 
genetic analyses mentioned below in detail. 
Tumor block (preferred) or slides must be sent 
to the central laboratory prior to randomization. 
Biopsy samples should be excisional, 
incisional, or core needle. Fine needle aspirates 
or other cytology samples are not acceptable. A 
tumor block is preferred, but if a block is not 
feasible, a minimum of 20 unstained slides is 
required. Slides should be unstained, have a 
recommended tissue section thickness of 4 
microns, and must be positively charged. 
Tumor tissue must contain adequate tumor 
content (≥ 100 tumor cells), as determined by 
hematoxylin and eosin (H&E) review at the 
central laboratory. If the initial tumor sample 
submission does not meet this criterion, an 
additional tissue submission (if available) is 
allowed. Participants must have an evaluable 
tumor tissue specimen to be eligible for 
randomization. A tumor biopsy upon TTTP by 
BICR or end of treatment is also highly 
recommended, if clinically feasible. 
Tumor samples may be used for the 
assessments described below. Please see 
Appendix 9 for country-specific criteria for the 
collection and analyses of tumor-tissue samples 
in China. 
9.8.1  Tumor for PD-L1 Analysis 
Tumor tissue will be obtained at 
baseline to assess PD-L1. Tumor 
block (preferred) or slides must be 
sent to the central laboratory prior to 
randomization. 
Biopsy 
samples 
should be excisional, incisional, or 
core needle. Fine needle aspirates or 
other cytology samples are not 
acceptable. 
A 
tumor 
block 
is 
preferred, but if a block is not feasible, 
a minimum of 5 unstained slides is 
required. Slides should be unstained, 
have a recommended tissue section 
thickness of 4 microns, and must be 
positively charged. Tumor tissue must 
contain adequate tumor content (≥ 
100 tumor cells), as determined by 
hematoxylin and eosin (H&E) review 
at the central laboratory. If the initial 
tumor sample submission does not 
meet this criteria, an additional tissue 
submission (if available) is allowed. 
Participants must have an evaluable 
tumor tissue specimen to be eligible 
for randomization. 


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Section 9.8.1.1 
Characterization of 
Tumor Infiltrating 
Lymphocytes and 
Tumor Antigens 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
Immunohistochemistry (IHC) may be used to 
assess tumor markers as well as the number and 
composition of immune infiltrates in order to 
define the immune cell subsets present within 
FFPE tumor tissue before therapy and upon 
TTTP by BICR or end of treatment. IHC 
analyses may include, but not necessarily be 
limited to, the following markers: major 
histocompatibility complex (MHC) class I/II, 
CD8, PD-1, PD-L1, PD-L2, and lymphocyte 
activating 3 (LAG3). 
Remove section. 
Section 9.8.1.2 Tumor 
Genomic Analysis 
Including Tumor 
Mutational Burden 
and Gene Expression 
Analysis 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
DNA from tumor samples will be analyzed using 
platforms, including, but not limited to, whole- 
exome sequencing to identify and quantify 
somatic mutations by using the whole blood 
DNA sample as a germline reference. Mutations 
that are detected may be analyzed for their 
ability to bind the MHC class I and MHC class 
II 
proteins 
using 
prediction 
algorithms. 
Evaluating the ability of tumor mutations to bind 
MHC molecules may provide evidence that 
these mutations are serving as antigens that are 
recognized by the immune system and are 
potential rejection antigens. MSI or MSI status 
may be derived from whole-exome sequencing 
data if MSI status is not already known. Lastly, 
RNA expression within tumor biopsies may be 
examined using RNAseq, whole-transcriptome 
sequencing, or other next-generation sequencing 
technologies to detect expression of all genes. 
Remove section. 
Section 9.8.2 
Peripheral Biomarkers 
Heading only 
Remove section 
Section 9.8.2.1 
Myeloid-derived 
Suppressor Cells 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
MDSCs are an immune cell population capable 
of 
suppressing 
T 
cell 
activation 
and 
proliferation. MDSCs will be measured prior to 
dosing on Cycle 1 Day 1, on-treatment, and upon 
TTTP by BICR or end of treatment to assess 
pharmacodynamic 
changes 
as 
well 
as 
associations with outcome. 
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Section 9.8.2.2 
Soluble Biomarkers 
and Other 
Assessments in Serum 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
Serum will be collected prior to dosing on Cycle 
1 Day 1, on-treatment, and upon TTTP by BICR 
or end of treatment to measure levels of 
cytokines, 
chemokines, 
other 
immune 
mediators, and extracellular matrix fragments. 
These factors will be assessed by techniques that 
may include, but are not limited to, enzyme- 
linked immunosorbent assay (ELISA) or 
multiplex assays. Analyses may include, but are 
not limited to, IFN-γ, C-X-C motif chemokine 
ligand (CXCL) 9, CXCL10, soluble PD-L1, 
collagen, 
and 
other 
extracellular 
matrix 
fragments. 
These 
analyses 
may 
identify 
potential biomarkers with prognostic and 
predictive value for outcomes. 
Remove section. 
Section 9.8.2.3 
Genomic Analysis of 
Circulating Tumor 
DNA in Plasma 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
Plasma will be collected prior to dosing on Cycle 
1 Day 1, on-treatment, and upon TTTP by BICR 
or end of treatment to enable genomic analysis 
of circulating tumor DNA (ctDNA). 
Remove section. 
Section 9.8.2.4 Whole 
Blood DNA and RNA 
Analyses 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
DNA in the whole blood samples may be used to 
examine germline (predisposing) characteristics 
as well as to help identify genetic information 
specific to the participant’s tumor, such as 
somatic DNA alterations. RNA in the whole 
blood sample may be used to assess the 
expression 
of 
genes 
associated 
with 
inflammation. These blood samples will be 
obtained prior to dosing on Cycle 1 Day 1 
(whole blood DNA and whole blood RNA) and 
on-treatment (whole blood RNA only) unless 
restricted by local requirements. 
Remove section. 
Section 9.8.2.5 Viral 
Safety Biomarkers 
At screening, HBV DNA, qualitative and 
quantitative 
hepatitis 
B 
surface 
antigen 
(qHBsAg), hepatitis B e-antigen (qHBeAg), 
hepatitis B surface antibody (HBsAb), HCV 
RNA, HCV antibody, and hepatitis D antibody 
(if chronic HBV infection) samples will be 
collected for all participants. On-treatment and 
during follow-up visits FU1 and FU2, HBV 
DNA will only be collected for HBV chronic- 
infected participants, and HCV RNA will only 
be  collected  for  HCV  chronic-infected 
Move to become a subsection of 
Section 9.4. 


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participants. Details regarding sample collection 
timepoints can be found in Section 2 (Schedule 
of Activities). These analyses will be performed 
at the central laboratory. Results of HBV DNA 
and HCV RNA will be provided to sites for 
management of virologic breakthrough (see 
Section 7.7.3.1 [Antiviral Therapy]). 
Section 9.8.3 
Microbiome Analysis 
Not applicable per Protocol Amendment 01. 
The following information refers to the 
original study design. 
An optional stool sample will be collected prior 
to dosing and while on-treatment to assess 
microbiome diversity and composition, unless 
restricted by local requirements. 
Remove section. 
Section 9.8.4 
Additional Research 
Collection 
Residual PK/IMG, tumor tissue, and serum, 
plasma, whole blood, and stool samples from 
collections (see Table 9.8.4-1 [Residual Sample 
Retention for Additional Research Schedule]) 
will also be retained for AR purposes. 
Residual PK/IMG and tumor tissue 
(see Table 9.8.4-1 [Residual Sample 
Retention for Additional Research 
Schedule]) will also be retained for 
AR purposes.” 


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APPENDIX 10 
RESPONSE EVALUATION CRITERIA MODIFIED FOR 
HEPATOCELLULAR CARCINOMA (mRECIST) WITH BMS 
ADAPTATIONS 
1 
EVALUATION OF LESIONS 
In this protocol, the response criteria modified for the assessment of HCC (mRECIST), published 
in the Journal of the National Cancer Institute (JNCI 2010) will be applied. This modified RECIST 
for HCC criteria is based on RECIST v1.1 but introduces the concept of the longest diameter of 
the viable tumor tissue for “typical” intrahepatic HCC lesions. Intrahepatic lesions are considered 
“typical” if they display hypervascularity in the arterial phase and a wash-out in the portal or late 
venous phase in dynamic contrast-enhanced CT or MRI. Differentiating between viable vs necrotic 
liver tumor tissue may allow a more accurate representation of anti-cancer treatment effects. In the 
context of this protocol, these criteria will be termed ‘Modified RECIST for HCC (mRECIST)’. 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
2 
MEASURABLE 
Liver lesions: Must be well-delineated, arterially enhancing lesions that can be accurately 
measured in at least one dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of: 
• contrast enhancement at least 10 mm by CT/MRI scan (scan slice thickness no greater than 
5 mm). 
 
Extrahepatic 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  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 


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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. 
3 
NON-MEASURABLE 
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm, liver lesions with atypical enhancement, 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. 
3.1 
Special considerations regarding lesion measurability 
3.1.1 
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. 
 
4 
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS 
The selection of target lesions will be initially guided by the presence of ‘typical’ intrahepatic 
lesions. 
‘Typical’ intrahepatic lesions MUST meet the following criteria: 
• Lesions can be classified as measurable lesion 
• Lesions are suitable for repeated measurements 
• Lesion shows typical vascular pattern of HCC in contrast-enhanced spiral CT or MRI studies, 
defined as: 
− Well delineated intrahepatic lesions 
− Hypervascularity in the arterial phase 
− Contrast agent wash-out in the portal and late venous phase 


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Measurable lesions in the liver meeting the criteria for ‘typical’ target lesions present at baseline, 
should be chosen as the sole intrahepatic target lesions. Up to five ‘typical’ intrahepatic lesions 
will be selected as target lesions. Measurement of the longest viable diameter, which is the longest 
diameter of the viable tumor lesion, will be applied to these lesions. 
HCC lesions that show local recurrence and/or residual disease after loco-regional therapy and 
have typical hypervascular patterns of HCC can be selected as target lesions. All other ‘atypical’ 
intrahepatic lesions will NOT be considered as target lesions. 
If measurable extrahepatic lesions are present in addition to the ‘typical’ intrahepatic lesions at 
baseline, up to five lesions (and a maximum of two lesions per organ), representative of all 
involved organs, will be identified as target lesions. 
Note: Outside of the liver, 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. 
All measurable intrahepatic lesions (up to a maximum of five lesions) and extrahepatic lesions (up 
to five lesions and a maximum of two lesions per organ) should be identified as target lesions to 
be measured and recorded at baseline. 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, up to ten total, 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. Non-target lesions may include: 
Intrahepatic lesions: 
• Poorly delineated HCC lesions including infiltrative-type and diffuse HCC 
• HCC lesions with atypical contrast-agent enhancement patterns 
• HCC lesions showing local recurrence after previous loco-regional treatment without meeting 
the criteria for ‘viable’ lesions (ie, lack of clear-cut hypervascular recurrence and/or 
well-delineation from the surrounding liver tissue) 
• Portal vein tumor invasion and/or thrombosis 
• Intrahepatic viable lesions in excess to the 5 lesions in the liver selected as target lesions 


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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’). 
5 
RESPONSE CRITERIA 
5.1 
Evaluation of Target Lesions 
• Complete Response (CR): For typical intrahepatic target, complete disappearance of any 
intratumoral contrast-agent enhancement in the arterial phase of CT or MRI. For atypical intra- 
and extrahepatic target, disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• 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. 
 
5.1.1 
Special Notes on the Assessment of Target Lesions 
5.1.1.1 
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. 
5.1.1.2 
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 


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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 
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. 
5.1.1.3 
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’. 
5.2 
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): For typical intrahepatic non-target lesions, complete 
disappearance of any intratumoral contrast-agent enhancement in the arterial phase of CT or 
MRI. For atypical intra- and extrahepatic non-target lesions, complete disappearance of all 
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. 
 
5.2.1 
Special Notes on Assessment of Progression of Non-Target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
5.2.1.1 
When the Participant 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 


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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. 
5.2.1.2 
When the Participant 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. 
5.2.2 
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. 
New hepatic lesion with the longest diameter of at least 10 mm with the vascular pattern 
characteristic for HCC (ie, hypervascularization) in the arterial phase with wash-out in the portal 
venous (or late venous) phase of contrast-enhanced CT or MRI imaging denotes disease 
progression. 
New hepatic lesions larger than 10 mm without the vascular pattern characteristic for HCC but 
evidence of growth of at least 10 mm in subsequent scans will also denote disease progression. 
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 


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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 PD. 
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
5.3 
Response Assessment 
5.3.1 
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. 
5.3.2 
Time Point Response 
At each protocol specified time point, a response assessment occurs. Table 5.3.2-1 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 5.3.2-2 is to be used. 
Table 5.3.2-1: 
Time Point Response 
 
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 
Abbreviations: CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
will clarify if it represents truly new disease. 


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Table 5.3.2-2: 
Time Point Response 
 
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 
Abbreviations: CR = complete response; NE = inevaluable; PD = progressive disease. 
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. 
 
5.3.3 
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 5.3.3-1. 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 5.3.3-1: 
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 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 


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Table 5.3.3-1: 
Best Overall Response (Confirmation of CR and PR Required) 
 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
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 
Abbreviations: CR = complete response NE = inevaluable, PD = progressive disease; PR = partial response; 
SD = stable disease. 
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. 
5.3.4 
Confirmation Scans 
 
 
6 
REFERENCES 
1 
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis 2010;30(1):52-60. 
Verification of Response: 
Verification of Progression: 


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APPENDIX 11 
FRANCE-SPECIFIC GENERAL GUIDANCE FOR TRANS- 
ARTERIAL CHEMO-EMBOLIZATION 
1 
PURPOSE 
This guidance provides information regarding the Trans-arterial Chemo-Embolization (TACE) 
procedure and is based on TACE procedure commonalities worldwide. For CA20974W, it is 
required that the same procedure technique, chemotherapy agent(s), and embolizing agent are used 
for each patient enrolled in this study. 
2 
PROCEDURE 
TACE will be performed following a standard procedure in each investigational site. The same 
chemotherapy agent(s) must be used for all TACE procedures on a patient. 
The general recommendation of TACE procedures are as follows: 
1) Confirm tumor enhancement and feeding artery by abdominal angiography. 
2) Insert a catheter into the feeding artery of the HCC, which is technically accessible, as close to 
the lesion as possible. 
3) EITHER 
a) Inject the emulsion of the anticancer agent(s) with lipiodol or another contrast agent. Drugs 
that may be considered include doxorubicin, epirubicin, idarubicin, oxaliplatin, cisplatin 
and mitomycin (see Table 2-1). 
4) Embolize the feeding artery with an embolization agent (eg, gelatin sponge), and complete the 
therapy. 
OR 
a) Inject Drug Eluting Beads (DEB). Only DEBs with single-agent chemotherapy, are 
allowed. The use of DEBs must be in accordance with the registered indication (see Table 
2-2). 
5) The end of TACE procedure is the cessation of arterial blood flow to the tumor. 
 
 
Table 2-1: 
Dose Ranges in Conventional TACE (per session) 
 
Drug 
Dose Range Per Session 
Doxorubicin 
30 - 150 mg 
Idarubicin 
5 - 20 mg 
Epirubicin 
30 - 60 mg 
Mitomycin 
5 - 20 mg 
Cisplatin 
30 - 100 mg 
Oxaliplatin 
50 - 100 mg 


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Table 2-2: 
Dose Ranges in DEB-TACE (per session) 
 
Drug 
Dose Range per Session 
Doxorubicin 
30 - 150 mg