Clinical trial NCT02576509
Conditions: Hepatocellular Carcinoma
Sponsor: Bristol-Myers Squibb
Start date: 2015-12-07; Completion date: 2024-02-07
Enrollment: 743 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if nivolumab or sorafenib is more effective in the treatment of Advanced Hepatocellular Carcinoma.

Detailed description:

Arms: arm 1: Nivolumab specified dose on specified days arm 2: Sorafenib specified dose on specified days
Interventions: intervention 1: Nivolumab intervention 2: Sorafenib
Intervention descriptions: intervention 1: Specified Dose on Specified Days intervention 2: Specified Dose on Specified Days

Protocol documents:
SAP_002.pdf: 
Official Title of Study: 
A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in 
Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and 
nivoluMAb Clinical Trial Evaluation 459) 
 
NCT Number: NCT02576509 
Document Date (Date in which document was last revised): 18 May 2020 


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STATISTICAL ANALYSIS PLAN 
 
A RANDOMIZED, MULTI-CENTER PHASE III STUDY OF NIVOLUMAB VERSUS 
SORAFENIB AS FIRST-LINE TREATMENT IN PATIENTS WITH ADVANCED 
HEPATOCELLULAR CARCINOMA 
(CHECKMATE 459: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 459) 
 
Protocol(S) CA209459 
 
 
VERSION # 4.0 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................ 1 
TABLE OF CONTENTS ................................................................................................................. 2 
.6 
.6 
.7 
.7 
.9 
.9 
.9 
2 
STUDY DESCRIPTION ............................................................................................ 10 
2.1 
Study Design ............................................................................................................... 10 
2.2 
Treatment Assignment ................................................................................................ 11 
2.3 
Blinding and Unblinding ............................................................................................. 12 
2.4 
Protocol Amendments ................................................................................................. 12 
2.5 
Data Monitoring Committee ....................................................................................... 12 
2.6 
Blinded Radiology Review Committee ....................................................................... 13 
3 
OBJECTIVES ............................................................................................................. 13 
3.1 
Primary ........................................................................................................................ 13 
3.2 
Secondary .................................................................................................................... 13 
. ............................................................................................................... 13 
4 
ENDPOINTS .............................................................................................................. 14 
4.1 
General Definitions of Efficacy Endpoints based on Tumor Assessment .................. 14 
4.1.1 
ORR ............................................................................................................................. 14 
4.1.2 
PFS .............................................................................................................................. 14 
4.1.3 
TTP .............................................................................................................................. 15 
4.1.4 
DOR ............................................................................................................................ 16 
4.1.5 
TTR .............................................................................................................................. 16 
4.1.6 
DCR ............................................................................................................................. 16 
4.1.7 
DDC ............................................................................................................................ 17 
4.2 
Primary endpoint OS ................................................................................................... 17 
4.3 
Secondary endpoints ................................................................................................... 17 
4.3.1 
ORR ............................................................................................................................. 17 
4.3.2 
PFS .............................................................................................................................. 17 
4.3.3 
PD-L1 expression ........................................................................................................ 17 
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20 
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5 
SAMPLE SIZE AND POWER ................................................................................... 21 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ....................................................................................................... 22 
6.1 
Study Periods .............................................................................................................. 22 
6.2 
Treatment Regimens ................................................................................................... 22 
6.3 
Populations for Analyses ............................................................................................ 22 
7 
STATISTICAL ANALYSES ...................................................................................... 23 
7.1 
General Methods ......................................................................................................... 23 
7.2 
Study Conduct ............................................................................................................. 24 
7.2.1 
Accrual ........................................................................................................................ 24 
7.2.2 
Relevant Protocol Deviations ..................................................................................... 24 
7.3 
Study Population ......................................................................................................... 25 
7.3.1 
Subject Disposition ...................................................................................................... 25 
7.3.2 
Demographics and Other Baseline Characteristics .................................................... 25 
7.3.2.1 
Demographics ............................................................................................................. 25 
7.3.2.2 
HCC Etiology .............................................................................................................. 26 
7.3.2.3 
HCC Disease Characteristics ..................................................................................... 26 
7.3.3 
Medical History and Pre-treatment Events ................................................................. 26 
7.3.4 
Prior Anti-Cancer Therapies ...................................................................................... 27 
7.3.5 
Baseline Examinations ................................................................................................ 27 
7.3.6 
Discrepancies Between IVRS and CRF Stratification Factors ................................... 27 
7.4 
Extent of Exposure ...................................................................................................... 27 
7.4.1 
Administration of Study Therapy ................................................................................ 27 
7.4.2 
Modification of Study Therapy .................................................................................... 28 
7.4.2.1 
Dose delay for nivolumab ........................................................................................... 28 
7.4.2.2 
Dose delay for sorafenib ............................................................................................. 28 
7.4.2.3 
Dose modifications for nivolumab .............................................................................. 28 
7.4.2.4 
Dose modifications for sorafenib ................................................................................ 29 
7.4.2.5 
Infusion interruptions and rate changes for nivolumab .............................................. 29 
7.4.3 
Concomitant Medications ........................................................................................... 29 
7.5 
Efficacy ....................................................................................................................... 29 
7.5.1 
Primary Efficacy Endpoint OS Analyses .................................................................... 29 
7.5.1.1 
Primary Analysis ......................................................................................................... 29 
7.5.1.2 
Secondary Analyses ..................................................................................................... 29 
7.5.1.3 
Sensitivity Analyses ..................................................................................................... 30 
7.5.1.4 
Consistency of Treatment Effect on OS in Subsets ..................................................... 30 
7.5.1.5 
Subject Follow-up ....................................................................................................... 31 
7.5.1.6 
Subsequent Therapy .................................................................................................... 31 
7.5.2 
Secondary Efficacy Endpoint ORR Analyses .............................................................. 31 
7.5.3 
Secondary Efficacy Endpoint PFS Analyses ............................................................... 32 
7.5.4 
Interim Analyses and Multiple Comparison ................................................................ 34 
7.5.4.1 
Interim Analyses .......................................................................................................... 34 


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7.5.4.2 
Stagewise Hierarchical Testing Procedure for Primary Endpoint OS and 
Secondary Endpoints ORR and PFS .......................................................................... 34 
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7.6 
Safety ......................................................................................................................... 37 
7.6.1 
Deaths ........................................................................................................................ 37 
7.6.2 
Serious Adverse Events .............................................................................................. 37 
7.6.3 
Adverse Events Leading to Discontinuation of Study Therapy .................................. 37 
7.6.4 
Adverse Events Leading to Dose Modification .......................................................... 37 
7.6.5 
Adverse Events ........................................................................................................... 37 
7.6.6 
Select Adverse Events ................................................................................................ 37 
7.6.7 
Immune modulating medication ................................................................................. 37 
7.6.8 
Multiple Events .......................................................................................................... 37 
7.6.9 
Other Events of Special Interest ................................................................................. 38 
7.6.10 
Immune-Mediated Adverse Events ............................................................................. 38 
7.6.11 
Laboratory Parameters .............................................................................................. 38 
7.6.12 
Vital Signs .................................................................................................................. 38 
7.6.13 
Immunogenicity Analysis ........................................................................................... 38 
7.6.14 
Pregnancy .................................................................................................................. 38 
7.6.15 
Adverse Events By Subgroup ..................................................................................... 38 
7.7 
Pharmacokinetics ....................................................................................................... 38 
. ............................................................................................................... 38 
7.8.1 
PD-L1 Expression ...................................................................................................... 38 
7.8.1.1 
Analyses of PD-L1 ..................................................................................................... 38 
41 
41 
41 
7.10 
Post Hoc Analyses ..................................................................................................... 42 
7.10.1 
Analyses Based on VI/EHS Status per BICR Assessment .......................................... 42 
7.10.1.1 
Background of Assessment for the VI/EHS Randomization Stratification 
Factor ......................................................................................................................... 42 
7.10.1.2 
Determination of VI/EHS Status per BICR Assessment ............................................. 43 
7.10.1.3 
Baseline characteristics ............................................................................................. 43 
7.10.1.4 
Stratified analyses ...................................................................................................... 43 
7.10.2 
Analyses for Investigating Non-Proportionality in OS Curves .................................. 45 
7.10.2.1 
Piecewise hazard ratio ............................................................................................... 45 


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7.10.2.2 
Max-Combo test .......................................................................................................... 45 
45 
8 
CONVENTIONS ........................................................................................................ 46 
8.1 
Date Imputation .......................................................................................................... 46 
8.2 
Duration Calculation and Conversion ......................................................................... 46 
8.3 
Decimal Places ............................................................................................................ 47 
8.4 
Analysis Software ....................................................................................................... 47 
9 
CONTENT OF REPORTS ......................................................................................... 47 
10 
DOCUMENT HISTORY ............................................................................................ 48 
11 
REFERENCES ............................................................................................................ 50 


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2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is an open-label, two-arm, randomized, Phase 3 study in adult (≥ 18 years) male and female 
subjects with advanced HCC. Subjects must not be amenable for management with surgery or 
loco-regional therapy or have progressed after surgery or loco-regional therapy. Subjects must not 
have received prior systemic therapy for advanced HCC in keeping with the first-line setting of 
this study. 
After screening for eligibility and signing of informed consent, qualified subjects will be 
randomized in a 1:1 ratio to receive nivolumab or sorafenib. It is expected that approximately 908 
subjects will be screened for the study with approximately 726 subjects will be randomized, e.g., 
approximately 363 subjects will be randomized to each study arm. Randomization will be stratified 
by etiology (HCV vs. non-HCV [ie, HBV and HCC with no history of hepatitis virus infection]), 
vascular invasion and/or extrahepatic spread (present or absent), geography (Asia vs Non-Asia). 
Subjects will receive open-label treatment with one of the following: 
• Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity 
• Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity 
 
The study design schematic is presented in Figure 2.1-1. 
Figure 2.1-1: 
Study Design Schematic 
 
On treatment visits will occur at Day 1 and every 2 weeks thereafter. Tumor imaging assessments 
will occur 8 weeks from the date of randomization (+/-1 wk), then every 8 weeks (+/- 1 wk) 
thereafter up to 48 weeks, then it will be every 12 weeks (+/- 1 week) until disease progression or 
treatment is discontinued (whichever occurs later). Subjects will be treated until unacceptable 


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toxicity or disease progression. Following discontinuation of therapy, safety will be assessed 
through post-treatment Follow Up visit 2 (~ 100 days from last dose). Survival status will be 
assessed every 3 months after follow up visits are completed, and may be completed via telephone 
or in person visits. 
On both arms, treatment beyond initial investigator-assessed RECIST 1.1 defined progression is 
permitted if the subject has investigator assessed clinical benefit and is tolerating study drug, as 
specified in the protocol31. 
This study’s primary endpoint is OS in all randomized subjects. Its secondary endpoints include 
objective response rate (ORR) and progression-free survival (PFS) based on tumor response 
assessed by a blinded and independent central review (BICR) according to RECIST 1.1. 
2.2 
Treatment Assignment 
CA209459 is a randomized, open-label study. After the subject’s initial eligibility is established 
and informed consent has been obtained, the subject must be enrolled into the study by calling an 
interactive voice response system (IVRS) to obtain the subject number. Every subject that signs 
the informed consent form must be assigned a subject number in IVRS. Specific instructions for 
using IVRS will be provided to the investigational site in a separate document. 
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment: 
• Date that informed consent was obtained 
• Date of birth 
• Gender at birth 
• Viral status at time of enrollment, if known 
 
Once enrolled in IVRS, enrolled subjects that have met all eligibility criteria will be ready to be 
randomized through IVRS. The following information is required for site entry in the IVRS prior 
to subject randomization: 
• Subject number 
• Date of birth 
• Vascular invasion and/or extrahepatic spread (present or absent) 
 
Additional information will be automatically transferred to the IVRS by the Central Lab and must 
be available prior to subject randomization: 
• Etiology (HCV vs non-HCV) 
• Confirmation of tumor tissue sample receipt and acceptability at Central Laboratory 


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Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to nivolumab or sorafenib, 
stratified by the following factors: 
• Etiology (HCV vs non-HCV) 
• Vascular invasion and/or extrahepatic spread (present or absent) 
• Geography (Asia vs Non-Asia) 
 
The randomization procedures will be carried out via permuted blocks within each stratum. The 
exact procedures for using the IVRS will be detailed in the IVRS manual. 
2.3 
Blinding and Unblinding 
This is an open-label study. 
2.4 
Protocol Amendments 
This statistical analysis plan (SAP) incorporates the amendments in Table 2.4-1. 
Table 2.4-1: 
Protocol Amendments 
 
Amendment 
Date of Issue 
Summary of Major Changes 
 
• 
Changed ORR from a co-primary objective to a secondary 
Amendment 16 
15-Aug-2017 
objective of the study. 
• 
OS is the sole primary endpoint of the study. 
 
 
Revised Protocol 02 
24-Aug-2016 
Incorporates Amendment 11 
 
• 
Updated Study Director/Medical Monitor information 
• 
Primary endpoint and objective changed from time to 
progression (TTP) to objective response rate (ORR) 
Amendment 11 
24-Aug-2016 
− 
Added requirement for confirmatory scan to be performed 
for CR/PR assessment of best overall response (BOR) 
• 
Management algorithms updated per revised nivolumab IB 
 
 
Revised Protocol 01 
01-Oct-2015 
Incorporates Amendment 02 
 
Addition of collection of peripheral blood mononuclear cells 
(PBMCs) and myeloid derived suppressor cells (MDSCs) collected 
Amendment 02 
01-Oct-2015 
from subjects at baseline from selected sites, reduction of frequency 
of HCV RNA testing for HCV infected subjects, clarification of 
locoregional therapy inclusion criteria, as well as other 
miscellaneous clarifications and corrections. 
 
 
2.5 
Data Monitoring Committee 
A DMC will be established to provide oversight and safety and efficacy considerations in protocol 
CA209459. The DMC will provide advice to the sponsor regarding actions the committee deems 
necessary for the continuing protection of subjects enrolled in the study. The DMC will be charged 
with assessing such actions in light of an acceptable benefit/risk profile for nivolumab. The DMC 
will act in an advisory capacity to BMS and will monitor subject safety and evaluate the available 
efficacy data for the study. 


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The BMS clinical study leadership will have responsibility for overall conduct of the study 
including managing the communication of study data. The group will be responsible for promptly 
reviewing the DMC recommendations, for providing guidance regarding the continuation or 
termination of the study, and for determining whether amendments to the protocol or changes to 
the study conduct are required. Adjudicated events will be submitted to the DMC and Health 
Authorities when required for review on a specified timeframe in accordance with the adjudication 
documentation. 
Details of the DMC responsibilities and procedures will be specified in the DMC charter30. Details 
of the statistical analysis plan supporting DMC review will be specified in a DMC SAP. 
2.6 
Blinded Radiology Review Committee 
In addition to local tumor assessments, images from this study will undergo a blinded, independent 
central review (BICR) to assess response based on the RECIST 1.1 and mRECIST assessment 
criteria. The centrally reviewed response data will be used in the analyses of ORR, PFS, duration 
of response (DOR), and time to response (TTR). 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 charter32. 
3 
OBJECTIVES 
3.1 
Primary 
To compare OS of nivolumab to sorafenib in subjects with advanced HCC who have not received 
prior systemic therapy. 
3.2 
Secondary 
• To compare ORR of nivolumab to sorafenib. ORR will be determined from assessment by 
BICR based on RECIST 1.1 
• To compare PFS of nivolumab and sorafenib. PFS will be determined from assessments by 
BICR based on RECIST 1.1 
• To evaluate the relationship between tumor PD-L1 expression and efficacy 
 


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4 
ENDPOINTS 
4.1 
General Definitions of Efficacy Endpoints based on Tumor Assessment 
Tumor assessment based efficacy endpoints such as ORR and PFS will be determined per 
RECIST 1.1 or mRECIST for HCC by BICR or investigators in different populations of interest. 
The following criteria will be used and specified in definitions of related endpoints in Section 4.2, 
4.3, and 
: BICR per RECIST 1.1, investigator per RECIST 1.1, and BICR per mRECIST for 
HCC. 
4.1.1 
ORR 
ORR is defined as the proportion of subjects whose best overall response (BOR) is either a 
complete response (CR) or partial response (PR) among all randomized subjects in a population 
of interest. BOR is defined as the best response designation recorded between the date of 
randomization and the date of first objectively documented progression or the date of subsequent 
anti-cancer therapy, whichever occurs first. For subjects without documented progression or 
subsequent anti-cancer therapy, all available response designations will contribute to the BOR 
determination. For a BOR of CR or PR, the initial response assessment must be confirmed by a 
consecutive assessment no less than 4 weeks (28 days) later. In the case of stable disease (SD), 
measurements must have met the SD criteria at least once after randomization at a minimum of 7 
weeks (49 days). Responder is defined as a subject whose BOR is either a CR or PR. 
Tumor imaging assessments will occur 8 weeks from the date of randomization (+/-1 wk), then 
every 8 weeks (+/- 1 wk) thereafter up to 48 weeks, then it will be every 12 weeks (+/- 1 week) 
until disease progression or treatment is discontinued (whichever occurs later). 
4.1.2 
PFS 
PFS is defined as the time from the date of randomization to the date of the first objectively 
documented tumor progression or death due to any cause in all randomized subjects. Subjects who 
die without a reported prior progression and without initiation of subsequent anti-cancer therapy 
will be considered to have progressed on the date of their death. Subjects who did not progress or 
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therapy (if there is any). Subjects who did not have baseline tumor assessment will be censored on 
the date they were randomized. Subjects who did not have any on study tumor assessments and 
did not die will be censored on the date they were randomized. Censoring rules for the primary 
analysis of PFS are summarized in Table 4.1.2-1. Further explanation for various censoring 
scenarios for the primary definition of PFS are presented in Figure 4.1.2-1. 
Table 4.1.2-1: 
Censoring Scheme used in Primary Analysis of PFS 
 
Situation 
Date of Progression or Censoring 
Outcome 
 
No baseline tumor assessment 
Date of randomization 
Censored 
No on study tumor assessments and no death 
Date of randomization 
Censored 
Documented progression 
Date of the first documented tumor 
progression 
Progressed 
No progression and no death 
Date of last tumor assessment 
Censored 
Subsequent anti-cancer therapies started without a prior 
reported progression 
Date of last tumor assessment prior 
to initiation of the subsequent 
therapy 
Censored 
Death without progression and without initiation of 
subsequent anti-cancer therapy 
 
Date of death 
Progressed 
 
 
Figure 4.1.2-1: 
Graphical display of PFS Primary Definition 
 
4.1.3 
TTP 
Time to Progression (TTP) is defined as the time from the date of randomization to the date of the 
first objectively documented tumor progression in all randomized subjects. The censoring scheme 
for the primary definition of TTP follows the graphical display in Figure 4.1.3-1. 


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Figure 4.1.3-1: 
Graphical display of TTP Primary Definition 
 
 
 
4.1.4 
DOR 
DOR is defined as the time between the date of first documented response (CR or PR as defined 
in Section 4.1.1) to the date of first documented tumor progression or death due to any cause, 
whichever occurs first. Subjects who neither progress nor die will be censored on the date of their 
last evaluable tumor assessment. Subjects who started any subsequent anti-cancer therapy without 
a prior reported progression will be censored at the last evaluable tumor assessment prior to or on 
the date of initiation of the subsequent anti-cancer therapy. Essentially, the DOR will be censored 
according to the same censoring scheme as the one for the primary definition of PFS (Section 4.1.2, 
with baseline and on-study scans available). DOR will be evaluated for responders (i.e. subjects 
with confirmed CR or PR) only. 
4.1.5 
TTR 
TTR is defined as the time from randomization to the date of the first confirmed CR or PR. TTR 
is derived for responders only. 
4.1.6 
DCR 
DCR is defined as the proportion of subjects whose BOR is CR or PR or SD or NON-CR/NON-PD 
among all randomized subjects of a population of interest based on BICR-assessed BOR. Based 
on investigator-assessed BOR, DCR is defined as the proportion of subjects whose BOR is CR 
or PR or SD among all randomized subjects of a population of interest. 


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4.1.7 
DDC 
DDC is defined as the time from the date of randomization to the date of the first documented 
tumor progression or death due to any cause in subjects whose BOR is CR or PR or SD or NON- 
CR/NON-PD based on BICR-assessed BOR. Disease of these subjects is considered to be 
controlled till progression or death. DDC follows the same censoring scheme as in for the primary 
definition of PFS (Section 4.1.2). Therefore, DDC is essentially PFS of subjects whose BOR is 
CR or PR or SD or NON-CR/NON-PD based on BICR-assessed BOR. 
Based on investigator-assessed BOR, DDC is defined as the time from the date of randomization 
to the date of the first documented tumor progression or death due to any cause in subjects whose 
BOR is CR or PR or SD; thus, DDC is essentially PFS of subjects whose BOR is CR or PR or SD. 
4.2 
Primary endpoint OS 
OS is the primary endpoint for this study. It is defined as the time from the date of randomization 
to the date of death due to any cause in all randomized subjects. Subjects who are alive will be 
censored at the last known alive dates. 
On treatment visits will occur at Day 1 and every 2 weeks thereafter. Subjects will be treated until 
unacceptable toxicity or disease progression. Following discontinuation of therapy, safety will be 
assessed through post-treatment Follow Up visit 2 (~ 100 days from last dose). Survival status will 
be assessed every 3 months after follow up visits are completed, and may be completed via 
telephone or in person visits. Note after discontinuation of therapy, tumor imaging assessment will 
continue until disease progression (see schedule of tumor imaging assessment in Section 4.1.1). 
4.3 
Secondary endpoints 
4.3.1 
ORR 
The secondary endpoint of ORR is the ORR (see Section 4.1.1) in all randomized subjects with 
BOR determined based on BICR-assessed tumor response according to RECIST 1.1. 
4.3.2 
PFS 
The secondary endpoint of PFS is the PFS (see Section 4.1.2) in all randomized subjects with 
progression is based on the first documented tumor progression assessed by BICR according to 
RECIST 1.1 or death. 
4.3.3 
PD-L1 expression 
Definition of PD-L1 expression is described as follows. 
PD-L1 expression missing: Subjects without an available tumor biopsy specimen for PD-L1 
evaluation will be considered as PD-L1 expression missing. 
For subjects with an available tumor biopsy specimen(s), the following will be considered: 
PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 
100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred 


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as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further 
classifies as: 
Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of 
the tumor biopsy specimen and not because of improper sample preparation or handling 
Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 
expression is neither quantifiable nor indeterminate) 
Baseline PD-L1 expression: If more than one tumor biopsy specimen is available, baseline PD-L1 
expression will be determined from the most recently collected specimen (prior to randomization) 
with a quantifiable result. If more than one baseline PD-L1 expression measurement is available 
at the same day for a subject, the highest baseline PD-L1 expression measurement will be used. If 
all specimens for a given subject are either indeterminate or not evaluable, then the PD-L1 
expression will be considered indeterminate as long as at least one specimen is indeterminate. 
Otherwise, PD-L1 expression will be considered not evaluable. 
PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression: 
• PD-L1 > X %: ≥ X % PD-L1 expression 
• PD-L1 < X %: < X % PD-L1 expression 
 
Where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be 
explored. 


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5 
SAMPLE SIZE AND POWER 
The sample size determination of this study is based on OS comparison between subjects 
randomized to receive nivolumab and sorafenib. With a total of 726 subjects randomized in a 1:1 
ratio to receive nivolumab or sorafenib, approximately 91.5% power will be achieved with an 
overall type I error 0.05. The sample size determination is based on simulation using R v3.2 for 
OS. Below are details of the sample size determination. 
General assumptions: 
• There are assumed 39% HCV-infected subjects among all randomized subjects. 
• In the sorafenib arm, median OS is 10 months for non-HCV infected and 14 months for HCV 
infected. 
• Exponential distribution is assumed for OS in each randomized arm. 
 
Estimated cumulated enrollment of randomized subjects is summarized in Table 5-1. 
 
Table 5-1: 
Estimated Cumulative Number of Randomized Patients 
 
 
 
 
HCV 
 
 
 
Sample size determination for OS 
Based on simulations under the assumptions stated above, approximately 726 subjects will be 
randomized and followed until at least 520 OS events are observed in order to provide 91.5% 
power for a hazard ratio of 0.74 with a two-sided type I error of 0.05. This accounts for a group 
sequential testing procedure with one interim analysis and one final analysis. The HR of 
0.74 corresponds to a 35% increase in the median OS for both non-HCV infected subjects and 
HCV infected subjects. 
The interim analysis will be conducted when 80% OS events are observed. The alpha allocation 
for the interim and final analyses is based on the Lan-DeMets alpha spending function approach 
using an O’Brien-Fleming stopping boundary controlling for a two-sided overall type 1 error of 
5%. The stopping boundary will depend on the actual number of OS events observed at the time 
of the interim analysis and the final analysis. However, if the interim analysis is performed exactly 
when 80% OS events are observed, then 0.024 alpha will be used for the interim analysis and 
0.043 alpha will be used for the final analysis. 
It is projected that an observed hazard ratio of 0.80 or less would result in a statistically significant 
improvement of nivolumab at the interim analysis of OS; and an observed hazard ratio of 0.84 or 
Month 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
HCV 
6 
17 
30 
45 
61 
81 
105 
131 
159 
188 
218 
250 
282 
Non- 
9 
25 
43 
67 
98 
132 
170 
210 
252 
297 
345 
394 
444 
All 
15 
42 
73 
112 
159 
213 
275 
341 
411 
485 
563 
644 
726 


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less would result in a statistically significant improvement of nivolumab at the final analysis of 
OS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES 
6.1 
Study Periods 
Refer to Core Safety SAP33 for definitions of baseline period and post baseline period for AEs and 
evaluations of laboratory tests, pulse oximetry and vital signs. 
6.2 
Treatment Regimens 
The treatment group as randomized will be retrieved from the IVRS system: 
• Nivolumab 240 mg 30 min IV 
• Sorafenib 400 mg PO 
 
The treatment group as treated will be the same as the treatment group randomized by IVRS. 
However, if a subject received the incorrect drug for the entire period of treatment, the subject’s 
treatment group will be defined as the incorrect drug the subject actually received. 
6.3 
Populations for Analyses 
All analyses will be performed using the treatment group as randomized (intent-to-treat) with the 
exception of extent of exposure (dosing) and safety, for which the treatment group as treated will 
be used. If a subject is randomized to nivolumab and receives at least 1 dose of nivolumab during 
the study, then the subject’s treatment group is considered nivolumab. Similarly, if a subject is 
randomized to sorafenib and receives at least 1 dose of sorafenib, then the subject’s treatment 
group is considered sorafenib. 


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When appropriate, the following definitions of different types of subjects will be applied to 
different populations of interest defined later in this section: 
• Enrolled Subjects: Subjects who signed an informed consent form and were registered into 
the IVRS. 
• Randomized Subjects: Enrolled subjects who were randomized to any treatment group in the 
study. This is the type of subjects for analyses of study conduct, study population and efficacy. 
• Treated Subjects: Randomized subjects who received at least one dose of study drug. This is 
the type of subjects for analyses of exposure and safety. 
• PK Subjects: Randomized subjects who are dosed with nivolumab and have serum time- 
concentration data available. 
• Response Evaluable Subjects: Randomized subjects who have target lesion(s) assessed at 
baseline and at least one post-baseline timepoint. 
• PD-L1 Quantifiable Subjects: Randomized subjects with quantifiable baseline PD-L1 
expression, which exclude randomized subjects with missing or indeterminate or not evaluable 
baseline PD-L1 expression (see Section 4.3.3). 
 
7 
STATISTICAL ANALYSES 
7.1 
General Methods 
Unless otherwise noted, the titles in the following subsections describe tabulations of discrete 
variables, by the frequency and proportion of subjects falling into each category, grouped by 
treatment (with total). Percentages given in these tables will be rounded and, therefore, may not 
always sum to 100%. Continuous variables will be summarized by treatment group (with total) 
using the mean, standard deviation, median, minimum and maximum values. If a missing category 
is not being presented in the data display, only those subjects with non-missing values for the 
parameter being assessed are included in the percentage calculation. 
Time to event distributions (i.e. PFS, OS, DOR and DDC) will be estimated using the KM method. 
When appropriate, the median along with the corresponding log-log transformed 95% CI will be 
estimated. Rates at fixed timepoints (e.g., OS at 12 months) will be derived from the KM estimate 
along with their corresponding log-log transformed 95% confidence intervals. 
Unless otherwise specified, the stratification factors for stratified analysis will be the following 
ones as entered into the IVRS: 
• Etiology (HCV vs non-HCV [ie, HBV and HCC with no history of hepatitis virus infection]) 
• Vascular invasion and/or extrahepatic spread (present vs absent) 
• Geography (Asia vs Non-Asia). 
 
The stratified log-rank test will be performed to test the comparison of time to event distributions 
(OS and PFS) between two treatment arms. 


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
The stratified hazard ratio between two treatment arms along with CI will be obtained by fitting a 
stratified Cox model with the treatment group variable as unique covariate. 
Confidence intervals for binomial proportions will be derived using the Clopper-Pearson 
method34. 
The difference in rates (e.g., ORR) between the two treatment arms along with their two-sided 
95% CI will be estimated using the following Cochran-Mantel-Haenszel (CMH) method of 
weighting35, adjusting for the stratification factors: 
^ 
 
w 2  pix (1− pix ) + piy (1− piy )   
^ ∑ wi θi 
 ∑ i   
n −1 
n −1 
  
θ =  i 
 ~ N θ , 
 i 
 
ix 
iy 
  
∑ wi 
 
 

2 
 
w 
i 
 
 ∑ i  
 
 
 i 
 
 
Where 0೦ = p − p 
is the rate difference of the ith stratum, w =  nixniy  , and n and n are 
i 
i 
i  
i 
n  + n 
ix 
iy 
ix 
iy 
the number of subjects randomized to treatments x and y, respectively, in the ith stratum. 
Associated odds-ratio will be derived. 
P-values other than those provided for the primary endpoint OS and the hierarchical testing of the 
secondary endpoints ORR and PFS are for descriptive purpose only and not adjusted for 
multiplicity. 
7.2 
Study Conduct 
7.2.1 
Accrual 
The accrual pattern will be summarized per country, investigational site and per month for all 
enrolled subjects. Randomization date, first dosing date, country, investigational site will be 
presented in a by-subject listing of accrual. 
7.2.2 
Relevant Protocol Deviations 
The relevant protocol deviations will be summarized for all randomized subjects, by treatment 
group and overall. The following programmable deviations from inclusion and exclusion criteria 
will be considered as relevant protocol deviations. Non-programmable relevant eligibility and on- 
treatment protocol deviations, as well as significant (both programmable and non-programmable) 
eligibility and on-treatment protocol deviations will be reported through ClinSIGHT listings. 
At Entrance: 
• Subjects with ECOG PS > 1. 
• Subjects with Child-Pugh B or higher. 
• Subjects without evaluable disease at baseline. 
• Subjects who received prior systemic therapy. 
• Subjects with serum albumin < 2.8 g/dL. 
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• Subjects with total bilirubin > 3 mg/dL. 
• Subjects with AST > 5 times the institutional upper limits of normal. 
• Subjects with ALT > 5 times the institutional upper limits of normal. 
• Subjects with co-infection of HBV and HCV. 
• Subjects with co-infection of HBV and HDV. 
 
On-study: 
• Subjects receiving concurrent anti-cancer therapy (defined as chemotherapy, systemic therapy, 
radiation therapy, non-systemic therapy for HCC (local only), and surgery for HCC). 
• Subjects treated differently as randomized (subjects who received the wrong treatment, 
excluding the never treated). 
 
A by-subject listing will also be produced. 
7.3 
Study Population 
Unless otherwise specified, efficacy analyses will be performed on randomized subjects with 
treatment group as randomized; safety analyses will be performed on treated subjects with 
treatment group as treated. 
7.3.1 
Subject Disposition 
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason of not being randomized. 
Number of subjects randomized but not treated along with the reason will be tabulated by treatment 
group as randomized. This analysis will be performed only on randomized subjects only. 
Number of subjects who discontinued treatment along with corresponding reason will be tabulated 
by treatment group as treated. 
A subject listing for all enrolled subjects will be provided showing the subject’s consent date, 
reason for not being randomized, and reason for not being treated. 
A subject listing for all treated subjects will be provided showing the subject’s randomization date, 
first and last dosing date, off treatment date and reason for going off-treatment. 
7.3.2 
Demographics and Other Baseline Characteristics 
The following baseline characteristics will be summarized by treatment group as randomized. All 
baseline presentations identify subjects with missing measurements. Listings will also be provided. 
7.3.2.1 
Demographics 
• Age (descriptive statistics) 
• Age categories (<65, ≥65 and <75, ≥75) 
• Gender (male, female) 


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• Race 
(White, 
Black/African 
American, 
American 
Indian/Alaska 
Native, 
Native 
Hawaiian/Other Pacific Islander, Asian Indian, Chinese, Japanese, Asian Other, Other) 
• Weight (descriptive statistics) 
• ECOG Performance Status (0, 1, > 1) 
• Region (US/Canada/Europe, Asia, Asia excluding Japan, Japan) 
 
7.3.2.2 
HCC Etiology 
HCC etiology is a description of disease subtype at baseline and includes HBV-infected, HCV- 
infected, uninfected, and HBV-HCV coinfection. HCC etiology is derived based on risk factors 
as collected on CRF, and described below: 
• Etiology is HBV-infected if HBV is a risk factor, and HCV is not included as a risk factor 
• Etiology is HCV-infected if HCV is a risk factor, and HBV is not included as a risk factor 
• Etiology is HBV-HCV coinfection if both HBV and HCV are included as risk factors 
• Etiology is uninfected if neither HBV nor HCV is considered as a risk factor 
 
Upon review of data, there are a few subjects with both HBV and HCV boxes checked in the risk 
factor CRF page. Clinical review suggested that these subjects might be similar to HCV subjects. 
Therefore, these subjects are grouped together with HCV subjects for all outputs of the clinical 
study report. 
7.3.2.3 
HCC Disease Characteristics 
The following disease characteristics will be summarized. All available data will be listed. 
• HCC Risk Factors 
• Vascular invasion (Yes/No) 
• Extrahepatic spread (Yes/No) 
• Disease etiology (Uninfected/HCV-infected/HBV-infected/HBV-HCV coinfection) 
• Child-Pugh Score (Class and Score) 
• Liver Nodules (Yes/No) 
• BCLC (Barcelona clinic liver cancer) stage 
• AFP (descriptive statistics) 
• AFP Category (≥ 200, < 200, ≥400, < 400) 
• Time from initial diagnosis of HCC to randomization 
 
7.3.3 
Medical History and Pre-treatment Events 
General medical history will be listed by subject. HCC or prior treatment-related pre-treatment 
events will be summarized by worst CTC grade, system organ class and preferred term. 


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7.3.4 
Prior Anti-Cancer Therapies 
Prior anti-cancer therapies include the following therapies and will be summarized. 
• Prior systemic cancer therapy (Yes/No) 
• Prior surgery therapy (Yes/No) 
• Prior radiotherapy (Yes/No) 
• Prior non-systemic treatment related to HCC local only (Yes/No) 
 
7.3.5 
Baseline Examinations 
Subjects with abnormal baseline physical examination will be tabulated by examination criteria 
and by treatment group. 
7.3.6 
Discrepancies Between IVRS and CRF Stratification Factors 
A summary table (cross-tabulation) by treatment group as randomized for stratification factor will 
be provided to show any discrepancies between what was reported through IVRS and CRF data. 
7.4 
Extent of Exposure 
Analyses in this section will be performed in all treated subjects by treatment group as treated (as 
defined in Section 6.3). Listings will include all available exposure data. 
Table 7.4-1 summarizes the key parameters used to calculate dosing data. 
Table 7.4-1: 
Administration of study therapy: definition of parameters 
 
 
 
Dosing schedule 
per protocol 
Nivolumab 
Sorafenib 
 
240mg every 2 weeks 
400mg BID 
 
 
Dose 
 
 
Cumulative 
Dose 
 
Relative dose 
intensity (%) 
Dose (mg) is defined as Total Dose 
administered. Dose administered in mg at 
each dosing date are collected on the 
CRF. 
Cum dose (mg) is sum of the doses (mg) 
administered to a subject during the 
treatment period. 
Cum dose (mg) / [(Last dose date - Start 
dose date + 14) x 240 / 14] x 100 
 
Dose (mg) is defined as Total Dose 
administered. Dose administered in mg at each 
dosing date are collected on the CRF. 
 
Cum dose (mg) is sum of the doses (mg) 
administered to a subject during the treatment 
period. 
Cum dose (mg) / [(Last dose date - Start dose 
date + 1) x 800] x 100 
Duration of 
treatment 
 
Last dose date - Start dose date +1 
Last dose date - Start dose date +1 
 
 
 
7.4.1 
Administration of Study Therapy 
The following parameters will be summarized by treatment group (descriptive statistics): 
• Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 
- < 110%; ≥ 110%. 


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• Number of doses received 
• Cumulative dose 
• Duration of treatment: duration of treatment will be presented using a KM curve whereby the 
last dose date will be the event date for subjects who discontinued study therapy and last dose 
date will be the censoring date for subjects who are still on study therapy. Median duration of 
treatment and associated 95% CI will be provided. 
• A by-subject listing of dosing of study medication (record of study medication and dose 
change) and a listing of batch number will be also provided. Infusion details will also be 
provided for nivolumab. 
• Time from randomization to first dose of nivolumab or sorafenib (0 to 3 days, 4-5 days, 
6-7 days, 8-14 days, 15-21 days, 22-28 days, > 28 days). 
 
7.4.2 
Modification of Study Therapy 
7.4.2.1 
Dose delay for nivolumab 
A dose given more than 3 days after the intended dose date will be considered a delay. Treatment 
may be delayed for up to a maximum of 6 weeks (42 days) from the last dose. 
Length of delay is defined as duration of interval from prior dose in days minus 14 days. Dose 
delays will be divided into following categories: 4 - 7 days, 8 - 14 days, 15 - 42 days, 43 - 84 days, 
and ≥ 85 days. Dose delay events and reason for dose delay will be retrieved from CRF dosing 
pages. 
The following parameters will be summarized for nivolumab treatment group: 
• Number of subjects with at least one dose delayed, number of dose delayed per subject, length 
of delay, and reason for dose delay 
 
7.4.2.2 
Dose delay for sorafenib 
Dose delay will occur if the subject did not receive any dose during at least one day for a different 
reason than “Dosing Error”, provided that treatment was resumed afterwards. 
Length of delay is defined as duration of interval from prior dose in days. Dose delays will be 
divided into following categories: <= 1 day, 2 - 3 days, 4 - 7 days, 8 - 14 days, 15 - 42 days, 43 - 
84 days, and ≥ 85 days. Dose delay events and reason for dose delay will be retrieved from CRF 
dosing pages. 
The following parameters will be summarized for sorafenib treatment group: 
• Number of subjects with at least one dose delayed, number of dose delayed per subject, length 
of delay, and reason for dose delay 
 
7.4.2.3 
Dose modifications for nivolumab 
No dose modifications for nivolumab are allowed. 


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7.4.2.4 
Dose modifications for sorafenib 
When dose reduction is necessary during the treatment of HCC, the sorafenib dose should initially 
be reduced to two tablets of 200 mg sorafenib once daily. For further dose reductions, refer to the 
sorafenib SmPC or locally approved product label for additional details. 
The following parameters will be summarized for sorafenib treatment group: 
• Number of subjects receiving sorafenib with at least one dose reduction and reasons for dose 
reduction. 
 
7.4.2.5 
Infusion interruptions and rate changes for nivolumab 
The following parameters will be summarized for nivolumab: 
• Number of subjects with at least one dose infusion interruption, number of infusion 
interruptions per subject, and the reason for interruption. 
• Number of subjects with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per subject, and the reason for reduction. 
 
7.4.3 
Concomitant Medications 
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary. 
The following summary tables will be provided: 
• Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term). 
 
A by-subject listing will accompany the table. 
7.5 
Efficacy 
Unless otherwise specified, all analyses are based on treatment group as randomized. 
7.5.1 
Primary Efficacy Endpoint OS Analyses 
7.5.1.1 
Primary Analysis 
The distribution of OS will be compared in two randomized arms via a two-sided α stratified log- 
rank test where α will be determined as per Section 7.5.4.2. 
7.5.1.2 
Secondary Analyses 
A stratified Cox proportional hazards regression model will be used to estimate hazard ratio (see 
Section 7.1) between treatment groups along with the 100(1-α)% CI where α will be determined 
as per Section 7.5.4.2. 
For descriptive purpose, the 95% CI for the estimated hazard ratio in Section 7.5.1.1 will be 
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The OS curves for each treatment group will be estimated using the KM product-limit method. 
Median OS and the corresponding two-sided 95% confidence intervals using the log-log 
transformation will be computed. 
Survival rates at 12, 18, 24, 36, 48 months and 5 years will be estimated using KM estimates on 
the OS curve for each randomized arm. Minimum follow-up (see its definition in Section 7.5.1.5) 
must be longer than a time period to generate a rate. Associated two-sided 95% CIs will be 
calculated. 
The status of subjects who are censored in the OS KM analysis will be tabulated for each treatment 
group using following categories: 
• On-study: (on treatment and not progressed, on-treatment progressed, in follow-up) 
• Off-study: (lost to follow-up, withdraw consent, other) 
 
7.5.1.3 
Sensitivity Analyses 
OS will be compared between treatment groups using a two-sided α (the same as in the primary 
analysis) unstratified log-rank test. 
OS will also be compared between treatment groups using the strata as determined at baseline 
(CRF source) if the stratification variables at IVRS and at baseline disagree for at least 10% of the 
randomized subjects. 
7.5.1.4 
Consistency of Treatment Effect on OS in Subsets 
To assess consistency of treatment effects in different subsets, a “forest” plot of the OS hazard 
ratio and 95% CI will be produced for the following variables, but not limited to: 
− Geography (Asia vs Non-Asia) 
− Region (US/Canada/Europe, Asia, Asia excluding Japan, Japan) 
− Age categorization I (< 65, ≥ 65) 
− Age categorization II (< 65, ≥ 65 - < 75, ≥ 75) 
− Age categorization III (< 65, ≥ 65 - < 75, ≥ 75 - < 85, ≥ 85) 
− Age categorization IV (< 30, ≥ 30 - < 45, ≥ 45 - < 60, ≥ 60) 
− Gender (Male vs. Female) 
− Race (White, Black/African American, American Indian/Alaska Native, Native 
Hawaiian/Other Pacific Islander, Asian Indian, Chinese, Japanese, Asian Other, Other) 
− ECOG (0, 1, > 1) 
− Child-Pugh Score (5, 6, (7, 8, 9 or above)) 
− Child-Pugh Class (A, B, C) 
− Etiology (HCV-infected, HBV-infected, uninfected, HBV-HCV coinfection) from CRF 
− Vascular invasion and/or extrahepatic spread (present or absent) from CRF 
− AFP categorization I at baseline (AFP > 200 ng/ml, and AFP ≥ 200 ng/ml) 


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− AFP categorization II at baseline (AFP < 400 ng/ml and AFP ≥ 400 ng/ml) 
− PD-L1 status at baseline (see Section 4.3.3) 
− BCLC category at baseline 
 
If a subgroup category has less than 10 subjects in a treatment group, then HR will not be reported 
for that subgroup. 
7.5.1.5 
Subject Follow-up 
The minimum follow-up will be reported. The minimum follow-up is defined as the time interval 
between the last patient’s randomization date and the clinical cutoff date. 
The extent of follow-up defined as the time between randomization date and last known date alive 
(for subjects who are alive) or death date (for subjects who died) will be summarized descriptively 
(median, min, max) for all randomized subjects. 
The currentness of follow-up for survival, defined as the time between last OS contact (ie, last 
known date alive or death date) and data cutoff date (defined by last patient last visit date), will be 
summarized by treatment group. Subjects who died before data cutoff date or subjects whose last 
known date alive is on or after data cut-off date will have currentness of follow-up set to zero. The 
currentness of follow-up will be categorized into the following categories: 0 day, 1 day-3 months, 
3-6 months, 6-9 months, 9-12 months and ≥ 12 months. 
7.5.1.6 
Subsequent Therapy 
Subsequent therapy will be summarized by treatment group and listed. The following information 
pertaining to subsequent therapies will be summarized: 
− Systemic anti-cancer therapy by drug name 
− Surgery 
− Radiotherapy 
− Non-systemic treatment for HCC (local only) 
 
A by-subject listing of follow-up therapy will be produced for subjects who had any subsequent 
therapy. 
7.5.2 
Secondary Efficacy Endpoint ORR Analyses 
Hierarchical testing of ORR will be performed upon demonstration of superiority in OS at OS 
interim or final analyses for all randomized subjects (see Section 7.5.4.2). P-values will not be 
presented for ORR if the endpoint OS whose null hypothesis could not be rejected. In this case, 
descriptive analysis and treatment difference estimations for ORR will still be presented. 
Primary Analysis 
ORR based on BICR assessment per RECIST 1.1 will be compared between two treatment groups 
using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by the stratification factors. 
This comparison will only be tested if the OS comparison is positive. 


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Secondary Analyses 
For descriptive purpose, the following statistics will be provided. 
• An estimate of the differences in ORRs and corresponding 95% CI will be calculated. 
• ORR along with its 95% exact CI using the Clopper-Pearson method will be computed for 
each treatment group. 
• In addition, the stratified (source: IVRS) odds ratios (Mantel-Haenszel estimator) between the 
treatments will be provided along with the 95% CI. 
• BOR will be summarized by response category. 
 
Sensitivity Analyses 
Similar analysis of ORR as in the secondary analyses will be performed for response evaluable 
subjects. 
ORR might also be analyzed in some key subgroups based on patients’ baseline characteristics. 
7.5.3 
Secondary Efficacy Endpoint PFS Analyses 
PFS as secondary efficacy endpoint is defined in Section 4.3.2. Hierarchical testing of PFS will be 
performed upon demonstration of superiority in OS and superiority in ORR at OS interim or final 
analyses for all randomized subjects (see Section 7.5.4.2). P-values will not be presented for PFS 
if the primary endpoint OS’s null hypothesis could not be rejected or the secondary endpoint 
ORR’s null hypothesis could not be rejected. In this case, descriptive analysis and treatment 
difference estimations for PFS will still be presented. 
Primary Analysis 
PFS will be compared between the two treatment groups via the stratified log-rank test. This 
comparison will only be tested if the OS comparison is positive and the ORR comparison is 
positive. 
Secondary Analyses 
A stratified Cox proportional hazards regression model will be used to estimate hazard ratio (see 
Section 7.1) between treatment groups along with the 100(1-α)% CI (adjusted for multiplicity, see 
Section 7.5.4.2). 
For descriptive purpose, the 95% CI for the estimated hazard ratio will be provided. 
The PFS curves for each treatment group will be estimated using the KM product-limit method. 
Median PFS and the corresponding two-sided 95% confidence intervals using the log-log 
transformation will be computed. 
In each treatment group, the 6, 12, 18, 24, 36, 48 months and 5 year PFS rate along with 95% CI 
will be estimated from the Kaplan-Meier estimate. Minimum follow-up (see its definition in 
Section 7.5.1.5) must be longer than a time period to generate a rate. The associated two-sided 
95% CI will also be calculated. 


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The source of progression (death vs progression) will be summarized by treatment group. 
The status of subjects who are censored in the PFS Kaplan-Meier analysis will be tabulated for 
each treatment group using following categories: 
− Never treated 
− On-study (on treatment, in follow-up) 
− Off-study (lost to follow-up, withdraw consent, other). 
− Received subsequent anti-cancer therapy 
 
Sensitivity Analyses 
Sensitivity analyses of PFS will also be performed using the following modification of PFS 
primary definition. 
PFS accounting for assessment on/after subsequent therapy It will be defined similarly to the 
primary definition except that events (progression or death) and tumor assessments that occurred 
on or after subsequent anticancer therapy will be taken into account (see censoring scheme in Table 
7.5.3-1 and Figure 7.5.3-1). 
 
 
Table 7.5.3-1: 
Censoring Scheme - PFS Sensitivity Analysis 
 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessment 
Date of randomization 
Censored 
No on study tumor assessments and no death 
Date of randomization 
Censored 
 
Documented progression per BICR assessment 
according to RECIST 1.1 
Date of the first documented tumor 
progression 
Progressed 
No progression and no death 
Date of last tumor assessment 
Censored 
Subsequent anti-cancer therapies started 
without a prior reported progression 
Date of subsequent anti-cancer therapy 
not considered 
 
None 
Death without progression and without initiation 
of subsequent anti-cancer therapy 
Death without progression after initiation of 
subsequent anti-cancer therapy 
 
Date of death 
Progressed 
 
Date of death 
Progressed 
 
 


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Figure 7.5.3-1: 
Graphical Display of PFS Definition for Sensitivity Analysis 
 
The secondary endpoint of PFS might also be analyzed in some key subgroups based on patients’ 
baseline characteristics. 
 
7.5.4 
Interim Analyses and Multiple Comparison 
7.5.4.1 
Interim Analyses 
An independent statistician external to BMS will perform the interim analyses, and DMC will have 
access to periodic unblinded interim reports of efficacy and safety. 
 
In addition to the formal planned interim analysis for OS, the DMC will conduct every 6 months 
review of safety. At each safety review, the DMC may have access to interim reports of safety and 
limited efficacy (such as KM curves of OS) to allow appropriate risk/benefit assessment. Details 
are included in the DMC charter. 
The DMC will review the safety and efficacy data from the interim analysis and will determine if 
the study should continue with or without changes or if accrual should be stopped. Subject 
enrollment will continue while waiting for the DMC’s decisions. More details of the interim 
analyses are discussed in the Data Monitoring Committee Charter. 
7.5.4.2 
Stagewise Hierarchical Testing Procedure for Primary Endpoint OS and 
Secondary Endpoints ORR and PFS 
Let i = 1, 2, 3 denote index indicating primary endpoint OS and secondary endpoints ORR and 
PFS, respectively. Accordingly, Hl , H2 , H3 denote two-sided null hypotheses of no effect in 
primary endpoint OS and secondary endpoints ORR and PFS, respectively. Let t = 1, 2 denote 


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l,l 
l,l 
l,l 
index indicating interim and final analysis timings, respectively. Correspondingly, pi,t denote 
nominal p-value of testing Hi at the analysis time t, and the corresponding decision boundaries can 
be expressed as nominal significance levels a∗ such that Hi is rejected if pi,t is smaller than a∗ 
at time t. 
i,t 
i,t 
To strongly control FWER at level 0.05 across three endpoints and repeated analyses at interim 
and final analyses, we adopted the stagewise hierarchical testing procedure36 to test Hl, H2, H3. 
Specifically, at the interim analysis time Hl is tested with nominal significance level a∗ , leading 
to the following two possibilities of rejecting Hl: 
• If pl,l < a∗ , Hl will be rejected, the trial will stop and H2 will be tested with nominal 
significance level a∗ . If p2,l < a∗ , H2 will be rejected and H3 will be tested with nominal 
2,l 
2,l 
significance level a∗ 
with p3,l < a∗ 
leading to the rejection of H3. If p2,l ≥ a∗  , H2 will 
3,l 
3,l 
2,l 
not be rejected and H3 will not be tested. 
• If pl,l ≥ a∗ , the trial continues to final analysis time and Hl will be tested with nominal 
significance level a∗ . If pl,2 < a∗ , Hl will be rejected and H2 will be tested with nominal 
l,2 
l,2 
significance level a∗ . If p2,2 < a∗ , H2 will be rejected and H3 will be tested with nominal 
2,2 
2,2 
significance level a∗ 
with p3,2 < a∗ 
leading to the rejection of H3. If p2,2 ≥ a∗ , H2 will 
3,2 
3,2 
2,2 
not be rejected and H3 will not be tested. 
 
The nominal significance levels for OS a∗ 
and a∗ 
will be computed using EAST software based 
l,l 
l,2 
on a generalization of the Lan-DeMets error spending function approach using an O’Brien- 
Fleming stopping boundary given overall two-sided alpha = 0.05. The stopping boundary will 
depend on the actual number of OS events observed at the time of the interim analysis and the final 
analysis. However, if the interim analysis is performed exactly when 80% OS events are observed, 
then a∗  = 0.024 will be used for the interim analysis and a∗  = 0.043 will be used for the final 
l,l 
analysis. 
l,2 
The nominal significance levels for ORR will be pre-specified as a∗ 
= 0.025 and a∗ 
= 0.025, 
as an equal Bonferroni splitting of the two-sided alpha = 0.05. 
2,l 
2,2 
The nominal significance levels for PFS a∗ 
and a∗ 
will be computed using EAST software 
3,l 
3,2 
based on a generalization of the Lan-DeMets error spending function approach using an Pocock 
stopping boundary given overall two-sided alpha = 0.05. The stopping boundary will depend on 
the actual number of PFS events observed at the time of the interim analysis and the final analysis. 
722 PFS events are expected at the final analysis time (of OS). 704 out of 722 or 97.5% PFS events 
are expected at the interim analysis time. If the interim analysis is performed exactly when 97.5% 
PFS events are observed, then a∗  = 0.049 and a∗  = 0.031 will be used. 
3,l 
3,2 


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7.6 
Safety 
7.6.1 
Deaths 
See Core Safety SAP.33 
7.6.2 
Serious Adverse Events 
See Core Safety SAP. 33 
7.6.3 
Adverse Events Leading to Discontinuation of Study Therapy 
See Core Safety SAP. 33 
7.6.4 
Adverse Events Leading to Dose Modification 
See Core Safety SAP. 33 
7.6.5 
Adverse Events 
See Core Safety SAP. 33 
7.6.6 
Select Adverse Events 
See Core Safety SAP. 33 
7.6.7 
Immune modulating medication 
See Core Safety SAP. 33 
7.6.8 
Multiple Events 
See Core Safety SAP. 33 


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7.6.9 
Other Events of Special Interest 
See Core Safety SAP. 33 
7.6.10 
Immune-Mediated Adverse Events 
See Core Safety SAP. 33 
7.6.11 
Laboratory Parameters 
See Core Safety SAP. 33 
7.6.12 
Vital Signs 
See Core Safety SAP. 33 
7.6.13 
Immunogenicity Analysis 
See Core Safety SAP. 33 
7.6.14 
Pregnancy 
See Core Safety SAP. 33 
7.6.15 
Adverse Events By Subgroup 
See Core Safety SAP. 33 Region subgroups are formed by US/Canada/Europe vs Asia vs Asia 
excluding Japan vs. Japan. 
7.7 
Pharmacokinetics 
The nivolumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop a population PK model. This model may 
be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab. In 
addition, exposure-response analyses with selected efficacy and safety endpoints may be 
conducted. Results of population PK and exposure response-analyses will be reported separately. 
 
 
 
 
 
7.8.1 
PD-L1 Expression 
The definition of PD-L1 expression and PD-L1 status is described in Section 4.3.3. Analyses of 
PD-L1 expression are descriptive in nature and intended to examine the distribution of PD-L1 
expression and assess potential association between PD-L1 expression and efficacy measures. All 
the analyses will be based on baseline PD-L1 expression. 
7.8.1.1 
Analyses of PD-L1 
Analyses of PD-L1 will include: 
1) Examine the distribution of PD-L1 expression 


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2) Assess potential association between PD-L1 expression and efficacy measures 
3) Evaluate the potential predictive relationship of the PD-L1 status and efficacy measures 
 
1) Descriptive statistics of PD-L1 expression and PD-L1 status 
• Listing of all PD-L1 IHC data, all randomized subjects 
• Summary of tumor specimen acquisition and characteristics, all randomized subjects 
• Summary statistics of PD-L1 expression by treatment group as randomized and overall, all 
PD-L1 quantifiable subjects 
• Frequency of PD-L1 categorization or status (≥ 1%, < 1%), including ‘missing’, 
‘indeterminate’ and ‘not evaluable’, by treatment group as randomized and overall, all 
randomized subjects 
 
2) Evaluation of associations between PD-L1 status and efficacy measures 
Analyses will be based on all randomized subjects if not otherwise specified. Each analysis will 
be performed for the subgroups listed below if not otherwise specified. 
• Each PD-L1 status subgroup 
• PD-L1 expression missing or indeterminate or not evaluable subgroup 
 
Analyses for OS: 
For each of the subgroups: 
• OS curves will be estimated using the KM product limit method for each treatment group. 
Two-sided, 95% confidence intervals for median OS will be computed by Brookmeyer and 
Crowley method. 
 
Analyses for ORR per BICR RECIST 1.1: 
For each of the subgroups: 
• Frequency and percentage of BOR will be summarized for each treatment group as 
randomized. 
• ORR will be computed by treatment group as randomized along with exact 95% CIs using the 
Clopper-Pearson method. 
• Odds ratios between the treatments will be provided along with the 95% CI. 
 
For PD-L1 quantifiable subjects, box plots of PD-L1 expression versus response status will be 
provided by treatment group as randomized. 
Receiver Operating Characteristics (ROC) analysis with BOR (CR+PR vs others) will be 
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For PD-L1 quantifiable subjects, plots of ROC curve by treatment group as randomized will be 
provided. 
Analyses for PFS per BICR RECIST 1.1: 
For each of the subgroups: 
• PFS curves will be estimated using the KM product limit method for each treatment group. 
Two-sided, 95% confidence intervals for median PFS will be computed by Brookmeyer and 
Crowley method. 
 
3) Evaluation of the potential predictive relationship of PD-L1 status for efficacy measures 
Analyses will be based on all PD-L1 quantifiable subjects. 
Analyses for OS: 
When appropriate, a Cox proportional hazards regression model will be fitted for OS with 
treatment (treatment groups as randomized), PD-L1 status, and treatment by PD-L1 status 
interaction. Although the study is not designed to have appropriate power to formally test the 
interaction of the model, an interaction test at significance level of 0.2 will warrant further 
exploration and the following statistics will be reported: 
• Interaction p-value 
• Hazard ratio of treatment vs. control and its associated 95% CI for each of the PD-L1 status 
subgroup 
• Hazard ratio PD-L1 ≥ 1% vs. < 1% and its associated 95% CI within each treatment group 
 
Analyses for ORR per BICR RECIST 1.1: 
When appropriate, a logistic regression model will be fitted for response status (yes=CR or PR, 
No=others) with treatment (treatment groups as randomized), PD-L1 status and the treatment by 
PD-L1 status interaction. Although the study is not designed to have appropriate power to formally 
test the interaction of the model, an interaction test at significance level of 0.2 will warrant further 
exploration and the following statistics will be reported: 
• Interaction p-value 
• Odds ratio of treatment vs. control and its associated 95% CI will be reported for each of the 
PD-L1 status subgroup 
• Odds ratio of PD-L1 ≥ 1% vs. < 1% and its associated 95% CI will be reported for each 
treatment group 
 
Analyses for PFS per BICR RECIST 1.1: 
When appropriate, a Cox proportional hazards regression model will be fitted for PFS with 
treatment, PD-L1 status, and treatment by PD-L1 status interaction. Although the study is not 
designed to have appropriate power to formally test the interaction of the model, an interaction test 


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at significance level of 0.2 will warrant further exploration and the following statistics will be 
reported: 
• Interaction p-value 
• Hazard ratio of treatment vs. control and its associated 95% CI for each of the PD-L1 status 
subgroup 
• Hazard ratio PD-L1 > 1% vs. < 1% and its associated 95% CI within each treatment group 


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7.10 
Post Hoc Analyses 
This section documents the statistical analyses plan being or to be conducted after the primary 
database lock for final OS analyses (Database locked on June 05, 2019). For ease of reference in 
this section, vascular invasion will be referred to as VI; extrahepatic spread will be referred to as 
EHS; correspondingly, vascular invasion and/or extrahepatic spread will be referred to as VI/EHS. 
There are three types of analyses. 
• Section 7.10.1 documents planned analyses using the VI/EHS stratification factor determined 
by BICR (see Independent Radiology Review Charter32) and efficacy data from the same 
database lock indicated above. BICR review of baseline scans is planned to be completed and 
BICR-based VI/EHS stratification factor locked in approximately August 2020. Analysis 
results will be summarized in a clinical study report (CSR) addendum. 
• Section 7.10.2 documents post-hoc sensitivity analyses for the primary endpoint of OS using 
statistical methods which account for the non-proportionality of the observed OS curves. 
 
Results of all above analyses will be summarized in clinical summary documents to support 
regulatory filings. 
7.10.1 
Analyses Based on VI/EHS Status per BICR Assessment 
7.10.1.1 
Background of Assessment for the VI/EHS Randomization Stratification 
Factor 
As background, the stratification factors for this study included HCV vs non-HCV status, VI/EHS 
(Yes vs No), and Asia vs non-Asia. In the March 2018 DMC routine safety review, BMS received 
an action item from the DMC that highlighted an observed discrepancy in values between the 
stratification factors via the IVRS and the CRF. In response to the DMC action item, BMS added 
a sensitivity analysis in the SAP to conduct a stratified analysis using CRF source if observed 
discrepancy rate for all stratification factors is at least 10% (see Section 7.5.1.3). Given that 
subjects were already randomized into the trial and enrollment was complete, it was not possible 
to make any changes to the stratification through the IVRS. As such, prior to the database lock on 
June 05, 2019, BMS conducted data review and queried the sites for all identified discrepancies 
with IVRS and CRF. After lock, the discrepancy rate between the IVRS and the CRF, was over 
pre-specified 10% (with 9.3% for VI/EHS stratification factor and 0.8% discrepancy in the HCV 
stratification factor). The pre-planned sensitivity analysis was therefore triggered as part of the 
final analyses of OS. 
During discussion with the FDA, concerns were raised by the Agency regarding the potential for 
bias as only discrepant cases were reviewed and the lack of complete justification for changes 
made in the CRF as a result of the review. Due to this, BMS proposed and planned to perform a 
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randomized subjects from the original baseline scan. The planned radiology review was 
documented in the BICR charter32. This section will describe the analyses to be performed utilizing 
the VI/EHS status per BICR. 
7.10.1.2 
Determination of VI/EHS Status per BICR Assessment 
According to the BICR charter32, the status of VI and EHS will be adjudicated separately and 
provided to BMS with three possible outcomes: Yes, no, or unknown (due to situations not 
evaluable). The overall status of VI/EHS will then be derived by BMS based on the following table 
with each case of VI status and EHS status for each subject. 
 
Table 7.10.1.2-1: 
VI/EHS Status per BICR 
VI 
EHS 
VI/EHS 
Yes 
Yes 
Yes 
Yes 
No 
Yes 
Yes 
Unknown 
Yes 
No 
Yes 
Yes 
No 
No 
No 
No 
Unknown 
Unknown 
Unknown 
Yes 
Yes 
Unknown 
No 
Unknown 
Unknown 
Unknown 
Unknown 
 
7.10.1.3 
Baseline characteristics 
The following baseline disease characteristics will be summarized by treatment group. By-subject 
listings will also be provided for subject level detail of the BICR assessment. 
• VI per BICR (Yes/No/Unknown) 
• EHS per BICR (Yes/No/Unknown) 
• VI/EHS per BICR (Yes/No/Unknown) 
 
A summary table (cross-tabulation) by treatment group for the stratification factor VI/EHS will be 
provided to show any discrepancies between what was reported through IVRS and the BICR 
assessment. A similar summary table will be provided for VI/EHS determined by CRF and by the 
BICR. 
7.10.1.4 
Stratified analyses 
To conduct stratified analyses based on VI/EHS assessed by BICR, we define the BICR strata as 
strata determined by the following factors at baseline: 
• VI/EHS per BICR 


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• HCV/non-HCV per IVRS 
• Asia/non-Asia per IVRS 
 
Stratified Analyses for OS 
The distribution of OS will be compared in two treatment groups via a two-sided stratified log- 
rank test using the BICR strata. In addition, based on the same strata, a stratified Cox proportional 
hazards regression model will be used to estimate hazard ratio between treatment groups along 
with the 95% CI. These are the same stratified analyses as outlined in Section 7.5.1.1 and Section 
7.5.1.2 with the VI/EHS stratification factor per IVRS replaced by the one per BICR. 
To assess consistency of treatment effects in subsets per different assessments of stratification 
factors, a forest plot of the OS hazard ratio and 95% CI will be produced for the following 
variables: 
• VI/EHS (Yes/No) per IVRS 
• VI/EHS (Yes/No/Unknown) per CRF 
• VI/EHS (Yes/No/Unknown) per BICR 
• VI (Yes/No) per IVRS 
• EHS (Yes/No) per IVRS 
• VI (Yes/No/Unknown) per CRF 
• EHS (Yes/No/Unknown) per CRF 
• VI (Yes/No/Unknown) per BICR 
• EHS (Yes/No/Unknown) per BICR 
 
If a subgroup category has less than 10 subjects in a treatment group, then HR will not be reported 
for that subgroup. 
Stratified analysis for ORR and PFS per BICR RECIST 1.1 
Based on the BICR strata, the following stratified analyses are planned for the ORR and PFS 
assessed by BICR per RECIST 1.1. 
ORR will be compared between two treatment groups using a stratified two-sided CMH test. The 
stratified odds ratios (Mantel-Haenszel estimator) between the treatments will be calculated along 
with the 95% CI. An estimate of the differences in ORRs and corresponding 95% CI will be 
calculated based on CMH method of weighting, stratified by the BICR strata. These are the same 
stratified analyses as outlined in Section 7.5.2, with the VI/EHS stratification factor per IVRS 
replaced by the one per BICR. 
PFS will be compared between the two treatment groups via the stratified log-rank test. A stratified 
Cox proportional hazards regression model will be used to estimate HR and 95% CI. These are the 
same stratified analyses as outlined in Section 7.5.3, with the VI/EHS stratification factor per IVRS 
replaced by the one per BICR. 


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7.10.2 
Analyses for Investigating Non-Proportionality in OS Curves 
7.10.2.1 
Piecewise hazard ratio 
Having examined the OS KM curves in the final analyses, we observed that the HR does not appear 
to be constant over time: the OS in nivolumab demonstrated similar benefit to sorafenib, with two 
curves overlapping with each other in the first 8 months; afterwards, the two curves started to 
separate, with clear separation towards the tails. Therefore, piecewise HRs and 95% CI will be 
calculated for the time periods of the first 8 months and the subsequent period later than the first 
8 months. The HRs and 95% CI will be estimated based on stratified Cox models with a time- 
dependent-covariate approach. The stratified analyses will be repeated for the three assessments 
of stratification factors: the stratification factors per IVRS, the ones per CRF, and the BICR strata. 
7.10.2.2 
Max-Combo test 
Since the OS curves indicate the HR is not constant over time with the clear delayed separation, 
the power of the standard logrank test is reduced. In this case, as suggested by the non-proportional 
hazards working group, the Max-Combo test is a promising approach with the flexibility of 
allowing different types of non-proportionality and robustness under model mis-specification37. 
The working group also provided the R package nphsim to facilitate such testing procedures. We 
will apply the Max-Combo test to the OS data with the following parameter setting (rho, gamma) 
of Fleming-Harrington class of weights: (rho = 0, gamma = 0) attributes equal weights to all; (rho 
= 1, gamma = 0) emphasizes early difference in survival curves; (rho = 0, gamma = 1) weight 
more for late difference; (rho = 1, gamma = 1) emphasizes middle difference. In the current 
implementation of the R package nphsim, stratification is not available. Therefore, the unstratified 
Max-Combo test in the package will be applied and the resulting p-value will be reported, along 
with estimated HR and adjusted 95% CI. Since the stratification is not involved, the results of this 
sensitivity analysis should only be compared with the original results of the unstratified analysis 
(see Section 7.5.1.3). 


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8 
CONVENTIONS 
8.1 
Date Imputation 
The following conventions may be used for imputing partial dates for analyses requiring dates: 
• For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification38. 
• Missing and partial Non-Study Medication Domain dates will be imputed using the derivation 
algorithm described in 4.3.3 of BMS Non-Study Medication Domain Requirements 
Specification39. 
• For death dates, the following conventions will be used for imputing partial dates: 
− If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known date alive day and the 
maximum will be considered as the death date. 
− If the month or the year is missing, the death date will be imputed as the last known date 
alive day 
− If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known date alive day 
• For date of progression, the following conventions will be used for imputing partial dates: 
− If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In cases where the date of death is present and complete, the imputed 
progression date will be compared to the date of death. The minimum of the imputed 
progression date and date of death will be considered as the date of progression. 
− If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
• For other partial/missing dates, the following conventions may be used: 
− If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
− If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
− If a date is completely missing, it will be considered as missing. 
 
8.2 
Duration Calculation and Conversion 
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days. 
Duration (e.g. time from first diagnosis to first dosing date, duration of response, and time to 
response) will be calculated as follows: 
Duration = (Last date - first date + 1) 


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8.3 
Decimal Places 
The number of decimal places displayed in all listings will be determined by the number of decimal 
places in the raw data. 
Unless otherwise specified, minimum and maximum will be reported to the precision as the data 
collected, one more decimal place for the mean and median, and two more decimal places for the 
standard deviation. The adjusted geometric mean, geometric mean ratio and the lower and upper 
limits of confidence interval will be displayed to three decimal places. 
8.4 
Analysis Software 
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted. 
9 
CONTENT OF REPORTS 
The analyses described in this statistical analysis plan will be included a clinical study report 
except where otherwise noted. Additional exploratory analyses may be performed. 


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10 
DOCUMENT HISTORY 
Table 10-1: 
Document History 
 
 
Version 
Number 
 
4.0 
 
 
 
 
 
 
 
 
 
 
 
3.0 
Author(s) 
Description 
 
18-May-2020 
Added section 7.10 to summarize post hoc data analyses performed after the 
databased lock for final analysis of OS 
Replaced all randomized population with all randomized subjects 
Changed the categories of Region (US/Canada, Europe, Asia, Rest of world) to 
Region (US/Canada/Europe, Asia, Asia excluding Japan, Japan) 
Added the imputation algorithm for imputing investigator BOR in 
Removed DCR and DDC based on Investigator Assessments according to 
RECIST 1.1 from exploratory endpoints 
Removed the analysis on concordance between BICR and Investigator 
Assessments 
Removed the description about China extension and definitions of all 
randomized population and all enrolled population to avoid confusion 
Clarified that a few subjects with both HBV and HCV boxes checked in the risk 
factor CRF page will be put into the HCV subgroup in the outputs of the clinical 
study report 
Added sensitivity analysis of OS in the case where the stratification variables at 
IVRS and at baseline (with CRF source) disagree for at least 10% of the 
randomized subjects 
 
 
 
 
2.0 
 
 
 
 
 
 
 
 
 
1.1 
08-Nov-2017 
Moved ORR comparison from primary objective to secondary objective. 
Changed ORR from one of primary endpoints to a secondary endpoint and 
moved its corresponding analysis plan to secondary endpoint analyses. 
Updated interim analysis and multiple comparison to reflect the endpoint 
change. 
Added clarification on DOR censoring: 
Subjects who neither progress nor die will be censored on the date of their last 
evaluable tumor assessment. Subjects who started any subsequent anti-cancer 
therapy without a prior reported progression will be censored at the last 
evaluable tumor assessment prior to or on the date of initiation of the 
subsequent anti-cancer therapy. Essentially, the DOR will be censored at the 
same time they will be censored according to the same censor scheme as for the 
primary definition of PFS (Section 4.1.2). 
Changed definition of response evaluable subjects to the following: 
• 
Response Evaluable Subjects: Randomized subjects who have target 
lesion(s) assessed at baseline and at least one post-baseline timepoint. 
Added clarification on the global study population enrollment date cutoff: 
 
 


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Table 10-1: 
Document History 
 
 
Version 
Number 
Author(s) 
Description 
A China extension is added to allow continued enrollment of subjects from 
China after the completion of the enrollment of the global study. The global 
study completed the enrollment on March 07, 2017. The enrolled subjects in the 
global study will be the analysis population of this statistical analysis plan (see 
population definitions below). Analyses related to enrolled subjects in China 
extension will be specified in another statistical analysis plan. 
Clarified the following population definitions: 
• 
ORR Population: Subjects who were randomized prior to or on September 
26, 2016 (that is, the first 373 randomized subjects). This population will be 
used for the efficacy analysis of the primary endpoint of ORR. 
• 
ORR Enrolled Population: Subjects who were randomized prior to or on 
September 26, 2016 or subjects who were enrolled prior to or on September 
26, 2016 but are never randomized. This is the enrollment population for 
the ORR population. 
• 
All Randomized Population: Subjects who were enrolled prior to or on 
March 07, 2017 and randomized. 
• 
All Enrolled Population: Subjects who were enrolled prior to or on March 
07, 2017. 
Modified one existing listing and added one by-subject listing for study 
disposition as follows: 
A subject listing for all enrolled subjects will be provided showing the subject’s 
consent date, reason for not being randomized, and reason for not being treated. 
A subject listing for all treated subjects will be provided showing the subject’s 
randomization date, first and last dosing date, off treatment date and reason for 
going off-treatment. 
Added one variable for demographics: 
Region (US/Canada, Europe, Asia, Rest of world) 
Added one category for etiology: HBV-HCV coinfection. • 
Etiology is 
HBV-HCV coinfection if both HBV and HCV are included as risk factors 
Removed multiplicity-adjusted CI for the difference in ORRs based on CMH 
method of weighting. 
Removed sensitivity analyses in the case of sources for stratification variables 
of IVRS and CRF baseline disagreeing at least 10%. 
Added Child-Pugh scores and classes as subset analyses 
 
 
1.0 
Initial version dated 12-28-2016 


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11 
REFERENCES 
 


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30  Data Monitoring Committee Charter. Study CA209459. 
31  Clinical Protocol CA209459. 
32  Independent Radiology Review Charter - BMS CA209459. 


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33 Core Safety Statistical Analysis Plan for Multiple Indications, Nivolumab Program, Protocols 
CA 209, Version 5 
34 Clopper CJ and Pearson E S. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 26: 404-413, 1934 
35 Statistical methodology in the pharmaceutical sciences / edited by Berry DA, Chapter 13 
Categorical Data analysis p. 415 and 417 ff., Marcel Dekker, 1990 
36 Glimm E, Maurer W, and Bretz F. Hierarchical Testing of Multiple Endpoints in Group 
Sequential Trials. Statistics in Medicine 29: 219-228, 2010 
37 Oncology Clinical Trials in the Presence of Non-Proportional Hazards. Public Workshop. 
Feburary 05, 2018. Washington, DC. 
38  Adverse Event Domain Requirements Specification. Bristol-Myers Squibb Co. PRI. Version 
2.1. April 23, 2012. 
39 Non-Study Medication Domain Requirements Specification. Bristol-Myers Squibb Co. PRI. 
Version 2.2 April 24, 2012. 

Prot_001.pdf: 
Page:
1
Protocol Number:
CA209459
IND Number:
126,406
EUDRACT Number
2015-002740-13
Date:
31-Jul-2015
Revised Date:
15-Jan-2019
Clinical Protocol CA209459
A Randomized, Multi-center Phase III Study of Nivolumab versus Sorafenib as First-Line 
Treatment in Patients with Advanced Hepatocellular Carcinoma
(CheckMate 459: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 459)
Revised Protocol Number: 04
Incorporates: Amendment 18 and Administrative Letter 04
Global Medical Monitor
Study Director
Christine dela Cruz, MD, MHScM
 
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
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Clinical Protocol
CA209459
BMS-936558
nivolumab
Revised Protocol No.: 04
Date:  15-Jan-2019
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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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Revised Protocol No.: 04
Date:  15-Jan-2019
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 04
15-Jan-2019
Incorporates Amendment 18 and Administrative Letter 04.
Amendment 
18
15-Jan-2019
The primary reason for this amendment is to update several protocol sections 
to reflect the most recent guidance for treating study participants with 
nivolumab. In addition, an exploratory objective evaluating the correlation of 
tumor inflammation with efficacy based on recent preliminary data has been 
added. Several minor inconsistencies in study objectives and endpoints and 
minor administrative changes are also addressed.
Administrative 
Letter 04
28-Aug-2017
Update summary of change for Amendment 16 to reflect implementation as 
soon as possible, and to update the overall alpha in Section 8.4.2.1
Revised 
Protocol 03
15-Aug-2017
Incorporates Amendment 16 and Administrative Letters 02 and 03
Amendment 
16
15-Aug-2017
The purpose of this amendment is to change Overall Response Rate (ORR) 
from a co-primary objective to a secondary objective of the study. Overall 
Survival (OS) will be the sole Primary Endpoint of the study.
 
 
 
 
 
 
 
 
 
 
 
 
his amendment applies to all subjects enrolled.
Administrative 
Letter 03
15-Mar-2017
Clarify that local Hepatitis D testing is an option in the event the Central 
Laboratory is unable to perform Hepatitis D testing in certain circumstances.
Administrative 
Letter 02
02-Mar-2017
Update to Study Director’s office location
Revised 
Protocol 02
24-Aug-2016
Incorporates Amendment 11
Amendment 
11
24-Aug-2016

Updated Study Director/Medical Monitor information

Co-primary endpoint and objective changed from time to progression 
(TTP) to objective response rate (ORR)

Added requirement for confirmatory scan to be performed for CR/PR 
assessment of best overall response (BOR)

Management algorithms updated per revised nivolumab IB
Revised 
Protocol 01
01-Oct-2015
Incorporates Amendment 02
Amendment 
02
01-Oct-2015
Addition of collection of peripheral blood mononuclear cells (PBMCs) and 
myeloid derived suppressor cells (MDSCs) collected from subjects at baseline
from selected sites, reduction of frequency of HCV RNA testing for HCV 
infected subjects, clarification of locoregional therapy inclusion criteria, as 
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nivolumab
SYNOPSIS
Clinical Protocol CA209459
(CheckMate 459: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 459)
Protocol Title: A Randomized, Multi-center Phase III Study of Nivolumab versus Sorafenib as First-Line Treatment 
in Patients with Advanced Hepatocellular Carcinoma 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 
Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity; 
Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity
Study Phase:  Phase 3
Research Hypothesis: Nivolumab administration in subjects with advanced hepatocellular carcinoma (HCC) who 
have not received prior systemic therapy will improve OS compared with sorafenib.
Objectives: 
Primary Objectives
To compare the overall survival (OS) of nivolumab to sorafenib in subjects with advanced HCC who have not received 
prior systemic therapy.
Secondary Objectives

To compare the objective response rate (ORR) of nivolumab to sorafenib. ORR will be determined from 
assessment by a blinded independent central review (BICR) based on RECIST 1.1.

To compare progression free survival (PFS) of nivolumab and sorafenib. PFS will be determined from 
assessments by a blinded independent central review (BICR) based on RECIST 1.1

To evaluate the relationship between tumor PD-L1 expression and efficacy
Study Design:  
* Subjects may be treated beyond disease progression under protocol-defined conditions.    See Section  3.1.6
Advanced HCC,
Systemic 
therapy naïve
Nivolumab
240 mg 30 min IV
q 2w
Sorafenib
400 mg PO BID
Unacceptable 
toxicity
or
Disease
Progression*
Follow-up & 
Survival 
Follow-up
Randomize 1:1
Stratification factors:
• Etiology (HCV vs. non-HCV [ie, HBV- and HCC with no history of hepatitis virus infection])
• Vascular invasion &/or extrahepatic spread (present or absent),
• Geography (Asia vs Non-Asia).
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Study Population: Adult (18 years) male and female subjects with advanced HCC. Subjects must not be amenable 
for management with surgery or loco-regional therapy or have progressed after surgery or loco-regional therapy. 
Surgical and/or locoregional therapy to reduce overall tumor burden prior to study entry is not allowed. Subjects must 
not have received prior systemic therapy for advanced HCC in keeping with the first-line setting of this study.
Eligibility criteria are defined in the protocol.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209459
Medication 
Potency 
IP/Non-IP 
Nivolumab Solution for Injection
100 mg (10 mg/mL)
IP
Sorafenib Tablets
200 mg
IP
Study Assessments: On treatment visits will occur at Day 1 and every 2 weeks thereafter. Tumor imaging 
assessments will occur 8 weeks from the date of randomization (+/-1 wk), then every 8 weeks (+/- 1 wk) thereafter up 
to 48 weeks, then it will be every 12 weeks (+/- 1 week) until disease progression or treatment is discontinued 
(whichever occurs later). Subjects will be treated until unacceptable toxicity or disease progression. Following 
discontinuation of therapy, safety will be assessed through post-treatment Follow Up visit 2 (~ 100 days from last 
dose). Survival status will be assessed every 3 months after follow up visits are completed, and may be completed via 
telephone or in person visits.
Statistical Considerations:
Sample Size: 
The sample size determination of this study is based on OS comparison between subjects randomized to receive 
nivolumab and sorafenib. With a total of 726 subjects randomized in a 1:1 ratio, approximately 91.5% power will be 
achieved with an overall type I error 0.05 for OS comparison. The number of events and power for the OS comparison 
are calculated based on simulation and assuming an exponential distribution for OS in each randomization arm. The 
study requires at least 520 OS events to ensure approximately 91.5% power to detect a hazard ratio of 0.74 with an 
overall type I error of 0.05 (two-sided) for OS. The HR of 0.74 corresponds to a 35% increase in the median OS for 
both non-HCV infected subjects and HCV infected subjects, assuming a median OS of 10 months for non-HCV 
infected subjects and a median OS of 14 months for HCV infected subjects in the sorafenib arm. One formal interim 
analysis will be conducted with 80% OS events observed. The stopping boundaries at the interim and final analyses 
will be derived based on the exact number of deaths using Lan-DeMets alpha spending function with O’Brien-Fleming 
boundaries. Assuming a piecewise constant accrual rate, it will take approximately 33 months to obtain the required 
number of deaths for the final OS analysis (13 months for randomization and 20 months for follow-up) and 
approximately 25 months (13 months for randomization and 12 months for follow-up) for the OS interim analysis.
Endpoints:
Primary Endpoints

Overall Survival (OS)
OS is defined as the time from the date of randomization to the date of death due to any cause in all randomized 
subjects. Subjects who are alive will be censored at the last known alive dates.
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Secondary Endpoints

Objective Response Rate (ORR)
ORR, as determined based on BICR-assessed tumor response according to RECIST 1.1, is defined as the 
proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR. BOR is determined 
by the best response designation recorded between the date of randomization and the date of first objectively 
documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For subjects 
without documented progression or subsequent anti-cancer therapy, all available response designations will 
contribute to the BOR determination. For a BOR of CR or PR, the initial response assessment must be confirmed 
by a consecutive assessment no less than 4 weeks (28 days) later.

Progression-Free Survival (PFS)
PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor 
progression as assessed by BICR according to RECIST 1.1 or death due to any cause. Subjects who die without 
a reported prior progression and without initiation of subsequent anti-cancer therapy will be considered to have 
progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their 
last tumor assessment. Subjects who did not have baseline tumor assessment will be censored on the date they 
were randomized. Subjects who did not have any on-study tumor assessments and did not die will be censored on 
the date they were randomized. Subjects who started any subsequent anti-cancer therapy without a prior reported 
progression will be censored at the last tumor assessment prior to subsequent anti-cancer therapy.

PD-L1 expression
The objective of evaluating the relationship between PD-L1 expression and efficacy will be measured by efficacy 
based on PD-L1 expression. Definition of PD-L1 expression will be described in the SAP.
Exploratory endpoints are described in detail in the protocol.
Analyses:  
Additional analyses are described in detail in the protocol.

Analysis of OS
A group sequential testing procedure will be applied to OS to control the overall type I error for interim and final 
analyses (overall alpha=0.05). The distribution of OS will be compared in the two randomized arms at the interim 
and final analyses via a two-sided, log-rank test stratified by the stratification factors using allocated alpha based 
on Lan-DeMets alpha spending function with O’Brien and Fleming type of boundary.. The hazard ratio (HR) and 
the corresponding 100x (1-adjusted alpha)% confidence interval (CI) will be estimated in a stratified Cox 
proportional hazards model using randomized arm as a single covariate. The OS curves for each randomized arm 
will be estimated using the Kaplan-Meier (KM) product limit method. Median OS and the corresponding two-
sided 95% CIs will be computed using the log-log transformation. Survival rates at select milestones will be 
computed as well as the corresponding two-sided 95% CIs using the log-log transformation.

Analysis of ORR
ORR based on BICR assessment per RECIST 1.1 between the two randomized arms in all randomized subjects 
will be compared using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by the stratification factors. 
The associated odds ratio and CI will also be calculated. ORR along with its 95% exact CI using the Clopper-
Pearson method will be provided for each randomization arm. Hierarchical testing of ORR will be performed 
upon demonstration of superiority in OS at OS interim or final analyses for all randomized subjects.

Analysis of PFS
Hierarchical testing of PFS will be performed upon demonstration of superiority in ORR at OS interim or final 
analysis for all randomized subjects. Details of timing for the analysis and alpha allocated will be described in 
the SAP.
PFS will be compared using a two-sided stratified log-rank test. The HR and the corresponding two-sided 
confidence intervals (CIs) will be estimated in a Cox proportional hazards model using treatment as a single 
covariate, stratified by the stratification factors. PFS curves will be estimated using the KM product-limit method. 
Median PFS and the corresponding two-sided 95% CIs will be computed using the log-log transformation. In 
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addition, PFS rate at select milestone will be computed as well as the corresponding two sided 95% CIs using the 
log-log transformation.

Safety Analysis
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety will be presented using 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 by 
treatment arm. All on-treatment AEs, drug-related AEs, SAEs and drug-related SAEs will be tabulated using 
worst grade per NCI CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab parameters 
including hematology, coagulation, chemistry, liver function and renal function will be summarized using worst 
grade per NCI CTCAE v 4.0 criteria.
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Introduction ....................................................................................................... 
 
 
 
 
 
 
 
 
 
 
1.3 Research Hypothesis ......................................................................................... 
1.4 Objectives(s) ..................................................................................................... 
1.4.1 Primary Objectives .................................................................................. 
1.4.2 Secondary Objectives ............................................................................... 
 
 
 
 
1.6 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening Phase ....................................................................................... 
3.1.2 Treatment Phase ...................................................................................... 
3.1.3 Follow Up Phase...................................................................................... 
3.1.4 Study Duration ......................................................................................... 
3.1.5 Review of Safety ....................................................................................... 
3.1.6 Treatment beyond progression ................................................................ 
3.2 Post-Study Access to Therapy .......................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Permitted Therapy ................................................................................... 
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3.4.1.1 Antiviral therapy ............................................................................. 
3.4.1.2 Steroids ........................................................................................... 
3.4.1.3 Vaccines .......................................................................................... 
3.4.1.4 Other Systemic Therapy .................................................................. 
3.4.1.5 Palliative Local Therapy................................................................. 
3.4.2 Prohibited and/or Restricted Treatments................................................. 
3.4.2.1 All subjects ...................................................................................... 
3.4.2.2 Subjects randomized to nivolumab treatment ................................. 
3.4.2.3 Subjects randomized to sorafenib treatment ................................... 
3.4.3 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post-Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.3.1 Nivolumab (BMS-936558) ....................................................................... 
4.3.2 Sorafenib .................................................................................................. 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Nivolumab Dosing ................................................................................... 
4.5.1.1 Nivolumab Dose and Schedule ....................................................... 
4.5.1.2 Dose Modifications for Nivolumab ................................................. 
4.5.1.3 Dose Delay Criteria for Nivolumab ................................................ 
4.5.1.4 Criteria to Resume Dosing for Nivolumab ..................................... 
4.5.1.5 Treatment Discontinuation Criteria for Nivolumab ....................... 
4.5.1.6 Treatment Beyond Progression for Nivolumab .............................. 
 
 
 
 
4.5.3 Sorafenib Dosing ..................................................................................... 
4.5.3.1 Sorafenib Dose and Schedule ......................................................... 
4.5.3.2 Dose Reductions for Sorafenib ....................................................... 
4.5.3.3 Treatment Interruption or Discontinuation Criteria for Sorafenib  
4.5.3.4 Treatment Beyond Progression for Sorafenib ................................ 
4.5.3.5 Management of Sorafenib Adverse Events ..................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
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5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening Period ......................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessment ............................................................... 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetic and Immunogenicity Collection and Processing ......... 
 
 
 
 
 
 
 
 
 
 
 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
7.1 Data Monitoring Committee ............................................................................. 
7.2 Blinded Radiology Review Committee ............................................................ 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
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8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Analysis of OS ................................................................................. 
8.4.2.2 Analysis of ORR .............................................................................. 
8.4.2.3 Analysis of PFS ............................................................................... 
8.4.2.4 Analysis of Association between PD-L1 Expression and Efficacy 
Measures ............................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 RECIST 1.1 ........................................................................................... 
APPENDIX 2 CHILD-PUGH SCORE ........................................................................ 
APPENDIX 3 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 4 NYHA CLASSIFICATION .................................................................. 
 
 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second 
leading cause of cancer-related death. The incidence of HCC varies geographically largely due to 
variations in hepatitis B and C virus infection. The majority (> 80%) of cases occur in sub-Saharan 
Africa and eastern Asia. China alone accounts for 55% of cases worldwide. In almost all 
populations, males have higher rates of liver cancer than females with an overall sex ratio around 
2.41.
HCC has the highest mortality-to-incidence rate ratio of 0.98 followed by lung (0.85) and 
esophageal (0.83) cancers2. The numbers of deaths is close to the number of new cases because 
most HCCs are detected at an advanced stage and occur in patients with underlying liver 
dysfunction, making HCC a highly lethal cancer. The prognosis is also poor because of the low 
effectiveness of available treatments. The 5-year HCC survival rate is approximately 5%-6% 
compared with 72% and 22% for breast cancer stages III and IV respectively3,4,5.
Treatment of HCC is challenging because the disease is highly heterogeneous with different 
etiologies, varying approaches to diagnosis and treatment, and variations in responses to therapy6.
In contrast to other high-incidence cancers, treatment decisions in HCC are hampered by the limits 
of high-quality evidence across all clinical scenarios. As with other tumors, treatment selection 
depends on disease stage, the tumor extent, and the patient’s performance status. However, the 
patient’s underlying liver function has an important influence on HCC treatment decisions. A total 
of 90% of HCC patients have an underlying cirrhosis requiring management of both the
malignancy and the cirrhosis. Additionally, many patients require ongoing support for concomitant 
underlying disease such as hepatitis B virus (HBV) or hepatitis C virus (HCV) or non-viral related 
liver disease, eg, non-alcoholic steatohepatitis (NASH). Treatment strategies are therefore 
complex and best served by a multidisciplinary team7.
Relatively few patients are eligible for curative treatment because of the late appearance of 
symptoms.7 In the West, only around 30% of all patients are diagnosed early enough to be eligible 
for potentially curative treatment such as resection, transplantation and radiofrequency ablation. 
Approximately 20% are diagnosed in the intermediate stage and can gain survival benefits of up 
to 20 months from transarterial chemoembolization (TACE). The majority of patients, however, 
are diagnosed in the advanced stages of the disease when the disease is beyond resection and 
locoregional treatments are ineffective. The prognosis for these patients is poor8.
The multi-tyrosine kinase inhibitor, sorafenib, is the only systemic agent proven to provide a 
survival benefit in patients who are not expected to benefit from surgery or locoregional therapies. 
However, the prognosis of patients with advanced HCC has not been radically improved.9 The 
survival improvement with sorafenib over placebo is modest, at 2.8 months in the pivotal Western 
trial and 2.3 months in the related Asian trial.10,11 GIDEON, the largest real-life study conducted 
on the use of sorafenib, reported sorafenib-related adverse events (AEs) in 64% of patients, 23% 
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of which were Grade 3 or 4 AEs. In 28% of patients, AEs resulted in permanent discontinuation 
of sorafenib.12 In the 2 pivotal sorafenib trials, dose reductions were common. Hand-foot-skin 
reactions (HFSR) (10%-11% of patients) and diarrhea (5%-7% of patients) were the most common
significant AEs leading to dose reduction.10,11 Asians experience more HFSR than other 
populations with a reported rate of 45% for any Grade in the sorafenib Asia-Pacific study 
compared with 21% in the West. The landmark sorafenib trials also failed to demonstrate 
symptomatic improvement or improvement in quality of life.7 Post-marketing clinical studies 
showed that although sorafenib treatment has shown a significant increase in mean overall survival 
in different studies, only a portion of patients show real benefits, while the incidence of drug related 
significant adverse effects and the economic costs are relatively high.13 Finally, predictive 
biomarkers for sorafenib benefit that could refine the risk-benefit ratio for therapy have not yet 
been validated.7,8 All other drugs tested for HCC in recent years have failed in both the first and 
second line settings.14,15 There therefore is a need for new treatment options for advanced HCC.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.3
Research Hypothesis 
Nivolumab administration in subjects with advanced hepatocellular carcinoma (HCC) who have 
not received prior systemic therapy will improve OS compared with sorafenib.
1.4
Objectives(s)
1.4.1
Primary Objectives
To compare the overall survival (OS) of nivolumab to sorafenib in subjects with advanced HCC 
who have not received prior systemic therapy.
1.4.2
Secondary Objectives

To compare the objective response rate (ORR) of nivolumab to sorafenib. ORR will be 
determined from assessment by a blinded independent central review (BICR) based on 
RECIST 1.1.

To compare progression free survival (PFS) of nivolumab and sorafenib. PFS will be 
determined from assessments by a blinded independent central review (BICR) based on 
RECIST 1.1

To evaluate the relationship between tumor PD-L1 expression and efficacy
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) and Regulatory Authority (ies) approval/favorable opinion prior to 
initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC
for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
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Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, two-arm, randomized, Phase 3 study in adult (18 years) male and female 
subjects with advanced HCC. Subjects must not be amenable for management with surgery or 
loco-regional therapy or have progressed after surgery or loco-regional therapy. Subjects must not 
have received prior systemic therapy for advanced HCC in keeping with the first-line setting of 
this study.
After screening for eligibility and signing of informed consent, qualified subjects will be 
randomized in a 1:1 ratio to receive nivolumab or sorafenib. It is expected that approximately 908 
subjects will be screened for the study with approximately 726 subjects entering the treatment 
phase. Approximately 363 subjects will be randomized to each study arm. Stratification will occur 
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by etiology (HCV vs. non-HCV [ie, HBV- and HCC with no history of hepatitis virus infection]),
vascular invasion &/or extrahepatic spread (present or absent), geography (Asia vs Non-Asia).  
Subjects will receive open-label treatment with one of the following:

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity
On both arms, treatment beyond initial investigator-assessed RECIST 1.1 defined progression is 
permitted if the subject has investigator assessed clinical benefit and is tolerating study drug, as 
specified in Section 3.1.6. Specific requirements for subjects treated with nivolumab and sorafenib 
are described in Sections 4.5.1.6 and 4.5.3.4, respectively.
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
3.1.1
Screening Phase

Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF)

Subject is enrolled using the Interactive Voice Response System (IVRS)

Subject is assessed for study eligibility with the required timeframe found in Table 5.1-1

Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker 
analysis. Central lab must provide IVRS with confirmation of receipt of evaluable tumor tissue 
prior to subject randomization (The tissue submitted will be assessed for quality with an H&E 
stain and only those subjects who have meet tissue quality thresholds can be randomized)

The screening phase either ends with confirmation of full eligibility and treatment assignment 
of the subject or with the confirmation that the subject is a screen failure.
* Subjects may be treated beyond disease progression under protocol-defined conditions.    See Section  3.1.6
Advanced HCC,
Systemic 
therapy naïve
Nivolumab
240 mg 30 min IV
q 2w
Sorafenib
400 mg PO BID
Unacceptable 
toxicity
or
Disease
Progression*
Follow-up & 
Survival 
Follow-up
Randomize 1:1
Stratification factors:
• Etiology (HCV vs. non-HCV [ie, HBV- and HCC with no history of hepatitis virus infection])
• Vascular invasion &/or extrahepatic spread (present or absent),
• Geography (Asia vs Non-Asia).
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3.1.2
Treatment Phase
The treatment phase begins with the randomization call to the IVRS. The subject is randomly 
assigned to one of the two treatment arms. Study treatment must begin within 3 days of 
randomization.
Nivolumab 240 mg IV is administered as a 30-minute IV infusion every 2 weeks. Sorafenib 
400 mg is administered twice a day. Both study drugs are continued until disease progression, 
unacceptable toxicity, withdrawal of consent or study closure. Study assessments are to be 
collected as outlined in Table 5.1-2 and Table 5.1-3.
Nivolumab or sorafenib treatment beyond initial investigator-assessed RECIST 1.1-defined 
progression is permitted if the subject has investigator assessed clinical benefit and is tolerating 
study drug, as specified in Section 3.1.6. Specific requirements for subjects treated with nivolumab 
and sorafenib, including dose modifications, dose delays, and treatment discontinuation criteria
are described in Sections 4.5.1 and 4.5.3, respectively.
The treatment phase ends when the subject is discontinued from study drug (see Section 3.5).
Subjects will then enter the Study Follow-Up Phase.
3.1.3
Follow Up Phase
This phase begins when the decision to discontinue study drug is made. Two follow up visits are 
required, occurring 35 days 7 days from the last dose (X01) and 80 days 7 days from X01 
(X02). Follow up visits include targeted physical examination, laboratory tests, tumor assessments, 
adverse event and concomitant medication assessments, and PRO instrument collection.
Additional details and requirements are outlined in Table 5.1-4. After completion of the first two 
follow-up visits, subjects will be followed every 3 months for survival, as outlined in Table 5.1-4.
Subjects who discontinue study drug for reasons other than radiographic disease progression will 
continue to have tumor assessments (if clinically feasible) according to the schedule in Table 5.1-
2 and Table 5.1-3 until progression.
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to baseline 
or are deemed irreversible. All adverse events will be documented for a minimum of 100 days 
after the last dose of study drug.
3.1.4
Study Duration
The duration of the study from start of randomization to final analysis of OS will be approximately 
33 months, when the requested number of death events are expected to occur. The study may be 
stopped earlier for superiority at OS interim analysis. Additional survival follow-up may continue 
for up to 5 years from the time of this analysis. The study will end once survival follow-up 
collection has concluded.
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3.1.5
Review of Safety
The subjects’ safety will be monitored on an ongoing basis as described fully in Section 6. In 
addition, a BMS medical surveillance team (MST) routinely reviews safety signals across the 
entire nivolumab program. A Data Monitoring Committee (DMC) will also be established to 
provide oversight and safety and efficacy considerations in protocol CA209459 (see Section 7.1).
3.1.6
Treatment beyond progression
Accumulating clinical evidence indicates some subjects treated with immune system stimulating 
agents may develop disease progression by conventional response criteria before demonstrating 
clinical objective responses and/or stable disease (see Section 1.2.6). This phenomenon was 
observed in the Phase I study of nivolumab, CA209003 and confirmed in multiple phase 3 studies 
(ie, lung CA20901745; melanoma CA20903747, CA20906647, and CA20906748). Two hypotheses 
explain this phenomenon. First, enhanced inflammation within tumors could lead to an increase in 
tumor size which would appear as enlarged index lesions and as newly visible small non-index 
lesions. Over time, both the malignant and inflammatory portions of the mass may then decrease 
leading to overt signs of clinical improvement. Alternatively, in some individuals, the kinetics of 
tumor growth may initially outpace anti-tumor immune activity. With sufficient time, the anti-
tumor activity will dominate and become clinically apparent. 
Similarly there are data to suggest that sorafenib administration beyond first radiological PD could 
continuously suppress HCC growth and may have survival benefit (See Section 1.2.6.2).  
Therefore, subjects will be allowed to continue study therapy after an initial investigator-assessed 
RECIST 1.1-defined progression (Appendix 1) as long as they meet the following criteria:

Investigator assessed clinical benefit, and

Subject is tolerating the study drug (nivolumab or sorafenib)
These criteria aim to ensure the risk/benefit for continuing treatment will continue to favor the 
subjects. The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. Palliative 
local therapy for isolated lesions may be permitted if the patient is considered to have progressed 
and is discussed with the BMS Medical Monitor. All decisions to continue treatment beyond initial 
progression must be discussed with the BMS Medical Monitor and documented in the study 
records. Subjects will be re-consented with an ICF describing any reasonably foreseeable risks or 
discomforts.
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden from time of initial progression (including all 
target lesions and new measurable lesions). New lesions are considered measurable if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a short axis of 
at least 15 mm). Any new lesion considered non-measurable may become measurable and 
therefore included in the tumor burden measurement if the longest diameter increases to at least 
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10 mm (except for pathological lymph nodes, which must have an increase in short axis to at least 
15 mm). 
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.
3.2
Post-Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS supplied study drug if any of the following occur: a) the marketing application is rejected 
by responsible health authority; b) the study is terminated due to safety concerns; c) the subject 
can obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
c) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has 
not been treated). If re-enrolled, the subject must be re-consented 
2. Target Population
a) Subjects with advanced hepatocellular carcinoma
i)
disease not eligible for curative surgical and/or locoregional therapies, OR
ii) progressive disease after surgical and /or locoregional therapies
Note: Surgical and/or locoregional therapy to reduce overall tumor burden prior to study 
entry is not allowed.
b) No prior systemic therapy for hepatocellular carcinoma
c) Histologic confirmation of hepatocellular carcinoma.
i)
Subjects 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.
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ii) Tumor tissue (formalin-fixed, paraffin embedded archival or recent acquisition) must 
be received by the central vendor (1 block or 15 unstained slides) for correlative studies 
outlined in Section 5.6.1 in order to conduct the randomization call in the IVRS (the 
tissue submitted will be assessed for quality with a H&E stain and only those subjects 
who have meet tissue quality thresholds can be randomized). If archived samples are 
not available, subjects must consent to a pre-treatment fresh biopsy as a condition of 
protocol participation. (Note: Fine needle aspiration (FNA) and bone metastases
samples are not acceptable for submission).
d) At least one RECIST 1.1 measurable untreated lesion. All subjects must have at least one 
previously untreated, unidimensionally measurable lesion by contrast-enhanced spiral 
computed tomography (CT) 10 mm or contrast enhanced dynamic magnetic resonance 
imaging (MRI) scan 10 mm (malignant lymph nodes must be 15 mm on short axis) 
(additional details are included in Appendix 1). 
i)
The lesion can be accurately measured uni-dimensionally according to RECIST 1.1 
criteria
ii) The lesion has not been previously treated with surgery, radiotherapy, and/or 
locoregional therapy (eg: radiofrequency ablation [RFA], percutaneous ethanol [PEI] 
or acetic acid injection [PAI], cryoablation, high-intensity focused ultrasound [HIFU], 
transarterial chemoembolization [TACE], transarterial embolization [TAE], etc.)
e) For subjects who progressed after locoregional therapy, the locoregional procedure must 
have been completed at least 4 weeks prior to the baseline scan. In addition, all acute toxic 
effects of the locoregional procedure must have resolved to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Grade 1.
f)
Cirrhotic status of Child-Pugh Class A (Appendix 2)
g) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. See 
Appendix 3 for ECOG Performance Status scale
h) Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, or 
HCV-HCC defined as follows:
i)
HBV-HCC:  Resolved HBV infection (as evidenced by detectable HBV surface 
antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable 
HBV surface antigen) or Chronic HBV infection (as evidenced by detectable HBV 
surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV 
DNA < 100 IU/mL and must be on antiviral therapy.
ii) HCV-HCC:  Active or resolved HCV infection as evidenced by detectable HCV RNA 
or antibody
i)
Screening laboratory values must meet the following criteria, without continuous 
supportive treatment such as growth factor administration, blood transfusion, coagulation 
factors and/or platelet transfusion, or albumin transfusion, and should be obtained within 
14 days prior to randomization)
i)
Adequate hematologic function:
(1) WBC 2000/μL
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(2) Neutrophils 1500/μL
(3) Platelets 60 x 103/μL 
(4) Hemoglobin 8.5 g/dL
ii) Prothrombin time (PT)-international normalized ratio (INR) 2.3 or Prothrombin time 
(PT) 6 seconds above control
iii) Adequate hepatic function as documented by:
(1) serum albumin 2.8 g/dL
(2) total bilirubin 3 mg/dl, and 
(3) AST 5 times the institutional upper limits of normal 
(4) ALT 5 times the institutional upper limits of normal
iv) Adequate renal function with a serum creatinine of < 1.5x ULN or a creatinine 
clearance > 50 mL/min (Cockcroft-Gault formula)
j)
Adequate cardiac function with a left ventricular ejection fraction (LVEF) > 50% as 
measured by 2-D echocardiography
3. Age and Reproductive Status
a) Males and Females, ages 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception as indicated in the informed consent form, for the duration of 
treatment with study drug(s) [nivolumab or sorafenib] plus approximately 5 half-lives of 
the study drug(s) [nivolumab or sorafenib] plus 30 days (duration of ovulatory cycle):
i)
Subjects randomized to nivolumab: total of 5 months post-treatment completion
ii) Subjects randomized to sorafenib: total of 40 days post-treatment completion
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception as indicated in the informed consent form, for the duration of 
treatment with study drug (s) [nivolumab or sorafenib] plus approximately 5 half-lives of 
the study drug(s) [nivolumab or sorafenib] plus 90 days (duration of sperm turnover):
i)
Subjects randomized to nivolumab: total of 7 months post-treatment completion
ii) Subjects randomized to sorafenib: total of 100 days post-treatment completion
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
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3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
b) Prior liver transplant
c) History of hepatic encephalopathy
d) 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 current 
ascites requiring treatment
e) Evidence of portal hypertension with bleeding esophageal or gastric varices within the past 
6 months
f)
Active brain metastases or leptomeningeal metastases. Subjects with treated brain 
metastases are eligible if the following criteria are fulfilled: 
i)
The brain lesions have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for at least 4 weeks after treatment is complete and within 28 
days prior to randomization. (If an MRI is contraindicated, a CT scan is acceptable after 
discussion with the study Medical Monitor.)
ii) There is no requirement for immunosuppressive doses of corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration
iii) The case is discussed with the study Medical Monitor
2. Medical History and Concurrent Diseases
a) Infections:
i)
Active co-infection with:
(1) Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV 
DNA and HCV RNA, OR
(2) Hepatitis D infection in subjects with hepatitis B
ii) Subjects with a history of coinfection with both hepatitis B and C, including, but not 
limited to:
(1) HBV DNA positive or HBV surface antigen positive subjects with detectable HCV 
antibody, OR
(2) HCV RNA positive subjects with resolved HBV infection as evidenced by 
detectable HBV surface antibody, detectable HBV core antibody, undetectable 
HBV DNA, and undetectable HBV surface antigen OR 
(3) Any positive test for HBV excluding HBV surface antibody indicating chronic or 
resolved HBV infection (positive HBV core antibody, positive HBV surface 
antigen, or detectable HBV DNA) and any positive test for HCV indicating chronic 
or resolved infection (positive HCV antibody or detectable HCV RNA)
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iii) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)
iv) Active bacterial or fungal infections requiring systemic treatment within 7 days prior 
to study drug dosing 
b) Interstitial lung disease that is symptomatic or may interfere with the detection and 
management of suspected drug-related pulmonary toxicity
c) History of active cardiac disease as evidenced by the following:
i)
Uncontrolled hypertension which is defined as systolic blood pressure > 150 mmHg or 
diastolic blood pressure > 90 mmHg despite optimal medical management
ii) Congestive heart failure NYHA (New York Heart Association) class > 2 (Appendix 4)
iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial 
infarction < 6 months prior to study entry
iv) Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or 
digoxin
v) Valvular heart disease > CTCAE Grade 2
vi) QTc (Fridericia) > 450 msec on two consecutive ECGs (baseline ECG should be 
repeated if QTc is found to be > 450 msec)
d) Thrombotic or embolic events (except HCC tumor thrombus) within the past 6 months, 
such as cerebrovascular accident (including transient ischemic attacks), pulmonary 
embolism
e) Any other hemorrhage/bleeding event CTCAE Grade 3 within 8 weeks except for 
esophageal or gastric varices (Exclusion criteria 1.e.) 
f)
History of non-healing wounds or ulcers, within 3 months of study entry. Bone fractures at 
risk of bleeding, within 3 months of study entry, are also excluded.
g) Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior 
to start of investigational product administration or those who receive minor surgical 
procedures (eg, core biopsy) within 1 week prior to the start of investigational product.
h) Prior organ allograft or allogeneic bone marrow transplantation
i)
Subjects who are unable to swallow tablets, requiring intravenous alimentation, 
malabsorption syndrome, or any conditions affecting gastrointestinal absorption; or active 
peptic ulcer disease.
j)
Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the 
normal range with medication.
k) Subjects with any active, known, or suspected autoimmune disease, with the following 
exceptions:
i)
Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy are 
permitted to enroll.
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ii) Subjects with suspected autoimmune thyroid disorders may be enrolled if they are 
currently euthyroid or with residual hypothyroidism requiring only hormone 
replacement.
iii) Subjects with psoriasis requiring systemic therapy must be excluded from enrollment
l)
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.
m) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 
14 days of study administration. Inhaled or topical steroids and adrenal replacement doses 
> 10 mg/day prednisone equivalents are permitted in the absence of active autoimmmune 
disease, with the exception of criteria 1f, ii
n) Any serious or uncontrolled medical disorder that in the opinion of the investigator may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
3. Prior and Current Therapies
a) Subjects with history of life-threatening toxicity related to prior immune therapy (eg. with 
anti-CTLA-4 or anti-PD-1/PD-L1 treatment) except those that are unlikely to re-occur with 
standard countermeasures (eg. Hormone replacement after adrenal crisis); VEGF 
inhibitors, Raf-kinase inhibitors, MEK inhibitors, Farnesyl transferase inhibitors or other 
immunotherapy agents for HCC
b) Prior use of systemic investigational agents for HCC
c) Treatment with strong CYP3A4 inducers within 7 days of study entry, including rifampin 
(and its analogues) or St. John’s wort.
d) Current anticoagulation therapy
e) Treatment with anti-platelet therapy (aspirin at dose 300 mg/day, clopidogrel at dose 
75 mg/day)
f)
Radiotherapy within 4 weeks prior to start of study drug. Palliative radiotherapy for 
symptomatic control is acceptable (if completed at least 2 weeks prior to study drug 
administration) and no additional radiotherapy for the same lesion is planned.
4. Physical and Laboratory Test Findings
a) Positive pregnancy test
b) Baseline serum sodium < 130 mmol/L 
c) Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to 
restore the serum potassium above this level prior to study entry)
5. Allergies and Adverse Drug Reaction
a) Known or suspected allergy to nivolumab or sorafenib or study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody
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6. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
7. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 
40mIU/mL to confirm menopause.
*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 judgment
in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
3.4
Concomitant Treatments
3.4.1
Permitted Therapy
3.4.1.1
Antiviral therapy
Subjects on antiviral therapy for hepatitis B or C should continue the treatment during the study. 
Changing of dosage and regimens of antiviral therapy will be at the discretion of the investigator.
If a subject 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 subject has documented virologic 
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breakthrough due to antiviral resistance, then this should be managed based on standardized 
regional guidelines and treatment with nivolumab temporarily held. The subject may resume 
treatment with nivolumab once virologic control is reestablished (HBV DNA < 100 IU/mL).
For any subject who continues to be HCV RNA positive after receiving nivolumab, current 
guidelines for management of chronic HCV infection, including those from AASLD, EASL, or 
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.
3.4.1.2
Steroids
For subjects randomized to nivolumab, steroid therapy is permitted as follows:

Topical, ocular, intranasal, intra-articular, and inhalational corticosteroids (with minimal 
systemic absorption).

Adrenal replacement steroid doses including doses > 10 mg daily prednisone equivalent in the 
absence of active immune disease.

Immunosuppressive doses (eg, prednisone > 10 mg/day or equivalent) in the context of treating 
adverse events. 

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).
Steroid restrictions do not apply to subjects randomized to sorafenib treatment.
3.4.1.3
Vaccines
The use of any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio 
and measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose of 
nivolumab is prohibited.
3.4.1.4
Other Systemic Therapy

Hormone replacement therapy - subjects may continue to receive hormonal replacement 
therapy if initiated prior to randomization.

Biphosphonates and RANK-L inhibitors

For subjects randomized to nivolumab, these are allowed for bone metastases

For subjects randomized to sorafenib, please follow local guidelines when combining 
biphosphonates and RANK-L inhibitors with anti-angiogenesis agents49,50,51
3.4.1.5
Palliative Local Therapy
Palliative local therapy for clinically symptomatic tumor sites (eg, bone pain), including palliative 
(limited-field) radiation therapy and palliative surgical resection may be considered if the 
following criteria are met:
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
The subject is considered to have progressed at the time of palliative local therapy and meets 
the criteria to continue with treatment beyond progression. (Section 3.1.6)

The lesion for palliative local therapy is a non-target lesion.

The case is discussed with the BMS Medical Monitor prior to the initiation of palliative local 
therapy.
The potential for overlapping toxicities with radiotherapy and nivolumab currently is not known; 
however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and nivolumab 
have not been formally evaluated, in cases where palliative radiotherapy is required for a tumor 
lesion, then nivolumab should be withheld for at least 1 week before, during, and 1 week after 
radiation. Subjects should be closely monitored for any potential toxicity during and after receiving 
radiotherapy, and AEs should resolve to Grade < 1 prior to resuming nivolumab.
Tumor lesions requiring palliative local therapy should be evaluated for objective evidence of 
disease progression prior to the initiation of such therapy. 
Palliative therapy must be clearly documented in the source records and electronic case report 
form. Details in the source records should include: dates of treatment, anatomical site, dose 
administered and fractionation schedule, and adverse events. 
3.4.2
Prohibited and/or Restricted Treatments
3.4.2.1
All subjects
The following are prohibited for all subjects during the study:

Loco-regional therapy for HCC

Any concurrent antineoplastic therapy such as chemotherapy, molecular targeted therapy, 
hormonal therapy, immunotherapy, botanical formulations with an approved indication for 
cancer treatment (eg, traditional Chinese medicines) radiation therapy (except for palliative 
radiation therapy described in Section 3.4.1.5)

Immunosuppressive agents (except to treat a drug-related adverse event)

Investigational agents for the treatment of cancer
Supportive care for disease-related symptoms may be offered to all subjects on the trial.
3.4.2.2
Subjects randomized to nivolumab treatment
Systemic corticosteroids > 10 mg daily prednisone equivalent are not permitted, except as stated 
in Section 3.4.1.2 or to treat a drug-related adverse event.
3.4.2.3
Subjects randomized to sorafenib treatment

Medications contraindicated with sorafenib treatment (refer to the package insert, summary of 
product characteristics (SmPC) or similar document)52
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3.4.3
Other Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, allergy 
history, diabetic history and renal status), the appropriate imaging modality and contrast regimen 
for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with 
severe 
renal 
insufficiency 
(ie, 
estimated 
glomerular 
filtration 
rate 
(eGFR) 
< 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Specific criteria for discontinuation of study drugs are outlined for nivolumab in 
Section 4.5.1.5 and for sorafenib in Section 4.5.3.3.

Disease progression unless the subject is eligible for treatment beyond progression 
(Section 4.5.1.6 for nivolumab and Section 4.5.3.4 for sorafenib)
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
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If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post-Study Drug Study Follow up
In this study, overall survival is the primary endpoint. Post-study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drug must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
Subjects who discontinue study drug for reasons other than disease progression will continue to 
have tumor assessments (if clinically feasible) according to the schedule in Table 5.1-2 and Table 
5.1-3 until progression.  
BMS may request that survival data be collected on all treated subjects outside of the protocol 
window (Table 5.1-4). At the time of this request, each subject will be contacted to determine their 
survival status unless the subject has withdrawn consent for all contacts or is lost to follow up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
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lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA209459: 
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging/ Appearance
Storage Conditions
(per label)
Nivolumab Solution for 
Injectiona
100 mg (10 mg/mL)
IP
Open Label
10 mL per vial (5 or 10 vials/carton)
Clear to opalescent colorless to pale 
yellow liquid. May contain particles
2 to 8C. Protect from 
light and freezing
Sorafenib Tabletsb  
200 mg
IP
Open Label
Wallet/blister card containing 28 
film-coated tablets. 
Red and round with the Bayer cross 
on one side and “200” on the other 
side. 
Store at 15°C to 25°C
a May be labeled as either BMS-936558-01 or Nivolumab
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC)
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational products are: BMS-936558 (nivolumab) and Sorafenib.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information for BMS-936558 
(nivolumab).
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.3.1
Nivolumab (BMS-936558)
Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets 
for complete storage, handling, dispensing, and infusion information for BMS-936558 
(nivolumab).
BMS-936558 (nivolumab) is to be administered as an IV infusion over 30 minutes. At the end of 
the infusion, flush the line with a sufficient quantity of dextrose or normal saline.
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4.3.2
Sorafenib
Please refer to the SmPC for complete storage, handling and dispensing information for 
sorafenib52.
4.4
Method of Assigning Subject Identification
CA209459 is a randomized, open-label study. After the subject’s initial eligibility is established 
and informed consent has been obtained, the subject must be enrolled into the study by calling an 
interactive voice response system (IVRS) to obtain the subject number. Every subject that signs 
the informed consent form must be assigned a subject number in IVRS. Specific instructions for 
using IVRS will be provided to the investigational site in a separate document. 
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth

Viral status at time of enrollment, if known 
Once enrolled in IVRS, enrolled subjects that have met all eligibility criteria will be ready to be 
randomized through IVRS. The following information is required for site entry in the IVRS prior 
to subject randomization:

Subject number

Date of birth

Vascular invasion and/or extrahepatic spread (present or absent)
Additional information will be automatically transferred to the IVRS by the Central Lab and must
be available prior to subject randomization:

Etiology (HCV vs non-HCV) 

Confirmation of tumor tissue sample receipt and acceptability at Central Laboratory
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to nivolumab or sorafenib, 
stratified by the following factors:

Etiology - HCV vs non-HCV

Vascular invasion and/or extrahepatic spread (present or absent)

Geography (Asia vs. Non-Asia)
The randomization procedures will be carried out via permuted blocks within each stratum. The 
exact procedures for using the IVRS will be detailed in the IVRS manual.
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4.5
Selection and Timing of Dose for Each Subject
Dosing schedules for both arms are detailed in Table 4.5-1. The first dose of study drug is to be 
administered within 3 days of randomization. Treatment dosing details are described separately 
for each Arm below. All subjects will be monitored continuously for AEs while on study treatment. 
Treatment modifications (eg, dose delay, reduction, or discontinuation) will be based on specific 
laboratory and adverse event criteria, as described in Sections 4.5.1 and 4.5.3.
Table 4.5-1:
Selection and Timing of Dose for Each Subject
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Nivolumab
240 mg
Every 2 weeks
30 minute 
intravenous (IV) 
administration
Until progression, 
unacceptable 
toxicity, or 
discontinuation 
from study
Sorafenib
400 mg (2 x 200 mg 
tablets)
Twice daily (BID)
PO
Until progression, 
unacceptable 
toxicity, or 
discontinuation 
from study
4.5.1
Nivolumab Dosing 
4.5.1.1
Nivolumab Dose and Schedule 
Subjects randomized to nivolumab will receive treatment with nivolumab at a dose of 240 mg as 
a 30-minute IV infusion, on Day 1 of each treatment cycle every 2 weeks, until progression, 
unacceptable toxicity, withdrawal of consent, or study end, whichever occurs first.
Subjects may be dosed no less than 12 days between doses. Subjects may be dosed up to 3 days 
after the scheduled date if necessary. A dose given more than 3 days after the intended dose date 
will be considered a delay. Subsequent dosing should be based on the actual date of administration 
of the previous dose of drug.
4.5.1.2
Dose Modifications for Nivolumab 
No dose modifications for nivolumab are allowed.
4.5.1.3
Dose Delay Criteria for Nivolumab
Nivolumab administration should be delayed for the following:

Any Grade 2 non-skin drug-related adverse event, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Any Grade 3 skin drug-related adverse event

Any Grade 3 drug-related laboratory abnormality with the following exceptions:
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
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay. 

Dose delay for changes in AST or ALT as follows:

If a subject has a baseline AST or ALT that is within normal limits, delay dosing for drug-
related Grade 2 toxicity (2 grade shift)

If a subject has baseline AST or ALT within the Grade 1 toxicity range, delay dosing for 
drug-related Grade 3 toxicity (2 grade shift)

If a subject has baseline AST or ALT within the Grade 2 toxicity range, delay dosing for a
two-fold drug-related increase in AST or ALT or for AST or ALT values 8x ULN 
(whichever is lower).

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated. It is recommended to monitor elevations in AST or ALT approximately every 
3 days till levels peak or begin to decline. Nivolumab dosing can be resumed when re-treatment 
criteria are met (Section 4.5.1.4).
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed.
4.5.1.4
Criteria to Resume Dosing for Nivolumab
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade 1 
or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue.

Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.

Subjects with baseline Grade 1 AST, ALT, or total bilirubin who require dose delays for 
reasons other than a drug-related hepatic event may resume treatment in the presence of Grade 
2 AST, ALT, or total bilirubin.

Subjects who require dose delays for drug-related elevations in AST, ALT, or total bilirubin 
may resume treatment when these values have returned to their baseline CTCAE Grade or 
normal, provided the criteria for permanent discontinuation are not met (Section 4.5.1.5).

Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. If treatment is delayed > 6 weeks from the last dose, the subject must be 
permanently discontinued from study therapy, except as specified in Section 4.5.1.5 and 
Section 4.5.1.6. Please see also Appendix 5 (Algorithms for Management of Side Effects) for 
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guidance on appropriate management and follow-up of adverse events. For hepatic AE 
management, see Section 4.5.2.2.
4.5.1.5
Treatment Discontinuation Criteria for Nivolumab
Treatment with nivolumab should be permanently discontinued for the following

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment.

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.

Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation

Hepatotoxicity as evidenced by the following:

AST or ALT > 10 x ULN for > 2 weeks,

AST or ALT > 15 x ULN irrespective of duration,

Total bilirubin > 5 x ULN for those with normal total bilirubin at entry or > 8 x ULN for 
subjects with elevated bilirubin at study entry, irrespective of duration.

Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:

Grade 4 neutropenia < 7 days

Grade 4 lymphopenia or leukopenia

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. The BMS Medical Monitor should be consulted for 
Grade 4 amylase or lipase abnormalities.

Isolated Grade 4 electrolyte imbalances or abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation and appropriate management 
within 72 hours of their onset. 

Grade 4 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation.

Any dosing delay lasting > 6 weeks with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events
are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 
weeks, the BMS medical monitor must be consulted. Tumor assessments should continue 
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as per protocol even if dosing is delayed. Periodic study visits to assess safety and 
laboratory studies should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing delays.

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a subject with a dosing delay lasting > 6 weeks, the BMS Medical Monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays. 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.

Investigator assessed disease progression according to RECIST 1.1 (unless subject meets 
criteria as specified in Section 4.5.1.6)
Tumor assessments for all subjects should continue as per protocol even if study drug dosing is
discontinued. 
4.5.1.6
Treatment Beyond Progression for Nivolumab 
As described in Section 3.1.6 accumulating evidence indicates a minority of subjects treated with 
immunotherapy may derive clinical benefit despite initial evidence of progressive disease.
Subjects will be permitted to continue with nivolumab treatment beyond initial RECIST 1.1-
defined progressive disease as long as they meet the following criteria:

Investigator-assessed clinical benefit

Subject is tolerating nivolumab treatment

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Subject provides written informed consent prior to receiving any additional nivolumab 
treatment, using an ICF describing any reasonably foreseeable risks or discomforts, or other 
alternative treatment options.
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The decision to 
continue treatment beyond initial investigator-assessed progression should be discussed with the 
BMS Medical Monitor and documented in the study records.
If the decision is taken to continue nivolumab treatment beyond progression, the subject will 
remain on the trial and continue to be treated and monitored according to the Time and Events 
Schedule on Table 5.1-2. 
Subjects should discontinue study therapy upon further evidence of further progression, defined 
as an additional 10% or greater increase in tumor burden SLD (sum of longest diameters) from 
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time of initial progression (including all target lesions and new measurable lesions). New lesions 
are considered measurable if the longest diameter is at least 10 mm (except for pathological lymph 
nodes, which must have a short axis of at least 15 mm). Any new lesion considered non-measurable 
may become measurable and therefore included in the tumor burden measurement if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes, which must have an 
increase in short axis to at least 15 mm). Nivolumab treatment should be discontinued permanently 
upon documentation of further progression.
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event. 
For subjects discontinuing treatment because of global deterioration of health status without 
objective evidence of disease progression at that time, progression should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
(ie, radiographic confirmation) even after discontinuation of treatment.
 
 
 
 
 
 
 
 
 
 
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4.5.3
Sorafenib Dosing 
The criteria presented in this section are based on the sorafenib Summary of Product 
Characteristics (SmPC).52
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nivolumab
4.5.3.1
Sorafenib Dose and Schedule
Subjects randomized to sorafenib will receive treatment with sorafenib. Sorafenib (Nexavar®) will 
be self-administered orally at the recommended dose of 400 mg sorafenib (two tablets of 200 mg) 
twice daily without food or with a low or moderate fat meal. If the subject intends to have a high-fat 
meal, sorafenib tablets should be taken at least 1 hour before or 2 hours after the meal. The tablets 
should be swallowed with a glass of water. Refer to the sorafenib SmPC for additional details52.
Treatment will continue until progression, unacceptable toxicity, withdrawal of consent, or study 
end, whichever occurs first. Provisions for treatment beyond progression are detailed in 
Section 4.5.3.4.
Trained personnel will dispense a 2 week supply of sorafenib to subjects on Day 1 of each new 
cycle (every two weeks). Each time study drug is dispensed, compliance will be evaluated and 
encouraged. Treatment compliance will also be monitored by drug accountability and recorded in 
the subject’s medical record and eCRF. If the number of tablets returned does not agree with the 
expected number, the subject should be counseled and proper dosing reinforced.
Missed doses should be taken as soon as the subject remembers. However, if it is almost time for 
the next dose, the missed dose should be skipped and the subject should take his/her next dose as 
scheduled. A double dose should not be administered to make up for missed individual doses.
Refer to the sorafenib SmPC for additional details.52
Subjects should be monitored continuously for adverse events while receiving study therapy and 
will be instructed to notify their physician immediately for any and all adverse events.
Management of suspected adverse drug reactions may require temporary interruption and/or dose 
reduction of sorafenib therapy (Section 4.5.3.3). Dose modifications or delays may occur in the 
setting of a lower grade adverse event if the Investigator, in consultation with the Medical 
Monitor/sponsor, believes that it is in the interest of a subject’s safety.
4.5.3.2
Dose Reductions for Sorafenib 
When dose reduction is necessary during the treatment of HCC, the sorafenib dose should initially
be reduced to two tablets of 200 mg sorafenib once daily. For further dose reductions, refer to the 
sorafenib SmPC or locally approved product label for additional details.52
4.5.3.3
Treatment Interruption or Discontinuation Criteria for Sorafenib 
The decision to interrupt or discontinue sorafenib should follow local standards of care as guided 
by the locally approved product label or applicable SmPC.52
For any dose interruptions, re-initiation of study drugs therapy may be delayed for a maximum of 
30 days to allow recovery from any adverse event. In exceptional cases where subjects are 
responding, re-initiation of therapy after missing > 30 consecutive days of treatment may be done 
on a case by case basis after confirmation with the BMS medical monitor. 
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed.
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nivolumab
4.5.3.4
Treatment Beyond Progression for Sorafenib
Subjects will be permitted to continue with sorafenib treatment beyond initial RECIST 1.1- defined 
progressive disease as long as they meet the following criteria:

Investigator-assessed clinical benefit

Subject is tolerating sorafenib treatment

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Subject provides written informed consent, at the next clinic visit, prior to receiving any 
additional sorafenib treatment, using an ICF describing any reasonably foreseeable risks or 
discomforts, or other alternative treatment options.
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The decision to 
continue treatment beyond initial investigator-assessed progression should be discussed with the 
BMS Medical Monitor and documented in the study records.
If the decision is taken to continue sorafenib treatment beyond progression, the subject will remain 
on the trial and continue to be treated and monitored according to the Time and Events Schedule 
on Table 5.1-3.
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden (SLD: sum of the longest diameters) from time 
of initial progression (including all target lesions and new measurable lesions). New lesions are 
considered measurable if the longest diameter is at least 10 mm (except for pathological lymph 
nodes, which must have a short axis of at least 15 mm). Any new lesion considered non-measurable 
may become measurable and therefore included in the tumor burden measurement if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes, which must have an 
increase in short axis to at least 15 mm). Sorafenib treatment should be discontinued permanently 
upon documentation of further progression.
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.
4.5.3.5
Management of Sorafenib Adverse Events 
Toxicities attributable to sorafenib should be managed according to the locally approved product 
label or applicable SmPC.52 Dose reductions are discussed in Section 4.5.3.2.
4.6
Blinding/Unblinding
Not applicable
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nivolumab
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable
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nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209459)
Procedure
Pre-Treatment 
(Baseline)
Notes
Eligibility Assessments
Informed Consent
X
Original informed consent in screening for protocol participation. Study allows for re-
enrollment of a subject that has discontinued the study as a pre-treatment failure. If re-
enrolled, the subject must be re-consented and assigned a new subject number from IVRS.
Inclusion/Exclusion Criteria
X
Assessed during screening period and (re-enrollment if applicable).
Medical History
X
Child-Pugh Score
X
Safety Assessments
Physical examination
X
Within 14 days prior to first dose
Physical Measurements
X
Height and Weight. Within 14 days prior to first dose
ECOG Assessment
X
Vital Signs
X
Including BP, HR, temperature, respiratory rate. Obtain vital signs at the screening visit 
and within 72 hours prior to first dose.
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Concomitant Medication Collection
X
Within 14 days prior to first dose
12 lead ECG
X
Within 14 days prior to first dose
2D Echocardiogram
X
2-D echocardiogram, performed locally, for valve and LVEF evaluation is to be done 
within 14 days prior to first dose and as clinically indicated.
Laboratory Tests
X
Performed locally, within 14 days prior to randomization to include CBC w/differential and 
platelet count, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), Alpha fetoprotein 
(AFP), BUN or serum urea level, albumin, creatinine, Ca+, Mg++, Na+, K+, Cl-, LDH, 
amylase, lipase, Glucose, TSH, Free T4, Free T3
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Table 5.1-1:
Screening Procedural Outline (CA209459)
Procedure
Pre-Treatment 
(Baseline)
Notes
Serology for Hep B, Hep C, Hep D
X
HepB surface antigen, HepB surface antibody, Hep B Core antibody, HepB DNA Viral 
load (PCR), Hep C viral load (PCR) and Hep C Antibody, Hep D antibody.
Testing 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 lab testing resumes.  Local testing requires approval 
from BMS along with supporting local laboratory documentation.
Pregnancy test (WOCBP only) 
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG ) 
to be done at screening visit and repeated within 24 hours of first dose of study therapy
SNP Sample
X
Urinalysis
X
Coagulation profile
X
Include International Normalized Ratio (INR). If INR cannot be done by the local 
laboratory, then Prothrombin Time (PT) may be provided instead
Efficacy Assessments
Baseline tumor imaging assessment
X
CT of the chest, CT or MRI of abdomen, and pelvis with IV contrast, including required 
tri-phasic CT of the liver should be performed at baseline (must be performed within 28
days prior to randomization). CT chest without contrast or MRI abdomen/pelvis is 
acceptable if CT is contraindicated. Modality (CT or MRI) used at baseline should be used 
across all imaging timepoints. Bone scan is required if clinically indicated.
MRI brain within 28 days prior to randomization for subjects with a history of brain 
metastasis
Other Assessments
Tumor tissue sample (biopsy)
X
A formalin-fixed, paraffin-embedded tumor tissue (FFPET) block (preferred) or minimum 
of 15 unstained slides of tumor tissue (archival or recent) for biomarker evaluation must be 
obtained. The tissue submitted will be assessed for quality with a H&E stain (100 tumor 
cells) and only those subjects who have met tissue quality thresholds can be randomized.
Extent of Disease & Risk Factors
X
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BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209459)
Procedure
Pre-Treatment 
(Baseline)
Notes
Clinical Drug Supplies
Register subject in IVRS
X
A call must be made to the IVRS to register subject after signing informed consent.
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nivolumab
Table 5.1-2:
On treatment Period Procedural Outline - Nivolumab (CA209459)
Procedure
During Treatment
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, D1), 
Cycle 2 - Day 1 (C2 D1), 
(and every cycle 
thereafter)
Notes
Safety Assessments
Targeted Physical examination
X
Targeted examination must include at a minimum the following body systems, 
performed within 72 hours prior to dosing:
Cardiovascular
Gastrointestinal
Pulmonary
Skin
Physical Measurements
X
Weight and ECOG performance status within 72 hrs prior to dosing.
Child-Pugh Score
X
Vital Signs
X
Including BP, HR, temperature, and respiratory rate. Obtain vital signs within 72 
hrs prior to dosing.
Adverse Events Assessment
X
Review of Concomitant Medication
X
Laboratory Tests
X
Performed locally within 72 hours prior to dosing to include CBC w/differential 
and platelet count, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), alpha 
fetoprotein (AFP), BUN or serum urea level, albumin, creatinine, Ca+, Mg++, 
Na+, K+, Cl-, LDH, amylase, lipase.
In addition, the following tests every third cycle (3, 6, 9, etc.): glucose, TSH 
(Reflex to free T3 and free T4 if TSH abnormal. Total T3/T4 are acceptable if free 
T3/T4 are not available.)
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BMS-936558
nivolumab
Table 5.1-2:
On treatment Period Procedural Outline - Nivolumab (CA209459)
Procedure
During Treatment
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, D1), 
Cycle 2 - Day 1 (C2 D1), 
(and every cycle 
thereafter)
Notes
Testing to be completed at the Central Laboratory.
See Table 5.6.2-1.
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 monthly regardless 
of dosing schedule
Coagulation profile
X
Include International Normalized Ratio (INR). If INR cannot be done by the local 
laboratory, then Prothrombin Time (PT) may be provided instead.
Efficacy Assessments
Tumor imaging assessment
See note
Tumor imaging assessments will occur 8 weeks from the date of randomization
(+/-1 wk), then every 8 weeks (+/- 1 wk) thereafter up to 48 weeks, then it will be 
every 12 weeks (+/- 1 week) until disease progression or treatment is discontinued 
(whichever occurs later).
CT of the chest, CT or MRI of abdomen, and pelvis with IV contrast, including 
required tri-phasic CT of the liver should be performed. CT chest without contrast 
or MRI abdomen/pelvis is acceptable if CT is contraindicated. Modality (CT or 
MRI) used at baseline should be used across all imaging timepoints. Bone scan is 
required if clinically indicated.
Subjects with a history of brain metastasis may have surveillance MRI 
approximately every 12 weeks from the date of first dose, or sooner if clinically 
indicated
Other Assessments
PK/IMG sampling
X
PK and IMG samples should be collected at predose C1D1, C3D1, C8D1, Day 1 
of every 8th cycle thereafter. See Section 5.5.1
Serum sample (soluble factors)
See Note 
See Table 5.6.2-1 for details.
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CA209459
BMS-936558
nivolumab
Table 5.1-2:
On treatment Period Procedural Outline - Nivolumab (CA209459)
Procedure
During Treatment
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, D1), 
Cycle 2 - Day 1 (C2 D1), 
(and every cycle 
thereafter)
Notes
Peripheral blood mononuclear cells 
(PBMCs) and myeloid derived suppressor 
cells (MDSCs)
Cycle 1, Day 1
See sections 5.6.2.3 and 5.6.2.4, and Table 5.6.2-1 for details
Outcomes Research Assessment
Questionnaires should be administered at the start of the visit, before the subject 
sees the physician and before any study related procedures are done (with the 
exception of procedures completed 72 hours prior to visit).
EQ-5D-3L
See Note
To be completed on Cycle 1, Day 1, then every other cycle thereafter 
(Cycle 3, Day 1; Cycle 5, Day 1, etc.)
FACT-Hep
See Note
To be completed on Cycle 1, Day 1, then every other cycle thereafter 
Cycle 3, Day 1; Cycle 5, Day 1, etc.)
Health care resource use (HCRU)
X
Clinical Drug Supplies
Contact central randomization IVRS / 
Dispense Study Drug
X
Within 3 days from randomization, the subject must receive the first dose of study 
medication.
Subjects may be dosed no less than 12 days between doses.
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CA209459
BMS-936558
nivolumab
Table 5.1-3:
On treatment Period Procedural Outline - Sorafenib (CA209459)
Procedure
During Treatment:
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, 
D1), Cycle 2 - Day 1 (C2 
D1), (and every cycle 
thereafter)
Notes
Safety Assessments
Targeted Physical examination
X
Targeted examination must include at a minimum the following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Skin
Physical Measurements
X
Weight and ECOG performance status
Child-Pugh Score
X
Vital Signs
X
Including BP, HR, temperature, and respiratory rate.
BP monitoring frequency should follow local standards of care as guided by the 
locally approved sorafenib product label or applicable SmPC.52
2D Echocardiogram
See note
2-D echocardiogram, performed locally as clinically indicated.
Adverse Events Assessment
X
Review of Concomitant Medication
X
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BMS-936558
nivolumab
Table 5.1-3:
On treatment Period Procedural Outline - Sorafenib (CA209459)
Procedure
During Treatment:
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, 
D1), Cycle 2 - Day 1 (C2 
D1), (and every cycle 
thereafter)
Notes
Laboratory Tests
See Note
Performed locally up to 72 hours prior to Day 1 (ie, day of clinic visit) of each 
cycle to include CBC w/differential and platelet count, LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase), alpha fetoprotein (AFP), BUN or serum urea 
level, albumin, creatinine, Ca+, Mg++, Na+, K+, Cl-, LDH, amylase, lipase.
In addition, the following tests every third cycle (3, 6, 9, etc.): glucose, TSH 
(Reflex to free T3 and free T4 if TSH abnormal. Total T3/T4 are acceptable if free 
T3/T4 are not available.)
Pregnancy test (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 monthly regardless 
of dosing schedule
Coagulation profile
X
Include International Normalized Ratio (INR). If INR cannot be done by the local 
laboratory, then Prothrombin Time (PT) may be provided instead.
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BMS-936558
nivolumab
Table 5.1-3:
On treatment Period Procedural Outline - Sorafenib (CA209459)
Procedure
During Treatment:
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, 
D1), Cycle 2 - Day 1 (C2 
D1), (and every cycle 
thereafter)
Notes
Efficacy Assessments
Tumor imaging assessment
See note
Tumor imaging assessments will occur 8 weeks from the date of randomization 
(+/-1 wk), then every 8 weeks (+/- 1 wk) thereafter up to 48 weeks, then it will be 
every 12 weeks (+/- 1 week) until disease progression or treatment is discontinued 
(whichever occurs later). 
CT of the chest, CT or MRI of abdomen, and pelvis with IV contrast, including 
required tri-phasic CT of the liver should be performed. CT chest without contrast 
or MRI abdomen/pelvis is acceptable if CT is contraindicated. Modality (CT or 
MRI) used at baseline should be used across all imaging timepoints. Bone scan is 
required if clinically indicated.
Subjects with a history of brain metastasis may have surveillance MRI 
approximately every 12 weeks from the date of first dose, or sooner if clinically 
indicated
Other Assessments
Serum sample (soluble factors)
See Note 
See Table 5.6.2-1 for details.
Peripheral blood mononuclear cells 
(PBMCs) and myeloid derived suppressor 
cells (MDSCs)
Cycle 1, Day 1
See Section 5.6.2.3 and Table 5.6.2-1 for details
Outcomes Research Assessment
Questionnaires should be administered at the start of the visit, before the subject 
sees the physician and before any study related procedures are done (with the 
exception of procedures completed 72 hours prior to visit).
EQ-5D-3L
See Note
To be completed on Cycle 1, Day 1, then every other cycle thereafter 
(Cycle 3, Day 1; Cycle 5, Day 1, etc.)
FACT-Hep
See Note
To be completed on Cycle 1, Day 1, then every other cycle thereafter 
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CA209459
BMS-936558
nivolumab
Table 5.1-3:
On treatment Period Procedural Outline - Sorafenib (CA209459)
Procedure
During Treatment:
(Cycle = 2 weeks)
Cycle 1 - Day 1 (C1, 
D1), Cycle 2 - Day 1 (C2 
D1), (and every cycle 
thereafter)
Notes
Cycle 3, Day 1; Cycle 5, Day 1, etc.)
Health care resource use (HCRU) 
X
Clinical Drug Supplies
Contact central randomization IVRS / 
Dispense Study Drug
X
Within 3 days from randomization, the subject must receive the first dose of study 
medication.
IVRS should be contacted at each visit for provision of 2 week supply of 
sorafenib.
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CA209459
BMS-936558
nivolumab
Table 5.1-4:
Follow-Up Procedural Outline - all subjects (CA209459)
Procedure
Follow Up, Visits 1 
and 2 
(X visits)a
Survival Follow Up 
Visits 
(Y visits)b
Notes
Safety Assessments
Targeted Physical examination
X
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Skin
Adverse Events Assessment
X
X
Review of Concomitant Medications
X
Review of Subsequent Cancer Therapy
X
X
Laboratory Tests
X
Performed locally: CBC w/differential and platelet count, 
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), 
alpha fetoprotein (AFP), BUN or serum urea level, 
albumin, creatinine, Ca+, Mg++, Na+, K+, Cl-, LDH, 
amylase, lipase, glucose, TSH (Reflex to free T3 and free 
T4 if TSH abnormal. Total T3/T4 are acceptable if free 
T3/T4 are not available.)
To be done at FU1. To be repeated at FU2 if study related 
toxicity persists.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG).
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CA209459
BMS-936558
nivolumab
Table 5.1-4:
Follow-Up Procedural Outline - all subjects (CA209459)
Procedure
Follow Up, Visits 1 
and 2 
(X visits)a
Survival Follow Up 
Visits 
(Y visits)b
Notes
Coagulation profile
X
Include International Normalized Ratio (INR). If INR 
cannot be done by the local laboratory, then Prothrombin 
Time (PT) may be provided instead
Efficacy Assessments
Tumor imaging assessment
See Note
See Note
Tumor imaging assessments during Follow Up and Survival 
Follow up is required for subjects that have discontinued 
treatment prior due to reason other than radiologic disease 
progression. 
Tumor imaging assessments will occur 8 weeks from the 
date of randomization (+/-1 wk), then every 8 weeks (+/- 1 
wk) thereafter up to 48 weeks, then it will be every 12 
weeks (+/- 1 week) until disease progression.
CT of the chest, CT or MRI of abdomen, and pelvis with IV 
contrast, including required tri-phasic CT of the liver 
should be performed. CT chest without contrast or MRI 
abdomen/pelvis is acceptable if CT is contraindicated. 
Modality (CT or MRI) used at baseline should be used 
across all imaging timepoints. Bone scan is required if 
clinically indicated.
Subjects with a history of brain metastasis may have 
surveillance MRI approximately every 12 weeks from the 
date of first dose, or sooner if clinically indicated
Other Assessments
PK/IMG sampling
X
To be collected for nivolumab subjects only.  
See Section 5.5.1
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BMS-936558
nivolumab
Table 5.1-4:
Follow-Up Procedural Outline - all subjects (CA209459)
Procedure
Follow Up, Visits 1 
and 2 
(X visits)a
Survival Follow Up 
Visits 
(Y visits)b
Notes
Outcomes Research Assessment
The EQ-5D and FACT-Hep should be administered at the 
start of the visit, before the subject sees the physician and 
before any study related procedures are done
EQ-5D-3L
X
X
EQ-5D to be assessed during clinical visit or via a phone 
for survival follow-up visits
FACT-Hep
X
X
FACT-Hep to be assessed during clinical visit or via a 
phone for survival follow-up visits
Health care resource use (HCRU)
X
Health Care Resource Use (HCRU) to be assessed during 
clinical visit
Subject Status
Survival Status
X
Every 3 months after FU 2; may be accomplished by visit 
or phone contact
a X visits occur as follows: X01 = 35 days 7 days from last dose, X02 = 80 days 7 days from X01
b S, Survival visits continue every 3 months after X visits
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5.1.1
Retesting During Screening Period
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter
is clinically relevant.
5.2
Study Materials

NCI CTCAE version 4.0

BMS-936558 (nivolumab) Investigator Brochure

Sorafenib SmPC

Pharmacy Binder

Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens

Site manual for operation of interactive voice response system, including enrollment 
worksheets

Manual for entry of local laboratory data

Pregnancy Surveillance Forms

Serious Adverse Events (or eSAE) case report forms

EQ-5D-3L and FACT-Hep questionnaires

CA209459 Imaging Manual
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include signs and symptoms, weight, height, ECOG Performance 
Status, BP, HR, temperature, respiratory rate, and should be performed within 14 days prior to first 
dose except where noted in Table 5.1-1. Concomitant medications will also be collected from 
within 14 days prior to first dose and through the follow up period (See Table 5.1-1, Table 5.1-2, 
Table 5.1-3and Table 5.1-4). Baseline laboratory assessments should be done within 14 days prior 
to randomization and include (see Table 5.1-1): 

CBC w/differential and platelet count, 

LFTs (ALT, AST, total bilirubin, alkaline phosphatase), 

alpha fetoprotein (AFP), 

BUN or serum urea level, 
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
albumin, 

creatinine, 

Ca+, 

Mg++, 

Na+, 

K+, 

Cl-, 

LDH, 

glucose, 

amylase, 

lipase, 

TSH, (Reflex to free T3 and free T4 if TSH abnormal. Total T3/T4 are acceptable if free T3/T4 
are not available),

coagulation profile (INR or PT), and

urinalysis
Baseline serology should be obtained within 28 days prior to randomization and should include: 
Hep B surface antigen, Hep B surface antibody, Hep B core antibody, Hep B DNA viral load, Hep 
C viral load, Hep C antibody, and Hep D antibody.
Baseline 12-lead ECG and 2-D Echocardiogram are required, and should be performed locally
within 14 days prior to first dose. Pregnancy testing for WOCBP (done locally) to be done at 
screening, within 24 hours prior to first dose, and then monthly regardless of dosing schedule, and 
at each safety follow up visit.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be performed continuously during the treatment phase. During the safety follow-up phase 
(Table 5.1-4) toxicity assessments should be done in person. Once subjects reach the survival 
follow-up phase, either in-person visits or documented telephone calls to assess the subject’s status 
are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
On treatment weight, ECOG performance status, vital signs, laboratory tests and targeted physical 
examinations may be performed within 72 hours prior to nivolumab dosing, or during the Day 1
visit (ie, day of clinic visit) or subjects randomized to sorafenib. In addition, vital signs can also 
be taken as per institutional standard of care prior to; during and after the nivolumab infusion. The 
start and stop time of the nivolumab infusion should be documented. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
Blood pressure monitoring frequency for subjects randomized to sorafenib should follow local 
standards of care as guided by the locally approved sorafenib product label or applicable SmPC.52
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Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline or are deemed irreversible.
If a subject shows pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) 
consistent with possible pulmonary adverse events, the subject should be immediately evaluated 
to rule out pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity 
for subjects randomized to nivolumab can be found in Appendix 5.
Some of the previously referred to assessments may not be captured as data in the eCRF. They are 
intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Imaging Assessment for the Study
Images will be submitted to an imaging core lab for central review. Sites will be trained prior to 
scanning the first study subject. Image acquisition guidelines and submission process will be 
outlined in the CA209459 Imaging Manual to be provided by the core lab.
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.

CT/MRI
Contrast-enhanced Computed Tomography (CT) scans acquired on dedicated CT equipment is
preferred for this study. The CT with contrast of the chest, abdomen and pelvis including contrast-
enhanced triphasic CT of the abdomen is to be performed for tumor assessments until disease 
progression is documented or treatment is discontinued (whichever occurs later). CT scans should 
be acquired with 5 mm slices with no intervening gap (contiguous).
Should a subject have a contraindication for IV contrast, a non-contrast CT of the chest and a
contrast-enhanced MRI of the abdomen and pelvis may be obtained. MRIs should be acquired with 
slice thickness of < 5 mm with no gap (contiguous).
Every attempt should be made to image each subject using an identical acquisition protocol on the 
same scanner for all imaging time points.

Note: Use of CT component of a PET/CT scanner:
Combined modality scanning such as with FDG-PET/CT is increasingly used in clinical care, 
and is a modality/technology that is in rapid evolution; therefore, the recommendations 
outlined here may change rather quickly with time. At present, low dose or attenuation 
correction CT portions of a combined FDG-PET/CT are of limited use in anatomically based 
efficacy assessments and it is therefore suggested that they should not be substituted for 
dedicated diagnostic contrast enhanced CT scans for
anatomically based RECIST 
measurements. However, if a site can document that the CT performed as part of a 
FDG-PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) 
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then the CT portion of the FDG-PET/CT can be used for RECIST 1.1 measurements. Note, 
however, that the FDG-PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed.

MRI Brain
MRI of brain is required at screening in order to rule out active metastatic disease in subjects
with a history of brain metastasis. Subjects with a history of brain metastasis may have
surveillance MRI approximately every 12 weeks, or sooner if clinically indicated. MRI brain 
scans during on-study treatment and follow up periods are required only if there is a prior 
history of lesions present at Screening, or as clinically indicated for new signs and symptoms 
that suggest central nervous system (CNS) involvement.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
assessments should be performed within 28 days prior to randomization utilizing CT or MRI. In 
addition to chest, abdomen, and pelvis, all known sites of disease should be assessed at baseline. 
Subsequent assessments should include chest, abdomen, and pelvis, and all known sites of disease 
and should use the same imaging method as was used at baseline. Baseline MRI for brain must be 
done for known or suspected disease. Subjects will be evaluated for tumor response beginning
8 weeks from the date of randomization (+/-1 wk), then every 8 weeks (+/- 1 wk) thereafter up to 
48 weeks, then it will be every 12 weeks (+/- 1 week) until disease progression is documented or 
treatment is discontinued (whichever occurs later). 
Tumor imaging assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria, see 
Appendix 1. For a BOR of CR or PR, the initial response assessment must be confirmed by a 
consecutive assessment no less than 4 weeks (28 days) later. Responders are the subjects with 
BOR of confirmed CR or confirmed PR. In the case of stable disease (SD), measurements must 
have met the SD criteria at least once after randomization at a minimum of 7 weeks (49 days). All 
scans performed for study purposes will be submitted to an imaging core lab for a Blinded 
Independent Central Review (BICR) supporting primary and secondary efficacy endpoints.
5.4.1
Primary Efficacy Assessment 
The primary endpoint for this study is OS. Every effort will be made to collect survival data on all 
subjects including subjects withdrawn from treatment for any reason who are eligible to participate 
in the study and who have not withdrawn consent for survival data collection. If the death of a 
subject is not reported, all dates in this study representing a date of subject contact will be used in 
determination of the subject’s last known date alive.
5.4.2
Secondary Efficacy Assessment 
For the ORR secondary efficacy endpoint, all subjects will be monitored by radiographic 
assessment on an every 8-12 weeks schedule, to determine changes in tumor size according to 
Section 5.4.1. RECIST 1.1 criteria will be used for the assessment (see Appendix 1). For the PFS 
secondary efficacy endpoint, the same radiographic assessment is in place. In the case of stable 
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disease (SD), measurements must have met the SD criteria at least once after randomization at a 
minimum interval of 7 weeks, or approximately 8 weeks.
5.5
Pharmacokinetic Assessments
Samples for PK and immunogenicity assessments will be collected for all subjects receiving 
nivolumab as described in Table 5.5.1-1. All time points are relative to the start of study drug 
administration. All on-treatment time points are intended to align with days on which study drug 
is administered, if dosing occurs on a different day, the PK and immunogenicity sampling should 
be adjusted accordingly. Further details of sample collection, processing, and shipment will be
provided in the laboratory procedures manual.
5.5.1
Pharmacokinetic and Immunogenicity Collection and Processing
A detailed schedule of PK and immunogenicity evaluations is provided in Table 5.5.1-1. Samples 
are required for subjects randomized to nivolumab only. PK samples will be analyzed for 
nivolumab by a validated ligand binding assay. Immunogenicity samples will be analyzed for anti-
nivolumab antibodies by a validated immunogenicity assay; samples may also be analyzed for 
neutralizing antibodies by a validated method. Serum samples may be analyzed by an exploratory 
method that measures anti-drug antibodies for technology exploration purposes; exploratory 
results will not be reported. Serum samples designated for PK or biomarker assessments may also 
be used for immunogenicity analysis if required (eg, insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity related AE).
Table 5.5.1-1:
Pharmacokinetic and Immunogenicity Sampling Schedule
(Nivolumab subjects only)
Study Day
(1 Cycle = 2 Weeks)
Event 
(Relative to 
Start of 
Infusion)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 1 
predosea
00:00
X
X
Cycle 3 Day 1
predosea
00:00
X
X
Cycle 8 Day 1
predosea
00:00
X
X
Day 1 of every 8th cycle after Cycle 8 Day 
1 until discontinuation of study treatmentb
predosea
00:00
X
X
First 2 Follow-up visits- (approximately up 
to 100 days from the discontinuation of 
study drug)
X
X
a Predose samples should be taken just prior to the administration (preferably within 30 minutes). If the infusion is 
delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample.
b If a subject permanently discontinues study drug treatment during the sampling period, they will move to sampling 
at follow-up visits
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5.6.1
Tumor Tissue Specimens and Collection Details
Archival tumor specimens are acceptable. For subjects without available/acceptable archival
tissue, new biopsies must be obtained. The tissue submitted will be assessed for quality with a 
H&E stain (100 tumor cells) and only those subjects who have meet tissue quality thresholds can 
be randomized. Subjects whose tissue fails the initial quality assessment can be screen failed and 
re-enrolled if they consent/agree to a new biopsy.
Biopsy samples should be excisional, incisional or core needle. If a core biopsy is taken, up to 
4 cores are recommended with a minimum size 18 gauge needle and the length should be greater 
than 5mm. Fine needle aspirates or other cytology samples are not acceptable. An assessment of 
biopsy quality by a pathologist is encouraged at the time of the procedure. The tumor tissue that is 
obtained from these biopsies will be divided equally into a formalin fixed sample, which can be 
used for histologic confirmation of HCC and characterization of immune cell populations and 
tumor markers, and a RNAlater sample for DNA and RNA extraction for genomic analyses. Tumor 
samples obtained from bone metastases are not considered acceptable for PD-L1 testing because 
the PD-L1 assay does not include a decalcification step. For any cases where the only tumor tissue 
available is from a bone metastasis lesion, please discuss further with the study Medical Monitor. 
The investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the biopsy procedure and find it acceptable. Biopsies may be done with local 
anesthesia or conscious sedation. Institutional guidelines for the safe performance of biopsies 
should be followed. Excisional biopsies may be performed to obtain tumor biopsy samples. 
Invasive procedures that require general anesthesia should not be performed to obtain a biopsy 
specimen. However, if a surgical procedure is performed for a clinical indication, excess tumor 
tissue may be used for research purposes with the consent of the subject. De-identified pathology 
report should be provided with tumor samples.
In addition to the assessments shown below, formalin fixed paraffin embedded tissue (FFPET) 
may also be evaluated by additional technologies including but not limited to FISH, genetic 
mutation detection methods, and QPCR for exploratory analyses of prognostic or predictive 
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molecular markers associated with hepatocellular carcinoma (eg, gene mutation, amplification or 
overexpression), to determine if these factors influence response or safety of nivolumab.
5.6.1.1
Characterization of tumor infiltrating lymphocytes (TILs) and tumor 
antigens
Immunohistochemistry (IHC) will 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 
formalin-fixed, paraffin embedded (FFPE) tumor tissue. These IHC analyses will include, but not 
necessarily be limited to, the following markers: CD4, CD8, CD3, FOXp3, PD-1, PD-L1, and PD-
L2.
5.6.1.2
Whole Exome and Whole Transcriptome Sequencing
DNA and/or RNA extracted from tumor and/or blood provided may be subject to whole exome or 
transcriptome sequencing using next-generation sequencing or other technology to identify 
mutational load and transcriptional expression. RNA will also be extracted from tumor to assess 
expression of inflammation-related genes. 
5.6.2
Peripheral Blood Assessments
A variety of factors that may impact the immunomodulatory properties and efficacy of nivolumab 
will be investigated in peripheral blood specimens taken from all subjects prior to or during 
treatment. Data from these investigations will be evaluated for associations with response, 
survival, and/or safety (adverse event) data. Several analyses will be completed and are described 
briefly below, and outlined in Table 5.6.2-1.
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5.6.2.1
Single Nucleotide Polymorphisms (SNPs)
Whole blood will be collected from all subjects prior to treatment to generate genomic DNA for 
Single Nucleotide Polymorphism (SNP) analyses. Genes of interest include, but are not limited to, 
PD-1, PD-L1, IFN gamma, HLA, and other immunoregulatory signaling pathways to determine if 
natural variation within those genes is associated with response to nivolumab and/or with adverse 
events during treatment. Data from this study will be combined with SNP results from other studies 
to explore possible associations of SNPs and clinical activity or adverse events associated with 
nivolumab therapy. 
5.6.2.2
Serum-Soluble Factors
Baseline and on-treatment serum levels of chemokines, cytokines and other immune mediators 
will be assessed by techniques that may include, but are not limited to ELISA or multiplex assays.
Analytes may include, but are not limited to, IFN-, CXCL9, CXCL10, and soluble PD-L1.
5.6.2.3
Peripheral Blood Mononuclear Cells (PBMCs)
At participating sites, peripheral blood mononuclear cells in whole blood taken from subjects at 
Cycle 1 Day 1 will be analyzed by flow cytometry or other methods (eg, ELIspot) to assess immune 
cell activity. This blood collection may be canceled at the discretion of the sponsor.
5.6.2.4
Myeloid Derived Suppressor Cells (MDSCs)
Myeloid derived suppressor cells (MDSCs) are an immune cell population capable of suppressing 
T cell activation and proliferation. MDSCs will be measured at Cycle 1 Day 1 to assess 
pharmacodynamic changes or associations with outcome.
 
 
 
5.7
Outcomes Research Assessments
Subjects will be asked to complete the EQ-5D-3L and Functional Assessment of Cancer 
Therapy-Hepatobiliary (FACT-Hep) questionnaire, before any clinical activities are performed 
during on-study clinic visits and at designated visits during the follow-up phase. The 
questionnaires will be provided in the subject’s preferred language and may be administered by 
telephone during the follow-up phase. A standardized script will be used to facilitate telephone 
administration of the EQ-5D. A similar script does not exist for the FACT-Hep, though subjects 
will be provided with a hard copy of the FACT-Hep to take home and use as a visual aid during 
telephone interviews. Table 5.1-1, Table 5.1-2, Table 5.1-3 and Table 5.1-4 provide information 
regarding the timing of patient-reported outcomes assessments.
Subjects’ reports of general health status will be measured using the EQ-5D. These data will be 
collected to assess the impact of nivolumab on generic health status and may be used to inform 
economic evaluations of nivolumab for the treatment of HCC.
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The EQ-5D is a standardized instrument used to measure self-reports of health status and 
functioning. The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting 
"no health problems," "moderate health problems," and "extreme health 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 3. Thus, the vectors 11111 and 33333 represent the best 
health state and the worst health state, respectively, described by the EQ-5D. Altogether, the 
instrument describes 35 = 243 health states. Empirically derived weights can be applied to an 
individual’s responses to the EQ-5D descriptive system to generate an index measuring the value 
to society of his or her current health. Such preference-weighting systems have been developed 
for the UK, US, Spain, Germany, and numerous other populations. In addition, the EQ-5D includes 
a visual analog scale that allows respondents to rate their own current health on a 101-point scale 
ranging from “best imaginable” to “worst imaginable” health.
The FACT-Hep questionnaire will be used to assess the effects of HCC and its treatment on 
health-related quality of life (HRQL). As a generic cancer-related core, the questionnaire includes 
the FACT-General (FACT-G) to assess symptoms and treatment-related effects impacting 
physical well-being (PWB; seven items), social/family well-being (SWB; seven items), emotional 
well-being (EWB; six items), and functional well-being (FWB; seven 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. Each item 
is rated on a five-point scale ranging from 0 (not at all) to 4 (very much). 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 to be 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; 
and 8-9 points for the FACT-Hep total score.
Health care resource utilization data will be collected for all randomized subjects using an internal 
measure developed for use in previous trials. The questionnaire records information about medical 
care encounters, including hospital admissions and their duration, outpatient visits, diagnostic tests 
and procedures, concomitant medications, and reasons for encounters.
5.8
Other Assessments 
Blood samples for immunogenicity analyses of nivolumab will be collected according to the 
schedule given in Table 5.5.1-1. Samples will be evaluated for development of Anti-Drug 
Antibody (ADA) for nivolumab by validated immunoassays. Samples may also be analyzed for 
neutralizing ADA response to nivolumab.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
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does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, second cancer, and potential drug induced liver injury (DILI) are 
not always serious by regulatory definition, these events must be handled as SAEs.
(See Section 6.1.1 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
100 days of discontinuation of dosing. Subjects who are enrolled in the study but never treated 
with study drug must have SAEs collected for 30 days from the date of enrollment. If applicable, 
SAEs must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin 
biopsy).
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. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
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method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning.
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic). 
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
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6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details). The 
following definition takes into account anticipated baseline compromise of liver function in 
patients with HCC.
Potential drug induced liver injury is defined as: 
1) Concurrent ALT 10 x ULN, AND 
2) Total bilirubin 2 times ULN or baseline value (if elevated bilirubin at study entry), AND
3) No other immediately apparent possible causes of ALT elevation and hyperbilirubinemia, 
including, but not limited to, tumor progression, acute viral hepatitis, cholestasis, pre-existing 
hepatic disease or the administration of other drug(s), herbal medications and substances 
known to be hepatotoxic.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established to provide oversight and safety and 
efficacy considerations in protocol CA209459. The DMC will provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of subjects enrolled 
in the study. The DMC will be charged with assessing such actions in light of an acceptable 
benefit/risk profile for nivolumab. The DMC will act in an advisory capacity to BMS and will 
monitor subject safety and evaluate the available efficacy data for the study.
The BMS clinical study leadership will have responsibility for overall conduct of the study 
including managing the communication of study data. The group will be responsible for promptly 
reviewing the DMC recommendations, for providing guidance regarding the continuation or 
termination of the study, and for determining whether amendments to the protocol or changes to 
the study conduct are required. Adjudicated events will be submitted to the DMC and Health 
Authorities when required for review on a specified timeframe in accordance with the adjudication 
documentation.
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Details of the DMC responsibilities and procedures will be specified in the DMC charter.
7.2
Blinded Radiology Review Committee
In addition to local tumor assessments, images from this study will undergo a blinded, independent 
central review (BICR) to assess response based on the RECIST 1.1 assessment criteria. The 
centrally reviewed response data will be used in the analyses of ORR, PFS, duration of objective 
response, 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.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The sample size determination of this study is based on OS comparison between subjects 
randomized to receive nivolumab and sorafenib. With a total of 726 subjects randomized in a 1:1 
ratio to receive nivolumab or sorafenib, approximately 91.5% power will be achieved with an 
overall type I error 0.05. The sample size determination is based on simulation using R v3.2. Below 
are details of the sample size determination.
General assumptions:

There are assumed 39% HCV-infected subjects among all randomized subjects.

In the sorafenib arm, median OS is 10 months for non-HCV infected and 14 months for HCV 
infected.

Exponential distribution is assumed for OS in each randomized arm.
Estimated cumulated enrollment of randomized subjects is available in the SAP.  
Sample size determination for OS
Based on simulations under the assumptions stated above, approximately 726 subjects will be 
randomized and followed until at least 520 OS events are observed in order to provide 91.5% 
power for a hazard ratio of 0.74 with a two-sided type I error of 0.05. This accounts for a group 
sequential testing procedure with one interim analysis and one final analysis. 
The interim analysis will be conducted when 80% OS events are observed. The alpha allocation 
for the interim and final analyses is based on the Lan-DeMets alpha spending function approach 
using an O’Brien-Fleming stopping boundary controlling for a two-sided overall type 1 error of 
5%. The stopping boundary will depend on the actual number of deaths at the time of the interim 
analysis and the final analysis. However, if the interim analysis is performed exactly when 80% 
OS events are observed, then 0.024 alpha will be used for the interim analysis and 0.043 alpha will 
be used for the final analysis. 
It is projected that an observed hazard ratio of 0.80 or less would result in a statistically significant 
improvement of nivolumab at the interim analysis of OS; and an observed hazard ratio of 0.84 or 
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less would result in a statistically significant improvement of nivolumab at the final analysis of 
OS.  
Analysis Timing Projections
As stated above, approximately 726 subjects will be randomized to the two treatment arms in a 1:1 
ratio.

It will take approximately 13 months to complete the randomization.

OS interim analysis is projected to occur when there are at least 416 deaths (80% of target 
events) among approximately 726 randomized subjects, approximately 25 months after the 
first subject’s randomization date (13 months for randomization and 12 months for survival 
follow-up).

OS final analysis is projected to occur when there are at least 520 deaths among approximately 
726 randomized subjects, approximately 33 months after the first subject’s randomization date 
(13 months for randomization and 20 months for survival follow-up).
8.2
Populations for Analyses
All analyses will be performed using the treatment group as randomized (intent-to-treat) with the 
exception of extent of exposure (dosing) and safety, for which the treatment group as treated will 
be used. If a subject is randomized to nivolumab and receives at least 1 dose of nivolumab during 
the study, then the subject’s treatment group is considered nivolumab. Similarly, if a subject is 
randomized to sorafenib and receives at least 1 dose of sorafenib, then the subject’s treatment 
group is considered sorafenib. The following population datasets will be analyzed:

Enrolled Subjects: Subjects who signed an informed consent form and were registered into 
the IVRS.

Randomized Subjects: Subjects who were randomized to any treatment group in the study. 
This is the dataset for analyses of study conduct, study population and efficacy.

Treated Subjects: Subjects who received at least one dose of nivolumab or sorafenib. This is 
the dataset for analyses of exposure and safety.

PK Subjects: Subjects with available serum time-concentration data from randomized 
subjects dosed with nivolumab.

PD-L1 Measurable Subjects: Randomized subjects with a measurable PD-L1 expression 
result (ie, excludes indeterminate and unknown)
8.3
Endpoints
8.3.1
Primary Endpoint

Overall Survival (OS)
OS is the primary endpoint for this study. It is defined as the time from the date of 
randomization to the date of death due to any cause in all randomized subjects. Subjects who 
are alive will be censored at the last known alive dates.
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8.3.2
Secondary Endpoint(s)

Objective Response Rate (ORR)
ORR is defined as the proportion of subjects whose best overall response (BOR) is either a CR 
or PR. BOR is defined as the best response designation, as determined based on BICR-assessed 
tumor response according to RECIST 1.1, recorded between the date of randomization and the 
date of first objectively documented progression or the date of subsequent anti-cancer therapy, 
whichever occurs first. For subjects without documented progression or subsequent anti-cancer 
therapy, all available response designations will contribute to the BOR determination. For a 
BOR of CR or PR, the initial response assessment must be confirmed by a consecutive 
assessment no less than 4 weeks (28 days) later.

Progression-Free Survival (PFS)
PFS is defined as the time from the date of randomization to the date of the first objectively 
documented tumor progression as assessed by BICR according to RECIST 1.1 or death due to 
any cause in all randomized subjects. Subjects who die without a reported prior progression 
and without initiation of subsequent anti-cancer therapy will be considered to have progressed 
on the date of their death. Subjects who did not progress or die will be censored on the date of 
their last tumor assessment. Subjects who did not have baseline tumor assessment will be 
censored on the date they were randomized. Subjects who did not have any on study tumor 
assessments and did not die will be censored on the date they were randomized. Subjects who 
started any subsequent anti-cancer therapy without a prior reported progression will be
censored at the last tumor assessment prior to subsequent anti-cancer therapy. 

PD-L1 expression
The objective of evaluating the relationship between PD-L1 expression and efficacy will be 
measured by efficacy based on PD-L1 expression. Definition of PD-L1 expression will be 
described in the SAP.
 
 
 
 
 
 
 
 
 
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline laboratory results will be summarized by treatment arm as randomized 
using descriptive statistics for all randomized subjects.
8.4.2
Efficacy Analyses
8.4.2.1
Analysis of OS
A group sequential testing procedure will be applied to OS to control the overall type I error for 
interim and final analyses (overall alpha=0.05). The distribution of OS will be compared in the 
two randomized arms at the interim and final analyses via a two-sided, log-rank test stratified by 
the stratification factors using allocated alpha based on Lan-DeMets alpha spending function with 
O’Brien and Fleming type of boundary. The hazard ratio and the corresponding 100x (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 randomized arm will be estimated using the KM 
product limit method. The two-sided 95% CIs for median OS will be computed by Brookmeyer 
and Crowley method (using log-log transformation). In additional, survival rates at select 
milestones will be computed as well as the corresponding two-sided 95% CIs using the log-log 
transformation.
8.4.2.2
Analysis of ORR
ORR based on BICR assessment per RECIST 1.1 between the two randomized arms will be 
compared using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by the stratification 
factors. The associated odds ratio and CI will also be calculated. ORR along with its 95% exact CI 
will be provided for each randomization arm. Hierarchical testing of ORR will be performed upon 
demonstration of superiority in OS at OS interim or final analyses for all randomized subjects.
8.4.2.3
Analysis of PFS
Hierarchical testing of PFS will be performed upon demonstration of superiority in ORR at OS 
interim or final analyses for all randomized subjects. Details of timing for the analysis and alpha 
allocated will be described in the SAP.
PFS will be compared using a two-sided stratified log-rank test. The hazard ratio and the 
corresponding two-sided CIs will be estimated in a Cox proportional hazards model using
treatment as a single covariate, stratified by the stratification factors. PFS curves will be estimated 
using the KM product-limit method. The two-sided 95% CIs for median PFS will be computed by 
Brookmeyer and Crowley method (using log-log transformation). In additional, PFS rate at select 
milestone will be computed as well as the corresponding two-sided 95% CIs using the log-log 
transformation.
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8.4.2.4
Analysis of Association between PD-L1 Expression and Efficacy 
Measures
Analyses of PD-L1 expression will be descriptive. Distribution of PD-L1 expression will be 
examined PD-L1-measurable subjects. Potential associations between PD-L1 expression and 
primary efficacy measure OS will be assessed. OS curves for each randomized arm will be 
estimated using the Kaplan-Meier product-limit method for each PD L1 Expression subgroup. 
Two-sided, 95% confidence intervals for median OS will be computed by Brookmeyer and 
Crowley method. If there is an indication of a meaningful association, future work will evaluate 
PD-L1 expression as a predictive biomarker, including selection of an optimal PD-L1 expression 
cut-off to classify subjects as PD-L1 positive or PD-L1 negative. Cut-off selection and validation 
may be conducted across studies. More detailed analysis including potential associations between 
PD-L1 expression and secondary efficacy measures will be described in the SAP.
8.4.3
Safety Analyses
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 by treatment arm. All on-treatment AEs, drug-related AEs, SAEs 
and drug-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by 
system organ class and preferred term. On-study lab parameters including hematology, 
coagulation, chemistry, liver function and renal function will be summarized using worst grade 
per NCI CTCAE v 4.0 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development programs to develop or refine a population PK model. These 
models may be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of 
nivolumab and to determine measures of individual exposure. In addition, model determined 
exposures may be used for exposure-response analyses. Results of population PK and 
exposure-response analyses will be reported separately.
 
 
 
 
 
 
 
 
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8.4.6
Outcomes Research Analyses
The analysis of EQ-5D and FACT-Hep data will be performed in all randomized subjects who 
have an assessment at baseline (Day 1, assessment prior to administration of drug on day of first 
dose) and at least 1 subsequent assessment while on treatment. Questionnaire completion rate, 
defined as the proportion of questionnaires actually received out of the expected number, will be 
calculated and summarized at each assessment point.
EQ-5D data will be described by treatment group as randomized in the following ways:

EQ-5D index scores will be summarized at each assessment time point using descriptive 
statistics (ie, N, mean with standard deviation and 95% CI, median, first and third quartiles, 
minimum, maximum).

EQ-VAS scores will be summarized at each assessment time point using descriptive statistics 
(ie, N, mean with standard deviation and 95% CI, median, first and third quartiles, minimum, 
maximum).

The proportion (N) of subjects reporting no, moderate, or extreme problems will be presented 
for each of the 5 EQ-5D dimensions at each assessment time point. Subjects with missing data 
will be excluded from the analysis.

A by-subject listing of the level of problems in each dimension, corresponding EQ-5D health 
state (ie, 5-digit vector), EQ-5D index score, and EQ-VAS score will be provided.
FACT-Hep data will be described by treatment group as randomized in the following ways:

FACT-Hep total scores will be summarized at each assessment time point using descriptive 
statistics (ie, N, mean with standard deviation and 95% CI, median, first and third quartiles, 
minimum, maximum).

Changes from baseline in FACT-Hep total scores will be summarized at each post-baseline 
assessment time point using descriptive statistics (ie, N, mean with standard deviation and 95% 
CI, median, first and third quartiles, minimum, maximum).

The proportion (N) of subjects achieving a change of 8 points (ie, MID) in FACT-Hep total 
score will be summarized at each post-baseline assessment time point.
8.4.7
Other Analyses 
Methodology for exploratory analyses including immunogenicity is described in the statistical 
analysis plan.
8.5
Interim Analyses
A formal interim analysis for the OS is planned after 416 deaths have been observed, which is 
expected to occur approximately 25 months after the first subject’s randomization date. This 
formal comparison 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 analysis. However, if the analysis
is performed exactly when 416 deaths are observed, the study can be stopped by the DMC for 
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superiority if the p-value is < 0.024. An independent statistician from external to BMS will perform 
the analysis.
If the study continues beyond the interim analysis, the nominal significance level for the final look 
after 520 deaths would be 0.043. All events in the database at the time of the lock will be used. If 
number of final events exceeds the number specified per protocol (520 deaths), final boundary will 
not be recalculated using updated information fraction at interim. In addition to the formally 
planned interim analysis for OS, the DMC will have access to periodic unblinded interim reports 
of efficacy and safety to allow a risk/benefit assessment. 
Details will be included in the DMC charter.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC and Regulatory Authority (ies), if required by local regulations, of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
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with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
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9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
Records or logs must comply with applicable regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
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who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

Involvement in trial design

Subject recruitment (eg, among the top quartile of enrollers)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing [Study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA.
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10
LIST OF ABBREVIATIONS
Term
Definition
1L
first line
AASLD
American Association for the Study of Liver Diseases
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(0-T)
area under the concentration-time curve from time zero to the time of the
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
BICR
blinded independent central review
BID, bid
bis in die, twice daily
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
Cmax
maximum observed concentration
Cmin
trough observed concentration
CNS
Central nervous system
CR
complete response
CRF
Case Report Form, paper or electronic
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Term
Definition
CYP
cytochrome p-450
DCR
disease control rate
dL
Deciliter
DOR
duration of response
EASL
European Association for the Study of the Liver
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
Eg
exempli gratia (for example)
FACT-Hep
Functional Assessment of Cancer Therapy-Hepatobiliary
FDA
Food and Drug Administration
FHSI
Functional Assessment of Cancer Therapy–Hepatobiliary Symptom 
Index
FSH
follicle stimulating hormone
G
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotrophin
HCV
hepatitis C virus
HCRU
healthcare research utilization
HIFU
cryoablation, high-intensity focused ultrasound
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
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Term
Definition
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K+
potassium
kg
kilogram
KM
Kaplan-Meier
L
liter
LDH
lactate dehydrogenase
MDSCs
myeloid derived suppressor cells
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
Ng
nanogram
NIMP
non-investigational medicinal products 
NSCLC
Non-small-cell lung cancer
ORR
objective response rate
OS
overall survival
PAI
acetic acid injection
PBMCs
peripheral blood mononuclear cells
PD
progressive disease
PD-1
Programmed death receptor-1
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Term
Definition
PEI
percutaneous ethanol injection
PFS
progression free survival
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PR
partial response
PT
prothrombin time
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RFA
radiofrequency ablation
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SLD
sum of the longest diameters
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedures
TACE
transarterial chemoembolization
TAE
transarterial embolization
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
T-HALF
Half life
Treg
T regulatory cell
TTP
time to progression
TTR
time to response
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 1
RECIST 1.1
This Appendix has been excerpted from the full RECIST 1.1 criteria. For information pertaining 
to RECIST 1.1 criteria not contained in the study protocol or in this Appendix, please refer to the 
full publication.1
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least one measurable lesion.
1.1
Measurability of Tumor
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. All baseline evaluations should be performed as close as possible to the treatment start 
and never more than 4 weeks before the beginning of the treatment.
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:

10 mm by CT scan - (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)

20 mm by chest x-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
All measurements should be recorded in metric notation, using calipers if clinically assessed.
Special considerations regarding lesion measurability
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.

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.
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Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same patient, these are preferred for selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco 
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.
Non-measurable lesions are all other lesions, including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with 10 to < 15 mm short axis), as well as non-measurable lesions. 
Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
1.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination.
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. Measurability of lesions on CT scan is based on the assumption that CT 
slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than x-ray, particularly in identifying new lesions. However, 
lesions on chest x-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
10 mm diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As noted above, when 
lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may be reviewed at the end of the study.
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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
Target lesions: When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 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.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions: All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION AND RESPONSE CRITERIA
3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.
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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 from the baseline study to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Special notes on the assessment of target lesions

Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded and should be 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.

Target lesions that become ‘too small to measure’: All lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (eg, 2 mm). If the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
(i) if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.
(ii) if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness).
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 coalesced such that 
they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’.
3.2
Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
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Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).

The concept of progression of non-target disease requires additional explanation as follows:

When the patient also has measurable disease: To achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in 
the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status.

When the patient has only non-measurable disease: To achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening such 
that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: ie, an 
increase in tumor burden representing an additional 73% increase in ‘volume’ (which is 
equivalent to a 20% increase diameter in a measurable lesion). Examples include an increase 
in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized 
to widespread, or may be described in protocols as ‘sufficient to require a change in therapy’. 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall PD 
at that point.
3.3
New Lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be constituted PD even if 
he/she did not have brain imaging at baseline.
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If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents new disease. If repeat scans confirm that there is a new lesion, 
then progression should be declared using the date of the initial scan.
3.4
Tumor Markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially 
above the upper normal limit, however, they must normalize in order for a patient to be considered 
as having attained a complete response.
4
EVALUATION OF BEST OVERALL RESPONSE
4.1
Time Point Response
A response assessment should occur at each time point specified in the protocol.
For patients who have measurable disease at baseline Appendix Table 1 provides a summary of 
the overall response status calculation at each time point.
Table 1:
Summary of the Overall Response Status Calculation [Time point 
response: patients with target (+/-) non-target disease]
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
4.2
Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually 
the case is also considered NE at that time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of PD.
4.3
Best Overall Response - All Timepoints
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol. In this circumstance, the best overall response 
can be interpreted as in Appendix Table 2. In the case of stable disease (SD), measurements must 
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have met the SD criteria at least once after study entry at a minimum interval of 7 weeks, or 
approximately 8 weeks.
Table 2:
Best overall response when confirmation of CR and PR required
Overall Response
First Timepoint
Overall Response Subsequent 
Timepoint
Best Overall response
CR
CR
CR
CR
PR
SD, PD, PRa
CR
SD
SD provided minimum criteria for SD duration 
met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration 
met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration 
met, otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration 
met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration 
met, otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
4.4
Special notes 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).
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such patients 
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is to be determined by evaluation of target and non-target disease as shown in Appendix Table 1 
and Table 2.
For equivocal findings of progression (eg. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected.
5
ADDITIONAL CONSIDERATIONS
5.1
Duration of response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment 
(in randomized trials, from date of randomization) until the criteria for progression are met, taking 
as reference the smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD).
5.2
Lesions that Disappear and Reappear
If a lesion disappears and reappears at a subsequent time point it should continue to be measured. 
However, the patient’s response at the point in time when the lesion reappears will depend upon 
the status of his/her other lesions. For example, if the patient’s tumour had reached a CR status 
and the lesion reappeared, then the patient would be considered PD at the time of reappearance. In 
contrast, if the tumour status was a PR or SD and one lesion which had disappeared then reappears, 
its maximal diameter should be added to the sum of the remaining lesions for a calculated response: 
in other words, the reappearance of an apparently ‘disappeared’ single lesion amongst many which 
remain is not in itself enough to qualify for PD: that requires the sum of all lesions to meet the PD 
criteria. The rationale for such a categorization is based upon the realization that most lesions do 
not actually ‘disappear’ but are not visualized because they are beyond the resolving power of the 
imaging modality employed.
Reference:
1
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. (2009);45:228-247.
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APPENDIX 2
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 3
ECOG PERFORMANCE STATUS 
These scales are used by doctors and researchers to assess how a patient’s disease progressing, 
assess how the disease affects the dailing living abilitiesof the patient and determine appropriate 
treatment and prognosis. They are included here for health care professionsals to assess.
ECOG PERFORMANCE STATUS
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, e.g., 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
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. 
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APPENDIX 4
NYHA CLASSIFICATION
NYHA Classification
Class I
patients with no limitation of activities; they suffer no symptoms from 
ordinary activities
Class II
patients with slight, mild limitation of activity; they are comfortable with 
rest or with mild exertion.
Class III
patients with marked limitation of activity; they are comfortable only at 
rest.
Class IV
patients who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest. 
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