A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab in Combination With Ipilimumab in Advanced Hepatocellular Carcinoma Subjects With or Without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma Subjects Who Are Naive to Systemic Therapy
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab  
in Combination with Ipilimumab in Advanced Hepatocellular Carcinoma Subjects with or  
without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs  
Sorafenib in Advanced Hepatocellular Carcinoma Subjects who are Naïve to Systemic Therapy 
 
NCT Number: NCT01658878 
Document Date (Date in which document was last revised): October 26, 2016 
 
 
 

Page: 1
Protocol Number: CA209040
IND Number: 126,406
Ex-US Non-IND
EUDRACT Number 2012-001514-42
Date: 25-May-2012
Revised Date: 26-Oct-2016
Clinical ProtocolCA209040
A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab 
in Combination with Ipilimumab in Advanced Hepatocellular Carcinoma Subjects with or 
without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs 
Sorafenib in Advanced Hepatocellular Carcinoma Subjects who are Naiveto Systemic Therapy
Revised Protocol Number: 05
Incorporates Administrative Letters 05 and 06, and Amendment 14
Study Director
Central Medical Monitor
Bristol-Myers Squibb Company
Uxbridge Business Park, Sanderson Road
Uxbridge, UB8 1DH
United Kingdom
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
United States
Telephone (office): 
Telephone (office): 
Fax: 
Fax: 
24-hr Emergency Telephone Number
USA:1-866-470-2267
International: +1-248-844-7390
Bristol-Myers Squibb Research and Development
Avenue de Finlande 4, Building F –1st Floor
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose ofassessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (e.g., amendments) 
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Revised Protocol No.: 05
Date: 26-Oct-2016
2
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 rightsreserved.
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.: 05
Date: 26-Oct-2016
3
 &
()*+
Document
Date of Issue
Summary of Change
Revised Protocol 05
26-Oct-2016
Incorporates Administrative Letter 05, Administrative Letter 06, and 
Amendment 14
Amendment 14
26-Oct-2016
Modify the 1L Nivolumab vs Sorafenib Cohortefficacy analysis from 
a comparison of ORR to an estimation of ORR for both nivolumab and
sorafenib arms.
Administrative 
Letter 06
24-Jun-2016
Change of Medical Monitor
Administrative 
Letter 05
23-Mar-2016
ClarifiedthatSAEreportingtoOnoPharmaceuticalCo.,Ltd.isno
longer required.
Revised Protocol 04
31-Jul-2015
IncorporatesAdministrative Letter 03, Administrative Letter 04, and 
Amendment 08
Amendment 08
31-Jul-2015
Changes include addition of two new treatment arms to the study: 
1.1L nivolumab vs sorafenib,2. nivolumab plus ipilimumab 
combination, as well as other minor clarifications and edits
Administrative 
Letter 04
15-Jul-2015
Updatethe pharmacokinetic sampling schedule for subjects in the 
expansion cohorts.
Administrative 
Letter 03
28-Apr-2015
TheFDAissuedanewINDnumberfortheindicationof
hepatocellular carcinoma for nivolumab.
Revised Protocol 03
29-Oct-2014
Incorporates Amendment 04
Amendment 04
29-Oct-2014
Changes include addition of an expansion phase to the study, 
introduction of the possibility to re-initiate treatment after treatment 
discontinuation, to be treated beyond progression in certain conditions, 
switch of tumor evaluation criteria from mRECIST to RECIST 1.1, 
introduction of a quality of life questionnaire (EQ-5D) in the expansion 
phase, updates to the WOCBP and pregnancy wording and other minor 
clarifications and edits.
Administrative 
Letter 02
15-Apr-2014
Change in Study Director/Medical Monitor
Administrative 
Letter 01
15-Oct-2013
Change in Study Director/Medical Monitor
Revised Protocol 02
06-Sep-2013
Changes include updated text for antiviral medications for HCV and 
HBV arms; expanded laboratory and Child-Pugh ranges for 
inclusion/exclusion criteria; added new safety information concerning 
virally infected subjects treated with checkpoint inhibitors; added a 10 
mg/kg dose group to all three arms (uninfected, HCV infected, and 
HBV infected); minor clarifications and edits.
Amendment 03
06-Sep-2013
Revised Protocol 01
18-Mar-2013
Incorporates Amendment 02.
Amendment 02
18-Mar-2013
Changes include updated text for pre-clinical toxicology finding, 
addition of a reference for this finding, updated suggested language for 
contraception based on this finding and updated Medical Monitor 
information, protocol title in synopsis edited to be consistent with 
protocol.
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Document
Date of Issue
Summary of Change
Original Protocol
25-May-2012
Not applicable
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)+,)()
Clinical ProtocolCA209040
Protocol Title: A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab in 
Combination with Ipilimumab in Advanced Hepatocellular Carcinoma Subjects with or without Chronic Viral 
Hepatitis; and a Randomized, Open-label Study of Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma 
Subjects who are Naive to Systemic Therapy.  
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):   
In the Dose Escalation Phase Cohort:  Intravenous (IV) infusion of nivolumabat doses of 0.1 mg/kg, 0.3 mg/kg, 
1mg/kg, 3 mg/kg, and 10 mg/kgq2week.  
In the Expansion Phase Cohort:  IVinfusion of nivolumab at a dose of 3 mg/kg q2week.
In the 1L Nivolumab vsSorafenib Cohort:  Subjects will be randomized 1:1 to receive open-label
IVinfusion of nivolumab at a flat dose of 240mg q2week or
Sorafenib 400 mg po BID.
In the Nivolumab plus Ipilimumab Combination Cohort: Subjects will be randomized 1:1:1 to receive
Arm A--nivolumab 1mg/kg IV plus ipilimumab 3mg/kg IV q3 week x 4, followed by nivolumab 240mg IV 
q2week
Arm B--nivolumab 3mg/kg IV plus ipilimumab 1mg/kg IV q3weekx 4, followed by nivolumab 240mg IV 
q2week
Arm C--nivolumab 3 mg/kg IV q2week plus ipilimumab 1 mg/kg IV q6week.
All subjects upon activation of amendment 8 are to be treated until toxicity or disease progression.  Prior to 
activation of amendment 8, subjects in the Dose Escalation Phasewere treated until either a confirmed CR, 
completion of 2 years of therapy, toxicity, or disease progression.
Study Phase:  1/2
Research Hypothesis:
There is no formal hypothesis in the Dose Escalation Phaseto be tested statistically.  The purpose of the Dose 
Escalation Phaseis to evaluate the safety profile, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) 
following IV infusion at doses of 0.1, 0.3, 1, 3, and 10 mg/kg of nivolumab administered every 14days in subjects 
with advanced hepatocellular carcinoma (HCC).
In theExpansion Phase, treatment with nivolumab monotherapy will lead to clinical benefit as demonstrated by a 
clinically meaningful objective response rate (ORR) and duration of response in subjects with advanced HCC who 
have been previously treated with sorafenib. 
In the 1L Nivolumab vsSorafenib Cohort, nivolumab administration in subjects with advanced hepatocellular 
carcinoma (HCC) who are naive tosystemic therapy will improve ORR compared with sorafenib.
In the Nivolumab plus Ipilimumab Combination Cohort, treatment with nivolumab plus ipilimumab will lead to 
clinical benefit as demonstrated by a clinically meaningful objective response rate (ORR) and duration of response 
in subjects with advanced HCC who are previously treated with sorafenib.  In addition, the purpose of the cohort is 
to evaluate the safety profile of the combination in subjects with advanced HCC who have been previously treated 
with sorafenib. 
Revised Protocol No.: 05
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Objective(s): 
Primary Objective: 
Dose Escalation Phase: To establish the safety, tolerability, dose limiting toxicities (DLT) and maximum 
tolerated dose (MTD) for nivolumab administered every 14 days to subjects with advanced HCC.
Expansion Phase: To estimate the ORR and duration of response of nivolumab monotherapy in subjects with 
advanced HCC who are naive to sorafenib or have been previously treated with sorafenib.  ORR will be 
determined with a blinded independent central review (BICR) assessed tumor response based on RECIST 1.1.
1L Nivolumab vs Sorafenib Cohort: To estimateoverall response rate (ORR) of nivolumab and sorafenib in
subjects with advanced HCC who are naive to systemic therapy. ORR will be determined with Investigator 
assessed tumor response based on RECIST 1.1..
Nivolumab plus Ipilimumab Combination Cohort:  
- To establish the safety and tolerability of nivolumab plus ipilimumab in subjects with advanced HCC.
- To estimate the ORR and duration of response for nivolumab plus ipilimumab combination therapy in 
subjects with advanced HCC who have been previously treated with sorafenib.ORR will be determined 
with Investigator assessed tumor response based on RECIST 1.1.
Secondary Objectives:
Escalation and Expansion Phase:
- To assess antitumor activities (Time to Progression (TTP) and Progression Free Survival (PFS)) based on 
results ofBICR and/or investigators using RECIST 1.1.
- To evaluate overall survival (OS) in subjects treated with nivolumab monotherapy.
- To investigate the potential association between selected biomarker measures, such as PD-L1 expression, 
and clinical efficacy measures including overall survival.
- To characterize the pharmacokinetics of nivolumab in subjects with advanced HCC (Dose Escalation Phase
only).
- To assess the immunogenicity of nivolumab in subjects with advanced HCC (Dose Escalation Phaseonly).
1L Nivolumab vsSorafenib Cohort:
- To estimateTTP and PFS of nivolumab andsorafenib in subjects with advanced HCC who are naive to 
systemic therapy.
- To evaluate the overall survival (OS) of nivolumab and sorafenib in subjects with advanced HCC who are 
naive to systemic therapy.
- To evaluate the relationship between PD-L1 expression and efficacy.
Nivolumab plus Ipilimumab Combination Cohort
- To assess antitumor activities (TTP and PFS) based on results of BICR and/or investigators using 
RECIST1.1.
- To evaluate overall survival (OS) in subjects treated with nivolumab plus ipilimumab.
- To investigate the potential association between selected biomarker measures, such as PD-L1 expression, 
and clinical efficacy measures including overall survival.
Exploratory Objectives:
Escalation Phase:
- To assess antitumor activities based on results of BICR using mRECIST for HCC.
- To investigate the pharmacodynamic (PD) activity of nivolumab on antiviral immunologic biomarkers 
including HBV or HCV specific immune response in peripheral blood and cell phenotyping by flow 
cytometry.
Revised Protocol No.: 05
Date: 26-Oct-2016
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- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or hepatitis C virus 
(HCV) whether positive or negative as assessed by HCV or HBV viral load, quantitative Hepatitis surface 
antigen (HBsAg) levels, quantitative Hepatitis e antigen (HBeAg) levels, Hepatitis B surface antibody 
(HBsAb), and Hepatitis B e antibody (HBeAb).
- To investigate the pharmacodynamic activity of nivolumab on antitumor immunologic biomarkers in 
peripheral blood and tumor tissue in subjects with advanced HCC.
- To explore the association of oncologic and antiviral clinical activity and safety measures with SNPs.
- To assess the relationship between nivolumab exposure and measures of hepatic dysfunction.
Expansion Phase
- To assess antitumor activities based on results of BICR using mRECIST for HCC.
- To investigate the pharmacodynamic (PD) activity of nivolumab on antiviral immunologic biomarkers 
including HBV or HCV specific immune response in peripheral blood and cellphenotyping by flow 
cytometry.
- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or hepatitis C virus 
(HCV) whether positive or negative as assessed by HCV or HBV viral load, quantitative Hepatitis surface 
antigen (HBsAg) levels, quantitative Hepatitis e antigen (HBeAg) levels, Hepatitis B surface antibody 
(HBsAb), and Hepatitis B e antibody (HBeAb).
- To investigate the pharmacodynamic activity of nivolumab on antitumor immunologic biomarkers in 
peripheral blood and tumor tissue in subjects with advanced HCC.
- To explore the association of oncologic and antiviral clinical activity and safety measures with SNPs.
- To assess the relationship between nivolumab exposure and measures of hepatic dysfunction.
- To characterize the pharmacokinetics of nivolumab in subjects with advanced HCC.
- To assess the immunogenicity of nivolumab in subjects with advanced HCC.
- To assess self-reported health problems as measured using the descriptive system of the 3-level version of 
the EQ-5D (EQ-5D-3L) questionnaire.
- To assess changes in societal utility for self-reported health as measured using the EQ-5D-3L index score.
- To assess changes in subject ratings of own health as measured using the EQ-5D-3L visual analog scale 
(EQ-VAS) score.
1L NivolumabvsSorafenib Cohort
- To evaluate the safety of nivolumab and sorafenib.
- To estimateoverall response rate (ORR) of nivolumab and sorafenib insubjects with advanced HCC who 
are naive to systemic therapy. ORR will be determined with blinded independent central review (BICR) 
assessed tumor response based on RECIST 1.1.
- To assess antitumor activities of nivolumab vs sorafenib based on results of BICR using mRECIST for 
HCC.
- To evaluate disease control rate (DCR), duration of disease control, and time to response of nivolumab and 
sorafenib.
- To evaluate overall survival in subjects who have intrahepatic vsextrahepatic progression for nivolumab 
and sorafenib.
- To evaluate overall survival in subjects with baseline AFP < 400 ng/mLvs > 400 ng/mLfor nivolumab and 
sorafenib.
- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or hepatitis C virus 
(HCV) whether positive or negative as assessed by HCV or HBV viral load.
- To investigate the pharmacodynamic activity of nivolumab on antitumor immunologic biomarkers in 
peripheral blood in subjects with HCC.
- To investigate the potential association between selected biomarker measures in tumor tissue specimens 
and blood samples and clinical efficacy measures including overall survival.
- To explore the association of oncologic and antiviral clinical activity and safety measures with SNPs.
- To characterize the pharmacokinetics of nivolumab in subjects with advanced HCC.
Revised Protocol No.: 05
Date: 26-Oct-2016
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- To assess the immunogenicity of nivolumab in subjects with advanced HCC.
- To assess the subject’s overall health status using the EQ-5D-3L index and visual analog scale.
- To assess the subject’s cancer-related QoL using the Functional Assessment of Cancer 
Therapy-Hepatobiliary (FACT-Hep) questionnaire.
Nivolumab plus Ipilimumab Combination Cohort
- To estimate the ORR and duration of response for nivolumab plus ipilimumab combination therapy in 
subjects with advanced HCC who have been previously treated with sorafenib. ORR will be determined 
with a blinded independent central review (BICR) assessed tumor response based on RECIST 1.1.
- To assess antitumor activities based on results of BICR using mRECIST for HCC.
- To describe the effects of nivolumab plus ipilimumab in subjects infected with hepatitis B virus (HBV) or 
hepatitis C virus (HCV)whether positive or negative as assessed by HCV or HBV viral load.
- To investigate the pharmacodynamic activity of nivolumab plus ipilimumab on antitumor immunologic 
biomarkers in peripheral blood and tumor tissue in subjects with advanced HCC.
- To explore the association of oncologic and antiviral clinical activity and safety measures with SNPs.
- To assess the relationship between nivolumab plus ipilimumab exposure and measures of hepatic 
dysfunction.
- To assess the subject’s overall health status using the EQ-5D-3L index and visual analog scale.
- To characterize the pharmacokinetics of nivolumab and ipilimumab in subjects with advanced HCC.
- To assess the immunogenicity of nivolumab and ipilimumab in subjects with advanced HCC.
Study Design:
The Dose Escalation Phasewill consist of an open label, ascending, multi-dose, sequential 3-arm Phase I study.  
Subjects with differing underlying risk factors for the development of HCC will be evaluated in three separate dose 
escalation cohorts; HCC subjects with no active hepatitis virus infection (uninfected HCC), subjects with HCC due 
to chronic hepatitis C virus infection (HCC-HCV), and subjects with HCC due to chronic hepatitis B virus infection 
(HCC-HBV).  Dose escalation will be performed independently in each group because of the concern that virally 
infected subjects may have a toxicity profile that is more severe.  HBV infected subjects are thought to have the 
highest risk because viral DNA sequences can be found in virtually all hepatocytes even in subjects with complete 
viral clearance as assayed by standard methods.  PD-1 blockade may stimulate antigen-specific T cell responses to 
produce hepatotoxicity.  The study will open with subjects with non-viral HCC and HCC-HCV treated in parallel 
dose cohorts simultaneously.  The initial dose employed in the HCC-HBV cohort will be lower than that employed 
in the other two cohorts.
The Expansion Phasewill consist of treatment of approximately an additional 100uninfected HCC subjects at the 
3mg/kg dose level based on the established safety of the 10 mg/kg dose level in this cohort, observed preliminary 
anti-tumor activity, and preliminary PK analysis of a subset of subjects from CA209040 indicating exposures within 
the expected range of subjects from other tumor types.To further characterize nivolumab safety and activity in the
hepatitis virus cohorts, approximately 50 subjects each will be dosedat the 3 mg/kg dose level for the HCV-and 
HBV-infected cohorts.  This will be in keeping with the selected dose and schedule for expansion of the uninfected 
HCC cohort.  The viral cohorts will no longer be dose escalated to 10 mg/kg. 
The 1L Nivolumab vsSorafenib Cohortwill consist ofapproximately 130advanced HCC subjects who are naive 
to systemic therapy (uninfected, HCV-infected, or HBV-infected) who will be randomized 1:1 to receive open label 
flat dose nivolumab 240 mg Q2 week IV (Arm A) or sorafenib 400 mg po BID (Arm B) until unacceptable toxicity 
or RECIST 1.1disease progression or study discontinuation for any other reason.  Uninfected, HCV-infected, or 
HBV-infected subjects will be enrolled.  Subjects will be stratified by viral status (HCV vsnon-HCV [HBV infected 
or uninfected]) and presence of macrovascular invasion (MVI) or extrahepatic spread (EHS).  Subjects with resolved 
HCV infection will be stratified into the HCV group.  
The Nivolumab and Ipilimumab Combination Cohortwill consist of up to 120 subjects.  Uninfected, 
HCV-infected, or HBV-infected subjects with advanced HCC and previous treatment with sorafenib will be 
randomized 1:1:1 into 3 different dose arms: 
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Arm A--nivolumab 1 mg/kg + ipilimumab 3 mg/kg q3 week x 4 followed by flat dose nivolumab 240 mg IV 
q2week until toxicity or disease progression (n=40)
Arm B--nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3week x 4 followed by flat dose nivolumab 240 mg IV 
q2week until toxicity or disease progression (n=40)
Arm C--nivolumab 3 mg/kg q2week + ipilimumab 1 mg/kg q6week until toxicity or disease progression 
(n=40).
A 2-stage design will be employed foreach of the 3 dose arms.  Twelve subjects in each dose arm will undergo a 
safety and tolerability assessment at Week 13 (or prior to Week 13 if discontinued).  The safety evaluation 
(Section3.1.4) will be conducted independently for each dose cohort based on criteria described in Discontinuation 
Criteria (Sections 4.1.18for nivolumab and 4.2 for ipilimumab).  No additional subjects will be enrolled until the 
safety evaluation at Week 13 occurs.  After completion of Stage 1, enrollment in Stage 2 of the subsequent 
28subjects can occur in each dose arm and is contingent upon the results of the safety evaluation.
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Tumor response will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST1.1). It is 
recognized that there may be delayed responses following disease progression with nivolumab and other agents in 
this class. In these cases, subjects may continue treatment provided that they experience no clinical deterioration. 
These subjects will continue to be evaluated by RECIST1.1. 
Revised Protocol No.: 05
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Duration of Study: The study is expected to accrue over a period of approximately 5 years.  The study will end 
when survival follow-up collection has concluded. The last visit will be defined as the latest survival visit included 
in the final analysis of OS (ie. the latest subject death, loss to follow up, or withdrawal of consent).
Number of Subjects:  Approximately 500subjects including the Dose Escalation Phase(~50subjects), Expansion 
Phase(200 subjects), 1L Nivolumab vsSorafenib Cohort(~130subjects), and Nivolumab plus Ipilimumab 
Combination Cohort(120 subjects).
Study Population: The study population will include men and women age 18 or older with advanced HCC.  
Advanced HCC is HCC not appropriate for management with curative intent by surgery or local therapeutic 
measures. All subjects must have measurable disease at baseline. 
Statistical Considerations:  
Sample Size Determination
Dose Escalation: Sample size at each dose level depends on the observed toxicity and is not based on statistical 
considerations. Three to 6 subjects will be evaluated at each dose level.
Expansion Phase:  In order to better estimate efficacy of nivolumab, approximately an additional 100 uninfected 
subjects (50 Sorafenib progressors and 50 Sorafenib naive or intolerant), 50 HCV-infected subjects, and 
50HBV-infected subjects will be dosed at the 3 mg/kg dose level. If 50 subjects are treated at 3 mg/kg dose level in 
any of the four additional expansion arms and 10 of 50 subjects (20%) are responders (BOR of PR or CR), the lower 
bound of 95% confidence interval of the response rate is 10% using the Clopper-Pearson Method.
1L Nivolumab vsSorafenib Cohort: 
The sample size of about 130 for this cohort is considered to provide a reasonably reliable estimate of ORR for both 
nivolumab and sorafenib arm.  Table 1summarizes the exact 95% CIs and 90% lower bound for a sample size of 65 
subjects per arm when observed ORRs are 3.1% (2/65), 4.6% (3/65), 15.4% (10/65), and 20.0% (13/65) 
respectively. 
Table 1:
Observed ORR and CI under Sample Size of 65 per Arm
Observed ORR
Exact 95% CI
90% Lower Bound
3.1%
(0.4%, 10.7%)
0.8%
4.6%
(1.0%, 12.9%)
1.7%
15.4%
(7.6%, 26.5%)
9.8%
20.0%
(11.1%, 31.8%)
13.7%
Nivolumab plus Ipilimumab Combination Cohort:  The sample size of each arm is decided based on safety and 
efficacy considerations.An initial total of 36 subjects will be randomized 1:1:1 (n=12) into one of three arms within 
stage 1 to assess safety and tolerability.An additional 28 subjects will be enrolled into each arm that remains open 
within stage 2 to further establish efficacy and safety. With sufficient follow up for a total of 40 subjects in an arm, 
this will allow a stable estimate of ORR, adequate safety follow up, as well as information on duration of response. 
The maximum width of the exact 2-sided 95% confidence interval (CI) is 31.8% when the ORR is in the 20% to 
40% range. Table 2summarizes the exact 95% CIs and 90% lower bound for a sample size of 40 per arm when 
observed ORRs are 20% to 40%,respectively. 
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Table 2:
Observed ORR with Exact 95% CIand 90% Lower Bound
Observed ORR
Exact 95% CI
90% Lower Bound
20%
(9.1%, 35.7%)
12.0%
25%
(12.7%, 41.2%)
16.2%
30%
(16.6%, 46.5%)
20.5%
35%
(20.6%, 51.7%)
24.9%
40%
(24.9%, 56.7%)
29.4%
Primary Endpoint
Dose Escalation Phase
The primary objective is safety and tolerability of nivolumab as evaluated by the following endpoints: 
- Incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to 
discontinuation, and deaths.
- Incidence of clinical laboratory test abnormalities.
Expansion Phase
ORR, based on assessments by BICR under RECIST 1.1 criteria, is the primary endpoint. It is defined as the 
proportion of all treated subjectswhose BOR is CR or PR. BOR is the best response designation per subject 
over the study prior to subsequent anti-cancer therapy. For a BOR of CR or PR, the initial response assessment 
must have been confirmed by a consecutive assessment no less than 4 weeks (28days) later.
1L Nivolumab vsSorafenib Cohort
ORR, based on Investigator assessments under RECIST 1.1 criteria, is the primary endpoint. It is defined as the 
proportion of all randomized subjectswhose BOR is CR or PR.  For a BOR of CR or PR, the initial response 
assessment must have been confirmed by a consecutive assessment no less than 4weeks (28days) later.
Nivolumab plus Ipilimumab Combination Cohort
The primary objective is safety and tolerability of nivolumab plus ipilimumab asevaluated by the following 
endpoints.
- Incidence of adverse events (AEs), serious adverse events (SAEs), adverse events leading to 
discontinuation, and deaths.
- Incidence of clinical laboratory test abnormalities.
ORR, as assessed by Investigatorunder RECIST 1.1 criteria, is the co-primary endpoint. It is defined as the 
proportionof all treated subjectswhose BOR is CR or PR.  For a BOR of CR or PR, the initial response 
assessment must have been confirmed by a consecutive assessment no less than 4 weeks (28 days) later.
Secondary Endpoints
The secondary efficacy endpoints for assessing antitumor activities include objective response rate (ORR) (Dose 
Escalation Phaseonly), CR rate, disease control rate (DCR), duration of response (DOR), TTR (time to response), 
TTP (time to progression), TTP Rate and PFS (progression free survival), all of which are based on BICR or 
investigator assessed response evaluation according to RECIST 1.1. These endpoints, as well as OS (overall 
survival) and OSR (overall survival rate), will be applied to all cohorts for treatment groups either as randomized (in 
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1L Nivolumab vsSorafenib Cohort) or as treated (for all other cohorts).Definitions of the above secondary efficacy 
endpoints are available in Section 8.3.2.
The following pharmacokinetic parameters of nivolumab derived from serum concentration time profile of subjects 
in the dose escalation phasewill be included for PK analysis: Cmax, Tmax, AUC(TAU), Ctrough, Ceoinf,
AI_Cmax, AI_AUC, and Effective T-Half.
Cmax: Maximum observed serum concentration 
Tmax: Time of maximum observed serum concentration 
AUC(TAU): Area under the serum concentration time curve in the dosing interval 
Ctrough: Serum concentration achieved at the end of dosing interval (trough concentration) 
Ceoinf: Serum concentration achieved at the end of the infusion
AI_Cmax: Cmax at Cycle 3/ Cmax at Cycle 1
AI_AUC: AUC(TAU) at Cycle 3/ AUC(TAU)  at Cycle 1
Effective T-Half will be calculated by using formula below for AI>1 with AI being AI_AUC









1
ln
)
2
ln(
  
AI
AI
HALF
T
Effective

The secondary endpoints (for Dose Escalationand Expansion Phase) to assess the immunogenicity of nivolumab are 
incidence of subject ADA status, which include baseline ADA-positive, ADA-positive,and ADA-negative. 
Definitions of ADA status are described in theSAP.
Exploratory Endpoint(s) 
Exploratoryendpointsinclude, butarenot limited to, BOR or ORR based on BICR assessed response evaluation 
according to mRECIST for HCC, AFP summary statistics, viral load, EQ-5D and FACT-Hep summary statistics. 
Detailed descriptions of the above exploratory endpoints are seen in Section 8.3.3.
Analyses
Only safety analysis and primary efficacy endpoint analysis aredescribed below. Please refer to Section 8 for 
complete descriptions of statistical analyses.
Safety Analysis
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety will be presented using 
NCI CTCAE version 4.0 by treatment arm. Adverse events, 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, 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 Study Rationale 
................................................................................................. 
1.1.1 Rationale for Nivolumab in Hepatocellular Carcinoma ......................... 
1.1.2 Study Design Rationale for Dose Escalation Phase 
................................ 
1.1.3 Rationale for Expansion of Uninfected Cohorts in Expansion Phase 
..... 
1.1.4 Rationale for Expansion of Hepatitis Virus Infected Cohorts in Expansion 
Phase 
........................................................................................................... 
1.1.5 Rationale for the 1L Nivolumab vs Sorafenib Cohort ............................. 
1.1.6 Rationale for Open Label Design for 1L Nivolumab vs Sorafenib Cohort
.....................................................................................................................
1.1.7 Rationale for Stratification Factors in 1L Nivolumab vs Sorafenib Cohort
.....................................................................................................................
1.1.8 Rationale for Nivolumab plus Ipilimumab Combination Cohort ............ 
1.1.9 Rationale for Objective Response Rate as Primary Endpoint in 1L 
Sorafenib vs Nivolumab Cohort and Nivolumab plus Ipilimumab 
Combination Cohort 
................................................................................... 
1.2 Research Hypothesis 
......................................................................................... 
1.3 Objectives(s) 
..................................................................................................... 
1.3.1 Primary Objectives 
.................................................................................. 
1.3.2 Secondary Objectives 
............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background 
................................................................... 
1.4.1 Pharmacology 
.......................................................................................... 
1.4.1.1 Nonclinical Pharmacology 
............................................................. 
1.4.1.2 Metabolism and Excretion 
.............................................................. 
1.4.1.3 Clinical Pharmacokinetics of Nivolumab 
....................................... 
1.4.1.4 Clinical Pharmacokinetics of Ipilimumab 
...................................... 
1.4.2 Nivolumab Safety Summary 
..................................................................... 
1.4.3 Summary of Nivolumab Clinical Activity 
................................................. 
1.4.4 Summary of Nivolumab plus Ipilimumab Safety Data 
............................. 
1.4.5 Summary of Nivolumab plus Ipilimumab Clinical Activity 
...................... 
1.4.6 Summary of Preliminary Clinical Data from CA209040 ........................ 
1.4.7 Nivolumab Experience in Hepatitis C Infected Subjects ......................... 
1.4.8 Treatment Experiences with Other Immune Checkpoint Inhibitors in 
Subjects with Chronic Hepatitis.................................................................. 
1.4.9 Definitions for Sorafenib Intolerance and Progression........................... 
1.4.10 Rationale for Defining Dose Limiting Hepatic Toxicity in the Dose 
Escalation Phase 
......................................................................................... 
1.4.11 Rationale for Nivolumab Dose in Expansion Phase 
.............................. 
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1.4.12 Rationale for Nivolumab Flat Dosing in 1L Nivolumab vs Sorafenib 
Cohort and Nivolumab plus Ipilimumab Combination Cohort (Post 
Induction in Arms A and B) ........................................................................ 
1.4.13 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab 
.................................................................................................. 
1.4.14 Rationale for Shorter Infusion Times With 240 mg Flat Dose Nivolumab 
and Ipilimumab 
........................................................................................... 
1.4.15 Summary of Drug-related Hepatic Events in CA209040 
....................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS 
............................................................................... 
2.1 Good Clinical Practice 
...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee 
............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN 
.................................................................................... 
3.1 Study Design and Duration 
............................................................................... 
3.1.1 Treatment Flow 
........................................................................................ 
3.1.2 Duration of Study 
..................................................................................... 
3.1.3 Dose Escalation Phase ............................................................................ 
3.1.3.1 Dose Limiting Toxicity in the Dose Escalation Phase 
.................... 
3.1.4 Safety Evaluation of Stage 1 of the Nivolumab plus Ipilimumab 
Combination Cohort 
................................................................................... 
3.1.5 Evaluation of Risk/Benefit for a Cohort that does not meet Tolerability 
Criteria in the Nivolumab plus Ipilimumab Combination 
.......................... 
3.1.6 Stopping Rule for Dose Escalation Cohort 
.............................................. 
3.1.7 Stopping Rules for Clinical Deterioration 
............................................... 
3.1.8 Treatment Beyond Progression for Nivolumab or Nivolumab plus 
Ipilimumab 
.................................................................................................. 
3.2 Post Study Access Therapy 
............................................................................... 
3.3 Study Population 
............................................................................................... 
3.3.1 Dose Escalation and Expansion Phase 
.................................................... 
3.3.1.1 Inclusion Criteria 
............................................................................ 
3.3.1.2 Exclusion Criteria 
........................................................................... 
3.3.2 1L Nivolumab vs Sorafenib Cohort.......................................................... 
3.3.2.1 Inclusion Criteria 
............................................................................ 
3.3.2.2 Exclusion Criteria 
........................................................................... 
3.3.3 Nivolumab plus Ipilimumab Combination Cohort 
................................... 
3.3.3.1 Inclusion Criteria 
............................................................................ 
3.3.3.2 Exclusion Criteria 
........................................................................... 
3.3.4 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments 
................................................................................... 
3.4.1 Prohibited Treatments ............................................................................. 
3.4.2 Other Restrictions and Precautions 
......................................................... 
3.4.3 Palliative Local Therapy 
.......................................................................... 
3.4.4 Treatment of HBV Virological Breakthrough and Ongoing HCV 
........... 
3.5 Discontinuation of Subjects from Treatment 
.................................................... 
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3.6 Re-Initiation of Study Therapy For Subjects from the Dose Escalation Phase in 
the Follow-up Period (Not Applicable Post-Amendment 8) 
............................ 
3.7 Post Study Drug Study Follow-up 
.................................................................... 
3.8 Withdrawal of Consent 
..................................................................................... 
3.9 Lost to Follow-Up 
............................................................................................. 
4 TREATMENTS 
......................................................................................................... 
4.1 Study Treatments 
.............................................................................................. 
4.1.1 Investigational Product 
............................................................................ 
4.1.2 Noninvestigational Product 
..................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.1.4 Sorafenib Dose and Schedule 
.................................................................. 
4.1.5 Nivolumab or Ipilimumab Dose Modifications........................................ 
4.1.6 Nivolumab or Ipilimumab Intrasubject Dose Escalation 
........................ 
4.1.7 Nivolumab or Ipilimumab Dose Reductions 
............................................ 
4.1.8 Sorafenib Dose Reductions 
...................................................................... 
4.1.9 Management Algorithms for Immuno-Oncology Agents 
......................... 
4.1.10 Dose Delay for Nivolumab Monotherapy 
.............................................. 
4.1.11 Dose Delay for Nivolumab plus Ipilimumab Combination Cohort 
....... 
4.1.12 Treatment Interruption or Discontinuation for Sorafenib 
..................... 
4.1.13 Treatment Beyond Progression for Sorafenib ....................................... 
4.1.14 Management of Sorafenib Adverse Events ............................................ 
4.1.15 Protocol-Specific Recommendation for Management of Hepatic Events 
in Nivolumab or Nivolumab plus Ipilimumab Subjects .............................. 
4.1.16 Criteria to Resume Treatment with Nivolumab 
..................................... 
4.1.17 Criteria to Resume Treatment with Ipilimumab .................................... 
4.1.18 Nivolumab Permanent Discontinuation Due to Adverse Event(s) 
......... 
4.2 Ipilimumab Permanent Discontinuation Due to Adverse Event(s) 
................... 
4.3 Method of Assigning Subject Identification 
..................................................... 
4.4 Selection and Timing of Dose for Each Subject 
............................................... 
4.4.1 Treatment of Nivolumab or Ipilimumab Infusion Reactions 
.................... 
4.4.2 Re-Initiation of Study Therapy For Subjects from the Dose Escalation 
Phase in the Follow-up Period (Not Applicable Post-Amendment 8) 
........ 
4.5 Blinding/Unblinding 
......................................................................................... 
4.6 Treatment Compliance 
...................................................................................... 
4.7 Destruction and Return of Study Drug 
............................................................. 
4.7.1 Destruction of Study Drug 
....................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES 
..................................................... 
5.1 Flow Chart/Time and Events Schedule 
............................................................. 
5.2 Study Materials 
................................................................................................. 
5.3 Safety Assessments 
........................................................................................... 
5.4 Efficacy Assessments 
........................................................................................ 
5.5 Pharmacokinetic Assessments 
.......................................................................... 
5.5.1 Pharmacokinetics: Collection and Processing 
........................................ 
5.5.2 Pharmacokinetic Sample Analyses 
.......................................................... 
5.5.3 Labeling and Shipping of Biological Samples 
......................................... 
5.6 Exploratory Biomarker Assessments 
................................................................ 
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5.7 Outcomes Research Assessments 
..................................................................... 
5.8 Other Assessments 
............................................................................................ 
5.8.1 Immunogenicity Assessment 
..................................................................... 
5.9 Results of Central 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
................................................................................................................................. 
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 Endpoints ............................................................................... 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.4 Analyses 
............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses 
..................................................................................... 
8.4.2.1 Efficacy Analysis in 1L Nivolumab vs Sorafenib Cohort 
................ 
8.4.2.2 Efficacy Analysis in Expansion Phase and Nivolumab plus 
Ipilimumab Combination Cohort 
.......................................................... 
8.4.2.3 Efficacy Analysis in Dose Escalation Phase 
................................... 
8.4.2.4 Secondary analysis for association between PD-L1 expression and 
Efficacy ................................................................................................. 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses 
....................................................................... 
8.4.5 Biomarker Analyses 
................................................................................. 
8.4.5.1 Alpha-fetoprotein (AFP) 
................................................................. 
8.4.5.2 Antigen-specific Immune Response Assays and Cell Phenotyping by 
Flow Cytometry 
..................................................................................... 
8.4.5.3 Viral Biomarker Assays .................................................................. 
8.4.5.4 Soluble Factors 
............................................................................... 
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 
........................... 
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CA209040
nivolumab
Revised Protocol No.: 05
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9.1.2 Monitoring 
............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention 
.................................................................................... 
9.2.2 Study Drug Records 
................................................................................. 
9.2.3 Case Report Forms 
.................................................................................. 
9.3 Clinical Study Report and Publications 
............................................................ 
10 GLOSSARY OF TERMS 
........................................................................................ 
11 LIST OF ABBREVIATIONS 
.................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 ALGORITHMS FOR MANAGEMENT OF SIDE EFFECTS 
............ 
 
APPENDIX 2 RECIST 1.1 CRITERIA........................................................................ 
 
APPENDIX 3 CHILD-PUGH SCORE ........................................................................ 
 
APPENDIX 4 ECOG PERFORMANCE STATUS 
..................................................... 
 
APPENDIX 5 MODIFIED RECIST CRITERIA FOR HCC 
....................................... 
 
APPENDIX 6 NEW YORK HEART ASSOCIATION (NYHA) CHF 
CLASSIFICATION 
................................................................................................ 
 
APPENDIX 7 EUROQOL GROUP (EQ-5D) HEALTH QUESTIONNAIRE 
............ 
 
APPENDIX 8 FACT-HEP 
............................................................................................ 
 
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v

Clinical Protocol
CA209040
BMS-936558
nivolumab
(* (&W&)+&*W(WT
Programmed Cell Death-1 (PD-1; CD279) is a cell surface signaling molecule that delivers 
inhibitory signals that regulate the balance between T cell activation and tolerance by interacting 
with its ligands, PD-L1 (CD274; B7-H1) and PD-L2 (B7-DC/CD273).  Itis a 55 kD type I 
transmembrane protein that is a member of the CD28 family of T-cell costimulatory receptors, 
which also includes cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Inducible 
COStimulator (ICOS), and B-and T-lymphocyte attenuator (BTLA).
1 PD-1 contains an 
intracellular membrane proximal immunoreceptor tyrosine inhibitorymotif (ITIM) and a 
membrane distal immunoreceptor tyrosine-based switch motif (ITSM). PD-1 is primarily 
expressed on activated T, B, and myeloid cells.
2Its ligands, PD-L1 (B7-H1/CD274) and PD-L2 
(B7-DC/CD273), have been shown to down-regulate T-cell activation upon binding to PD-1 in 
both murine and human systems.
3,4PD-1 delivers a negative signal by the recruitment of SHP-2 
to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic region.
5,6
Evidence for a negative regulatory role of PD-1 comes from studies of PD-1-deficient mice. 
PD-1-deficient mice develop various autoimmune phenotypes, including dilated cardiomyopathy 
and a lupus-like syndrome with arthritis and nephritis.
7,8,9The emergence of autoimmunity is 
dependent upon the genetic background of the mouse strain; many of these phenotypes emerge at 
different times and show variable penetrance. In addition to the phenotypes of null mutations, 
PD-1 inhibition by antibody-mediated blockade in several murine models has been found to play 
a role in the development of autoimmune diseases such as encephalomyelitis, graft-versus-host 
disease, and type I diabetes.
10,11,12Taken together, these results suggest that PD-1 blockade has 
the potential to activate anti-self T-cell responses, but these responses are variable and dependent 
upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a 
universal loss of tolerance to self antigens. 
Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal 
antibodies (mAbs) can enhance the anti-tumor immune response and result in tumor rejection. 
This suggests that host mechanisms limit the antitumor response.
13,14,15,16,17,18
In humans, PD-L1 is constitutively expressed on macrophage-lineage cells, activated T cells, 
lung, vascular endothelial cells, and placental syncitiotrophoblasts.
19Aberrant expression of 
PD-L1 by tumor cells has been reported in a number of human malignancies.
20,21,22,23,24,25,26
PD-L1 expressed by tumor cells has been shown to enhance apoptosis of activated 
tumor-specific T cells in vitro.
27Moreover, the expression of PD-L1 may protect the tumor cells 
from the induction of apoptosis by effector T cells.
28Retrospective analyses of several human 
tumor types suggest that tumor over-expression (as measured by immunohistochemistry) of 
PD-L1 may permit immune evasion by tumors. In renal cell carcinoma, high surface expression 
levels of PD-L1 on tumor cells are related to tumor aggressiveness. Subjects with high tumor 
and/or lymphocyte PD-L1 levels are 4.5 times more likely to die from their cancer than subjects 
exhibiting low levels of PD-L1 expression.
29In multivariate analysis, high expression of PD-L1 
Revised Protocol No.: 05
Date: 26-Oct-2016
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CA209040
BMS-936558
nivolumab
in melanoma is an independent predictor of vertical growth of primary melanomas and of worse 
outcome.
30
BMS-936558 (nivolumab) is a fully human, IgG4 (kappa) isotype, mAb that binds to PD-1. 
Blockade of the PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction 
(MLR). PD-1 blockade resulted in a reproducible enhancement of `both proliferation and IFN-γ
release in the MLR.
31 The effect of nivolumab on antigen-specific recall response was 
investigated using a CMV-restimulation assay with human peripheral blood mononuclear cells 
(PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, versus an 
isotype-matched control antibody, augmented IFN-γsecretion from CMV-specific memory 
Tcells in a dose-dependent manner.
.)9U:I&*
954
A7
1.1.1
Rationale for Nivolumab in Hepatocellular Carcinoma
Expression of PD-L1 by malignant tumor cells and by other cells in the tumor microenvironment 
including infiltrating T cells, dendritic cells, and monocytes, has the potential to interact with 
tumor specific Tcells that express PD-1. The interaction of PD 1 on tumor specific cytotoxic 
Tcells with its ligands PD-L1 and PD-L2 causes a decrease in the ability of these cells to 
proliferate and exert cytotoxic effects, increases their apoptotic rate and alters thefunctional 
characteristics of the cells to produce a tolerogenic phenotype. This study will evaluate the 
effects of PD-1 blockade by nivolumab in subjects with hepatocellular carcinoma (HCC).  
There is a strong preclinical rationale for blocking PD-1 signaling in HCC.  Lymphocyte 
homeostasis is closely regulated by the differential effects of cytokines and an array of cell 
surface signaling molecules that exert opposing actions on T cell proliferation.
32,33,34One of the 
primary molecules responsible for T cell expansion in response to antigenic stimulation is CD28. 
The interaction of CD28 on the T cell with B7.1 or B7.2 on the antigen presenting cell stimulates 
T cell proliferation and survival through increased expression of bcl2 family members, increased 
production of IL-2 and decreases the threshold of T cell receptors required for activation.
35
CD28 ligation also increases production of interferon gamma.
36By necessity a mechanism for 
elimination of antigen stimulated T cells is required following control of the antigenic challenge 
to maintain the viability of the host. One important regulator of T cell contraction following 
antigen stimulation is CTLA4.
37CTLA4 expression on T cells is increased following antigen 
stimulation and has an affinity for B7.1 and B7.2 that is 10-fold greater than CD28. Upon control 
of an antigenic challenge CTLA4 preferentially interacts with the antigen presenting cell to 
inhibit proliferation of T cells and helps to effect the contraction of the expanded T cell 
population. Mice that are deficient in CTLA4 die within one month of birth due to massive organ 
infiltration with lymphocytes as a result of the lack of this inhibitory signaling pathway.
38
Asecond member of this family of molecules that regulates T cell contraction is PD-1and like 
CTLA4 its expression is increased following antigen stimulation.
Following most viral infections the host is capable of eliciting an effective innate and adaptive 
immune response to eliminate the virus and prevent reinfection. However, both in animals and 
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man there are examples of viral infections that are not eliminated following infection but instead 
a chronic viral infection is established. Examples include lymphocytic choriomeningitis virus 
(LCMV) in mice and hepatitis B and C in man. In chronic LCMV infection, antigen specific 
CD8 T cells demonstrate increased expression of PD-1.
39These T cells have been termed 
“exhausted” due to their inability to control the infecting virus. Administration of an antibody 
that prevents PD-1 interaction with its ligands restores the ability of the cells to eliminate the 
virus infection.
PD-L1 is expressed in tumor biopsies from subjects with HCC.  There is some controversy over 
the cell type that expresses PD-L1 and variability may exist between subjects with different 
stages of disease, etiologic factors associated with HCC, or immunologic response of the host to 
the tumor.
40,41,42,43  Hepatocytes and hepatoma cell lines express PD-L1 and its expression is 
increased by interferon gamma exposure.
44This implies that the malignant cell may be the 
source of PD-L1 expression in some tumors but its expression has variably been observed on the 
malignant cells in patient samples.  Some reports identify the hepatoma cells as PD-L1 positive 
whereas others show them to be negative for its expression.  Instead, PD-L1 is observed on the 
mononuclear cells at the periphery of the malignant cells, potentially acting as a barrier for entry 
of PD-1 positive T cells.  As in renal cell carcinoma and melanoma, expression of PD-L1 in the 
tumor is associated with an adverse outcome.
45,46In a study of 265 subjects with HCC, the 
median disease free survival (DFS)was 14.9 for PD-L1-positive subjects but was not reached for 
PD-L1-negative subjects.  Overall survival (OS) was also worse in subjects with PD-L1 positive 
tumors, 29.6 months versus 59.4 months.    
Hepatocellular carcinoma is diagnosed in more than 500,000 people globally and is the fifth 
most common cancer in men and seventh in women.
47 There is an uneven distribution of HCC 
throughout the world with a higher incidence in Asia and Africa.  This is related primarily to the 
differential rates of hepatitis B infection throughout the world and hepatitis B infection is found 
as a predisposing feature in about 50% of cases.  In the United States about 20,000 cases of HCC 
are diagnosed per year and the incidence is predicted to increase by 81% by 2020.  Risk factors 
for initiation of HCC are related to liver injury and repair particularly in association with liver 
cirrhosis.  Viral infection or other inflammatory insults to the liver account for most cases of 
HCC.  The risk factors for the development of HCC in hepatitis B carriers is highest in Asian 
men older than 40, Asian women over the age of 50, and in those with liver cirrhosis or a family 
history of HCC.  In subjects with chronic hepatitis B infection but without cirrhosis, HCC is 
dependent upon viral genotype, replication and the presence of inflammation.  Most other cases 
of HCC are associated with liver cirrhosis due to a variety of agents that damage the liver.  
Hepatitis C infection is found as the underlying etiology in about 25% of cases and is increasing 
significantly in the United States.  Virtually any cause of liver damage that leads to cirrhosis can 
predispose to HCC. The most common associated disorders include alcohol-induced liver 
disease, fatty liver disease, aflatoxin exposure, primary biliary cirrhosis, or genetic predisposition 
to liver damage including hemochromatosis, alpha-1 antitrypsin deficiencyor Wilson’s disease.  
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Advances in the treatment of HCC have been related to improved disease control due to early 
detection.  Early detection permits a curative surgical approach or use of local therapies such as 
radiofrequency ablation or cryotherapy asa curative option for management.  Unfortunately up 
to 70% of subjects will recur.  Liver transplantation is another curative treatment for HCC.
HCC is diagnosed at an advanced stage in more than 80% of subjects thus precluding potentially 
curative treatment approaches. The prognosis of advanced HCC largely depends not only on the 
characteristics of the tumor but also on the severity of the underlying chronic hepatic disease, as 
well as the patient’s general condition.
48,49,50 Although chemotherapy has demonstrated activity 
against HCC, the current standard of care for subjects with advanced HCC is sorafenib.
51  
Arandomized double-blind, placebo-controlled trial of sorafenib administered at a dose of 
400mg twice daily showed a 2.8 month improvement in medianoverall survival from 
7.9months to 10.7 months (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 
0.55 to 0.87; P<0.001).  The median time to radiologic progression was also improved in the 
sorafenib group from 2.8 months to 5.5 months.  There was however no significant difference in 
median time to symptomatic progression in those treated with sorafenib.  Following sorafenib 
progression there is currently no standard of care agents that demonstrate a survival advantage. 
1.1.2
Study Design Rationalefor Dose Escalation Phase
PK data from subjects with normal hepatic function (804 subjects) and those with mild hepatic 
impairment (92 subjects), indicate that nivolumab clearance is not affected by mild hepatic 
impairment (< 20% effect on clearance).   Exposures in mild hepatic impairment subjects that 
received nivolumab Q2W were comparable with normal subjects. Thus, mild hepatic impairment 
had no effect on nivolumab clearance and exposure, suggesting that no dose adjustment is 
needed for subjects with mild hepatic impairment.  However, PK data were not available for 
subjects with moderate and severe hepatic impairment.
52
HCC generally occurs in the setting of an underlying cirrhosis and impaired liver function.  In 
addition, nivolumab is known to have potential hepatic adverse events(Section1.4.2).  For this 
reason, this study was initially designed to specifically assess the safety and tolerability of 
multiple doses of nivolumab in subjects with HCC.
Furthermore, there were additional concerns for HCC subjects with on-going active hepatitis 
virus infections.  Stimulation of the immune system could potentially result in immune related 
viral clearance due to a cytolytic viral-specific response and additional hepatic toxicity.  This 
was of particular concern in subjects with chronic hepatitis B infection whotend to have a higher
number of infected hepatocytesexpressing viral-specific antigensthan subjects with chronic 
hepatitis C infection.  In addition, the potential for ALT flares due to complex and poorly 
characterized changes in viral-host interactions is a well-described phenomenon in subjects with 
chronic HBV infection which can result in significant morbidity and mortality.  Therefore, there 
was a significant concern that the immunostimulatory effect of nivolumab could result in a 
greater frequency of hepatic adverse events in virally-infected HCC subjects, with HBV-infected 
subjects perceived to have the greatest risk.   
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For these reasons, the study was initially designed with 3 separate HCC cohorts: an uninfected 
HCC cohort (no active hepatitis virus infection), an HCV-HCC cohort (with active HCV 
infection), and an HBV-HCC cohort (with active HBV infection).  Dose escalation was planned 
to proceed independently within each cohort.  In addition, the HBV-HCC cohort was started at 
0.1 mg/kg (one dose level belowthe starting dose of 0.3 mg/kg in the uninfected and HCV-HCC 
cohorts).
1.1.3
Rationale for Expansion of Uninfected Cohortsin Expansion Phase
Preliminary data from this study has demonstrated the safety and tolerability of nivolumab in 
uninfected HCC up to 10 mg/kg administered every 14 days.  As of 7-Oct-2014, nineteen 
uninfected HCC subjects have been treated in the current studyat doses of 0.1 mg/kg (n=1), 
0.3mg/kg (n=3), 1.0 mg/kg (n=3), 3.0 mg/kg (n=3), and 10.0 mg/kg (n=9).  Preliminary 
anti-tumor activity from 17 evaluable uninfected subjects has been observed with1 complete 
response (CR)at 1 mg/kg, 1 CR at 3 mg/kg, and 1 partial response (PR)at 10 mg/kg.  In 
addition, a BMS-assessed best overall response (BOR)of stable disease (SD)has been observed 
in 6subjects (with durable responses over 15 months).  These data are promising especially 
when compared to historical data with ORR of 2% to 7% and median TTP of 2.8 to 4.1 months 
in the first linesetting with sorafenib and warrants further exploration.
The uninfected HCC cohort in the dose escalation phase is a heterogeneous population of 
subjects who have progressed followingor intolerant of at least one line of therapy or refused 
sorafenib treatment.  Sorafenib is the only approved drug for the treatment of HCC and is the 
current standard of care for HCC patient not amenable to curative local therapy.  Of note, the 
majority (21 of 28[75%]) of subjects with evaluable responses in CA209040 have had prior 
sorafenib exposure, including all subjects (uninfected, HCV, or HBV cohorts) with either CR
(n=2) or PR(n=4).  In addition, 9 of 12 subjects with SDhave had prior sorafenib exposure.  
Sorafenib has been shown to have limited effects on antitumor immunity.  Low dose sorafenib 
may promote effector CD4+ T-cell function in peripheral blood mononuclear cells obtained from 
patients with HCC.  Sorafenib has also been reported to decrease Th2 and Treg cells in
peripheral blood from patients with HCC.
53  The tumor immunobiology may therefore be 
different between subjects who fail sorafenib and those with inadequate or no exposure to 
sorafenib.  Two expansion cohorts will therefore be added to further understand nivolumab’s 
effects in anuninfected cohort of HCC subjects who failed sorafenib and in an uninfected cohort 
of HCC subjects who are sorafenib naive or sorafenib intolerant.  
In the nivolumab clinical development program, the recommended nivolumab monotherapy dose 
and schedule of 3 mg/kg Q2W is the same across tumor-types.  This was based on the observed 
clinical safety and efficacy from the 306 subjects treated in CA209003 across different dose 
levels and tumor types (non-HCC: metastatic castrate resistantprostate cancer, renal cell 
carcinoma, colorectal adenocarcinoma, malignant melanoma, and non-small cell lung cancer).  
The multiple dose safety profile of nivolumab monotherapy is acceptable, in the context of the 
observed clinical activity, and manageable. The nature, frequency, and severity of AEs were 
similar across tumor types and dose levels. In the Phase 1 setting, dose escalation up to 10 mg/kg 
(0.1 to 10 mg/kg) was achieved without reaching a MTD.  In addition, an integrated assessment 
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of data from in vitro, preclinical, and clinical studies and exposure-response in multiple tumor
types was used to support the dose selection.  In exposure analysis for steady-state trough 
concentration and best overall response, a trend was observed for each tumor type, but appeared 
to plateau at 3 mg/kg Q2W doses for all tumor types.
Preliminary clinical safety data from this study indicates that the profile of nivolumab in subjects 
with advanced HCC is generally consistent with the safety profile from other tumortypes.  
Subjects in the uninfected cohort were safely dosed up to 10mg/kg Q2W.  Preliminary 
pharmacokinetic data in the uninfected HCC cohort indicate consistency with observations from 
other tumor types.  As of 07-Oct-2014, responses in 28evaluable subjects (across all 3 cohorts) 
have been observed at all dose levels ranging from 0.1 to 10.0 mg/kg; two CRs have been 
observed at 1.0 and 3.0 mg/kg, whereas 4 PRs have been observed at 0.1, 0.3, 1.0, and 
10.0mg/kg.  Based on the observed safety and efficacy of nivolumab from CA209003 and 
CA209040, in conjunction with clinical pharmacology profiles, 3 mg/kg IV Q2W was selected 
as the nivolumab monotherapy dose and schedule for expansion of the uninfected cohorts. The 
selected dose and schedule provides for unified monotherapy dosing across the nivolumab 
development program.
1.1.4
Rationale for Expansion of Hepatitis Virus Infected Cohorts in 
Expansion Phase
As of 07-Oct-2014, the 2 hepatitis virus infected cohorts were in the dose escalation period.  At 
that time, eight subjects each hadbeen treated in the HCV or HBV cohorts.  In both arms, 
preliminary anti-tumor activity has been observed.  In7 evaluable subjects in the HCV arm, 
there have been two PRs at0.3 mg/kg and 1.0mg/kg, 4 subjects with SD (2 at 0.3 mg/kg and 2 at 
1mg/kg), and 1 PD at 1.0 mg/kg; in 4 evaluable subjects in the HBV arm at 0.1 mg/kg, there has 
been 1 PR, 1 SD, and two subjects with PD.  Thus, preliminary efficacy data indicate anti-tumor 
effects regardless of viral etiology.  
In addition to the anti-tumor effects, preliminary results also suggest anti-viral activity.  In the 
HCV cohort, 3 subjects have experienced significant HCV RNA declines ranging from 1.0log10
to >4 log10.  Of these 3 subjects with evidence of significant antiviral activity, one had a 
transient decline in HCV RNA to < LOQ (limit of quantification); however, virologic rebound 
occurred and the subject has returned to baseline.  In the HBV cohort, none of the subjects has 
had a significant change in viral biomarkers at the lowest dose tested of 0.1 mg/kg.
In summary, preliminary data indicate anti-tumor as well as anti-viral effects in HCC subjects 
with viral hepatitis.  Nivolumab in this setting has also demonstrated an acceptable safety profile.  
Thus, the amendment 4 proposes to expand both HCV and HBV cohorts to enroll additional 
subjects and further characterize the safety, anti-tumor, and anti-viral propertiesof nivolumab.  
The uninfected HCC cohort has been safely dose escalated to the 10 mg/kg dose level.  This 
cohort will be expanded at the 3 mg/kg dose level in keeping with monotherapy dosing across 
the nivolumab program.  As such, the HCV and HBV viral cohorts (currently dosing at 3 mg/kg 
and 1 mg/kg, respectively, without any safety concerns) will no longer bedose escalated to the 
10 mg/kg dose level.  These expansions will take place atthe 3mg/kg dose level if no DLTs are 
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observed at this dose.  This will be in keeping with the selected dose and schedule selected for 
expansion of the uninfected HCC cohort. If however, the MTD is established at a lower dose 
level, expansions will take place at that lower dose level.
1.1.5
Rationale for the 1L Nivolumab vs Sorafenib Cohort
Based on an interim analysis with a data cutoff of 12-Mar-2015, 47 subjects with advanced HCC
had been treated with nivolumab at doses ranging from 0.1 mg/kg to 10 mg/kg.  As outlined in 
Section1.4.6, there have been 42 subjects with evaluableresponses.  Antitumor activity has been 
observed in uninfected and viral-infected subjects, and at dose levels ranging from 0.1 mg/kg to 
10 mg/kg.  Overall, investigator-assessed responses by RECIST1.1 have been observed in 8 of 
42 subjects (19%) with evaluable response data, including 2 CRs and 6 PRs, and median OS for 
all treated subjects is approximately 15 months.  These data are promising especially when 
compared to historical data of sorafenib (the only agent approved for treatment of subjects with 
advanced HCC) in the first linesetting (subjects naive to systemic treatment) with ORR of 2% 
to 7% by RECIST and 9% by mRECIST, median TTP of 2.8 to 4.1 months, and median OS of 
6.5 to 10.7months in patients with previously untreated HCC.
54,55,56,57,58 In addition to 
preliminary anti-tumor activity, nivolumab has demonstrated an acceptable safety profile for 
subjects with advanced HCC as outlined in Section1.4.6.  
Currently, there is only one approved agent for subjects with advanced HCC (sorafenib), and 
there are no approved therapies for patients with advanced HCC who are intolerant to sorafenib 
or have progressed after sorafenib treatment.  As described in Sections1.1.2and 3.1.3, study 
CA209040 was initially designed as a Phase 1 dose-escalation study to investigate the safety, 
immunoregulatory activity, pharmacokinetics, and preliminary anti-tumor activity of nivolumab 
in advanced HCC subjects with or without chronic viral hepatitis.  Given the preliminary yet 
promising antitumor activity of  nivolumab in advanced HCC as outlined in Section1.4.6in 
CA209040, a predominantly 2L(post-sorafenib)patient population, BMS proposes a randomized
cohort to explore efficacy of nivolumab vssorafenib in1L(systemic therapy naive)HCC 
patients.  
Despitethe demonstrated benefits of sorafenibin advanced HCC,the prognosis of patients with 
advanced HCC has not been radically improved.
59  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.
55,56 Furthermore, the landmark sorafenib trials also failed to demonstrate
symptomatic improvement or improvement in quality of life.
60  GIDEON, the largest real-life 
study conducted on the use of sorafenib, reported sorafenib-related adverse events in 64% of 
patients, 23% of which were Grade 3 or 4 AEs.  In 28% of patients, AEs resulted in permanent
discontinuation of sorafenib.
61  Overall, the most common adverse events were diarrhea (25%), 
hand-foot skin reaction (24%), fatigue (14%), rash/desquamation (12%), anorexia (9%), 
hypertension (7%), and alopecia (7%).  Asians further experience more hand-foot-skin reactions 
(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.  Predictive biomarkers for sorafenib benefit 
that could refine the risk-benefit ratio for therapy have not yet been validated.
60,62These data 
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highlight the continued unmet medical need for advanced HCC subjects in the 1L setting. Thus, 
given the efficacyand safety data observed in CA209040 as outlined in Section1.4.6, nivolumab 
monotherapy may offer improved benefit to subjects in the 1L setting. 
1.1.6
Rationale for Open Label Designfor 1L Nivolumab vsSorafenib Cohort
This cohortis an open-label randomized controlled trial design.  Nivolumab and sorafenib 
belong to two different drug classes with key differences in the mechanism of adverse events.  
The adverse event profiles of nivolumab and sorafenib have events like skin-, gastrointestinal-, 
and thyroid-related signs and symptoms that have different approaches to management.  In 
particular, there are different approaches to dose reductions and delays and the use of 
immunosuppressants.  An open-label design ensures that adverse events are appropriately 
identified and managed according to the studytherapy the subject is receiving.  
Because of the open label design, response-related endpoints for all randomized subjects will be 
determined by an Independent Radiologic Review of tumor assessments.
1.1.7
Rationale for Stratification Factorsin 1L Nivolumab vsSorafenib 
Cohort
Stratification factors for this cohort will include:
HCV vs non-HCV, and 
Presence of investigator-assessedvascular invasion or extrahepatic spread (VI/EHS)vs 
absence of VI/EHS.
The rationale for these 2 stratification factors is based on the following information summarized 
below.
Randomized phase 3 trials in HCC that followed after the sorafenib pivotal trials have all failed 
to demonstrate positive outcomes.  These include 4 phase 3 trials in the first-line setting with 
sunitinib, brivanib, linifanib, and erlotinib.
57,58,63,64The reasonsfor trial failure are considered
heterogeneous and include lack of understanding of critical drivers of tumor 
progression/dissemination, liver toxicity, flaws in trial design, or marginal tumor potency.
11   
With respect to trial design, publications have cited potential imbalances in prognostic baseline 
factors.
The randomized Phase 3 trials mostly stratified by the presence or absence of vascular invasion 
and/or extrahepatic spread (VI/EHS), region, and ECOG performance status (PS).  Despite 
stratification and randomization, there are notable differences in the outcomes.  Subset analysis 
of the 2pivotal sorafenib trials showed differences in the outcomes of patients who had VI/EHS 
compared to those who did not have VI/EHS.  Subjects who had VI/EHS had worse outcomes 
than subjects without VI/EHS.
65,66,67  This study will therefore stratify by VI/EHS.
An important issue that has emerged from the recent HCC trials is evidence that suggests that the 
benefits of angiogenesis inhibition may vary in patients with different etiologies.  Greater 
improvement in survival in the HCV-HCC subjects with both sorafenib and sunitinib 
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(14vs8.7months and 17.6 vs 9.2 months, respectively.
57 Literature has long cited that 
clinicopathologic features and prognoses differ among the different etiologies of HCC.
68  To 
date, most international clinical trials allow recruitment of HCC patients with different etiologies 
resulting in difficulties with data interpretation in a heterogeneous population.  The linifanib trial 
was the only large trial that stratified by etiology, ie, HBV+ HCC vsHBV-HCC.  No significant 
differences were observed in overall survival outcomes.  In the meta-analysis of the sorafenib 
trials, the synthesized hazard ratio for HCV-HCC patients was significantly lower than that for 
HCV(-) patients.  Differences in overall survival outcomes for HBV-HCC and non-viral HCC
(uninfected HCC)have not been distinctly difference.  This study will therefore stratify by 
etiology, specifically HCV-HCC vsnon-HCV-HCC.
No clear differences in regionaloutcomes emerged from the 2 pivotal sorafenib trials or from the 
erlotinib, brivanib, and sunitinib trials.  There was a trend toward better outcomes in Japan 
compared to the rest of Asia and the non-Asian regions in the linifanib trial.  A recent 
meta-analysis of 6 randomized controlled sorafenib trials did not find any differences between 
the Asian and non-Asian subjects.
69  Therefore, this study will not stratify by region.
Lastly, trial outcomes in the sorafenib pivotal trials and the sorafenib comparative trials did not 
differ by ECOG PS. The meta-analysis of sorafenib trials also did not demonstrate significantly 
different hazard ratios for patients with different ECOG PS.
69  ECOG PS will therefore not be a 
stratification factor in this trial.
1.1.8
Rationalefor Nivolumab plus Ipilimumab Combination Cohort
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of
immuno-oncology and treatment with investigational agents targeting this mechanism has
induced regressions in several types of cancer. Programmed death 1 (PD-1) receptor and 
cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) are two important cellular targets that 
play complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell 
exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation.In
preclinical models, combined blockade of PD-1 and CTLA-4 achieved more pronounced
antitumor activity than blockade of either pathway alone.
70
Ipilimumab is a fully humanized IgG1 monoclonal antibody binding to the anti-cytotoxic T-cell
lymphoma-4 antigen (CTLA-4). Ipilimumab is an approved therapy for metastatic melanoma
[YervoyPrescribing Information, 2011] and has demonstrated improved overall survival as
monotherapy and in combination with dacarbazine.
71,72 Ipilimumab has been studied in
combination with multiple standard of care (SOC) therapies including chemotherapy for
squamous and non-squamous NSCLC and radiotherapy for hormone resistant prostate cancer. 
Phase 3 studies are ongoing in NSCLC, SCLC, and prostate carcinoma.
73
Preliminary data in patients with advanced HCC support the continued developmentof 
Immuno-Oncology (IO)agents in this tumor type.  In a Phase 2, non-controlled, open-label, 
multicenter trial, tremelimumab, a monoclonal antibody that blocks CTLA-4, was administered 
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at a dose of 15 mg/kg IV every 90 days in20 subjects with advanced HCC and chronic HCV.
74  
In terms of antitumor responses, thispilot study in HCV-HCC patients treated with a CTLA-4 
blocking antibody, reported a partial response rate (PR) of 17.6%, a disease control rate (DCR) 
of 76.4%, and a time to progression of 6.48months, which compares favorably with sorafenib 
data as outlined above in Section1.1.3.  A rise in serum transaminases was observed after the 
first dose in more than half of the subjects.  Five of 20subjects (25%) experienced a Grade 3 or 
higher elevation in ALT.  However, in all cases, the transaminitis was transient, not associated 
with a decline in liver function, did not require steroid management, and did not recur with 
subsequent doses.  An HCC clinical trial is currently on-going for tremelimumab in combination 
with chemoembolization or ablation.
75  
In vitro combinations of nivolumab plus ipilimumab increase IFN-production 2-to 7-fold over
either agent alone in a mixed lymphocyte reaction. In a murine melanoma vaccine model,
blockade with either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 and
PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor
infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to
either agent alone.
63  
Combining immunotherapeutic agents with different mechanisms of action offers the possibility
of an additive tosynergistic response. PD-1 and CTLA-4 are both co-inhibitory molecules, but 
evidencesuggests that they use distinct mechanisms to limit T cell activation. Preliminary 
indirect datafrom peripheral T cell assessments suggest that a given T-cell checkpoint inhibitor 
may modulatehost immune cell phenotype rendering them more susceptible toalternate 
checkpoint inhibitorsand thereby enhancing anti-tumor activity.  In a Phase 1 study of the 
combination of nivolumab plus ipilimumab in advanced melanoma(CA209004), there was a 
41% response rate, including a 17% complete response rate (CR).
76Arandomized Phase 2 study 
(CA209069) comparing nivolumab plus ipilimumab versusipilimumab showed an objective 
response rate of 61%, including a 22% complete response rate,in previously untreated, advanced 
melanoma patients with BRAF wild-type mutation status,versus 11 % for ipilimumab alone.
77In 
addition, the combination regimen decreased the risk ofmelanoma progression or death 
compared to ipilimumab alone by 60%. 
In a Phase 3 trial of combined nivolumab and ipilimumab or monotherapy in untreated 
melanoma (CA209067), nivolumab alone or combined with ipilimumab resulted in significantly 
longer progression-free survival than ipilimumab alone. The median progression-free survival 
was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as 
compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or 
disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 
9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 
0.76; P<0.001).  In patients with PD-L1–negative tumors, the combination of PD-1 and 
CTLA-4 blockade was more effective than either agent alone.
78  Additional efficacy and safety 
results demonstrating the potential for a combination IO approach are outlined in Sections1.4.4
and 1.4.5.  
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Taken together, the preliminary monotherapy data of CTLA4 and PD-1 pathway inhibition in 
HCC demonstrate antitumor activity and manageable safety profiles.  Given the increased 
efficacy observed with combination approaches in other tumor types, nivolumab plus ipilimumab 
may offer subjects with advanced HCC, who have been previously treated with sorafenib and 
have no other approved treatment options, the potential for benefit.
1.1.9
Rationale for Objective Response Rateas Primary Endpoint in 1L 
Sorafenib vs Nivolumab Cohort and Nivolumab plus Ipilimumab 
Combination Cohort
As outlined in Section 1.4.6, the response rate for nivolumab in predominantly 2L advanced 
HCC subjects of 19% (8 of 42 subjects) in the Dose Escalation Phase of CA209040 and 
preliminary 1 year survival of 61% compares favorablyto sorafenib in the 1L setting as outlined 
in Section 1.1.5Antitumor activity has been observed in uninfected and viral-infected subjects, 
and at dose levels ranging from 0.1 mg/kg to 10 mg/kg.  Overall, responses as assessed by 
RECIST1.1 have been observed in 8 of 42 subjects (19%) with evaluable response data, 
including 2 CRs and 6 PRs.  In addition to preliminary anti-tumor activity, nivolumab has 
demonstrated an acceptable safety profile for subjects with advancedHCC(Section 1.4.6).
Objective Response Rate (ORR)as estimated by RECIST 1.1 assessments from a blinded 
independent central review (BICR)is the primary endpoint for therandomized 1L Nivolumab vs
Sorafenib Cohortand the Nivolumab plus Ipilimumab Combination Cohort.
The primary analysis of ORR will be performedat least6 months after the last patient first dose 
date. Six months follow-up is thought to be sufficient to characterize durableclinicalbenefit 
because in the dose escalation cohorts of CA209040,the majority of responses to nivolumab 
occurred early (by Week 12) in 7 of 8 subjects; the median duration of response (DOR)was 
approximately 12months; and in 1L trials with sorafenib the median time to progression is 
usually < 4 months. This will allow sufficient follow up for ORR to have a stable estimate, 
adequate safety follow up,as well as information on duration of response in the 1L Nivolumab 
vsSorafenib Cohortand Nivolumab plus Ipilimumab Combination Cohort.  Furthermore, in 
advancedHCC subjects who received a systemic multikinase inhibitor, brivanib(BRISK-PS), 
ORR has been shown to be an independent predictor of OS with median OS of 16.4 months in 
brivanib respondersvs8.3 months for brivanib non-responders (hazard ratio 0.28; 95%
CI0.14-0.55, P<0.01).
79
.M
*778B&IH9B75
The purpose of the Dose Escalation Phaseof this study is to evaluate the safety profile, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following IV infusion at doses 
of 0.1, 0.3, 1, 3, and10 mg/kg of nivolumab in subjects with advanced hepatocellular carcinoma 
(HCC) administered every 14days.
In the Expansion Phase, treatment with nivolumab monotherapy will lead to clinical benefit as 
demonstrated by a clinically meaningful objective response rate (ORR) and duration of response 
in subjects with advanced HCC who have been previously treated with sorafenib. 
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In the 1L Nivolumab vsSorafenib Cohort,nivolumab administration in subjects with advanced 
hepatocellular carcinoma (HCC) who are naive tosystemic therapy will improve ORRcompared 
with sorafenib.
In the Nivolumab plus Ipilimumab Combination Cohort, treatment with nivolumab plus 
ipilimumab will lead to clinical benefit as demonstrated by a clinically meaningful objective 
response rate (ORR) and duration of response in subjects with advanced HCC who are 
previously treated with sorafenib.  In addition, the purpose of the cohortis to evaluate the safety 
profile of the combination in subjects with advanced HCC who have been previously treated 
with sorafenib. 
./
Ka7895R7CG
1.3.1
Primary Objectives  
Dose Escalation Phase:To establish the safety, tolerability, dose limiting toxicities (DLT) 
and maximum tolerated dose (MTD) for nivolumab administered every 14 days to subjects 
with advanced HCC.
Expansion Phase: To estimate the ORR and duration of response of nivolumab monotherapy 
in subjects with advanced HCC who are naive to sorafenib orhave been previously treated 
with sorafenib.  ORR will be determined with a blinded independent central review (BICR) 
assessed tumor response based on RECIST 1.1.
1L Nivolumab vsSorafenib Cohort: To estimate overall response rate (ORR) of nivolumab 
and sorafenibinsubjects with advanced HCC who are naive to systemic therapy. ORR will 
be determined with Investigator assessed tumor response based on RECIST 1.1.
Nivolumabplus Ipilimumab Combination Cohort:  
- To establish the safety and tolerability of nivolumab plus ipilimumab in subjects with 
advanced HCC.
- To estimate the ORR and duration of response fornivolumab plus ipilimumab 
combination therapyin subjects with advanced HCC who have been previously treated 
with sorafenib. ORR will be determined with Investigatorassessed tumor response based 
on RECIST 1.1.
1.3.2
Secondary Objectives
Escalation and Expansion Phase:
- To assess antitumor activities(Time to Progression (TTP)and Progression Free Survival 
(PFS))based on results of blinded independent central review (BICR)and/or 
investigators using RECIST 1.1.
- To evaluate overall survival (OS) insubjects treated with nivolumab monotherapy.
- To investigate the potential association between selected biomarker measures, such as 
PD-L1 expression, and clinical efficacy measures including overall survival.
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- To characterize the pharmacokinetics of nivolumab in subjects with advanced HCC
(Dose Escalation Phaseonly).
- To assess the immunogenicity of nivolumab in subjects with advanced HCC (Dose 
Escalation Phaseonly).
1L Nivolumab vsSorafenib Cohort:
- To estimateTTP and PFS of nivolumab andsorafenib in subjects with advanced HCC 
who are naive to systemic therapy.
- To evaluatethe overall survival (OS)of nivolumab and sorafenib in subjects with 
advanced HCC who are naive to systemic therapy.
- To evaluate the relationship between PD-L1 expression and efficacy.
Nivolumab plus Ipilimumab Combination Cohort:
- To assess antitumor activities (TTP and PFS) based on results of BICR and/or 
investigators using RECIST 1.1.
- To evaluate overall survival (OS) insubjects treated with nivolumab plus ipilimumab.
- To investigate the potential association between selected biomarker measures, such as 
PD-L1 expression, and clinical efficacy measures including overall survival.
1.3.3
Exploratory Objectives
EscalationPhase:
- To assess antitumor activities based on results of BICRusing mRECIST for HCC.
- To investigate the pharmacodynamic (PD) activity of nivolumab on antiviral 
immunologic biomarkers including HBV or HCV specific immune response in peripheral 
blood and cell phenotyping by flow cytometry.
- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or 
hepatitis C virus (HCV) whether positive or negative as assessed by HCV or HBV viral 
load, quantitative Hepatitis surface antigen (HBsAg) levels, quantitative Hepatitis e 
antigen (HBeAg) levels, Hepatitis B surface antibody (HBsAb), and Hepatitis B e 
antibody (HBeAb).
- To investigate the pharmacodynamicactivity of nivolumab on antitumor immunologic 
biomarkers in peripheral blood and tumor tissue in subjects with advanced HCC.
- To explore the association of oncologic and antiviral clinical activity and safety measures 
with SNPs.
- To assess the relationship between nivolumab exposure and measures of hepatic 
dysfunction.
Expansion Phase:
- To assess antitumor activities based on results of BICRusing mRECIST for HCC.
- To investigate the pharmacodynamic (PD) activity of nivolumab on antiviral 
immunologic biomarkers including HBV or HCV specific immune response in peripheral
blood and cell phenotyping by flow cytometry.
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- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or 
hepatitis C virus (HCV) whether positive or negative as assessed by HCV or HBV viral 
load, quantitative Hepatitis surface antigen (HBsAg) levels, quantitative Hepatitis e 
antigen (HBeAg) levels, Hepatitis B surface antibody (HBsAb), and Hepatitis B e 
antibody (HBeAb).
- To investigate the pharmacodynamicactivity of nivolumab on antitumor immunologic 
biomarkers in peripheralblood and tumor tissue in subjects with advanced HCC.
- To explore the association of oncologic and antiviral clinical activity and safety measures 
with SNPs.
- To assess the relationship between nivolumab exposure and measures of hepatic 
dysfunction.
- To characterize the pharmacokinetics of nivolumab in subjects with advanced HCC.
- To assess the immunogenicity of nivolumab in subjects with advanced HCC.
- To assess self-reported health problems as measured using the descriptive system of the 
3-level version of the EQ-5D (EQ-5D-3L) questionnaire.
- To assess changes in societal utility for self-reported health as measured using the 
EQ-5D-3L index score.
- To assess changes in subject ratings of own health as measured using the EQ-5D-3L 
visual analog scale (EQ-VAS) score.
1L Nivolumab vs Sorafenib Cohort:
- To evaluate the safety of nivolumab and sorafenib.
- To estimate overall response rate (ORR) of nivolumab and sorafenib insubjects with 
advanced HCC who are naive to systemic therapy. ORR will be determined with blinded 
independent central review (BICR) assessed tumor response based on RECIST 1.1.
- To assess antitumor activities of nivolumab vssorafenib based on results of BICRusing 
mRECIST for HCC.
- To evaluate disease control rate (DCR), duration of disease control, andtime to response 
of nivolumab and sorafenib.
- To evaluate overall survival in subjects who have intrahepatic vs extrahepatic progression
for nivolumab and sorafenib.
- To evaluate overall survival in subjectstreated with nivolumab or sorafenibwith baseline 
AFP < 400 ng/mLvs > 400 ng/mL.
- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or 
hepatitis C virus (HCV) whether positive or negative as assessed by HCV or HBV viral 
load.
- To investigate the pharmacodynamicactivity of nivolumab on antitumor immunologic 
biomarkers in peripheral blood in subjects with HCC.
- To investigate the potential association between selected biomarker measures in tumor 
tissue specimens and blood samples and clinical efficacy measures including overall 
survival.
- To explore the association of oncologic and antiviral clinical activity and safety measures 
with SNPs.
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- To characterize the pharmacokinetics of nivolumab in subjects with advanced HCC.
- To assess the immunogenicity of nivolumab in subjects with advanced HCC.
- To assess the subject’s overall health status using the EQ-5D-3L index and visual analog 
scale.
- To assess the subject’s cancer-related QoL using the Functional Assessment of Cancer 
Therapy-Hepatobiliary (FACT-Hep) questionnaire.
Nivolumab plus Ipilimumab Combination Cohort:
- To estimate the ORR and duration of response fornivolumab plus ipilimumab 
combination therapyin subjects with advanced HCC who have been previously treated 
with sorafenib. ORR will be determined with a blindedindependent central review 
(BICR) assessed tumor response based on RECIST 1.1.
- To assess antitumor activities based on results of BICR using mRECIST for HCC.
- To describe the effects of nivolumab in subjects infected with hepatitis B virus (HBV) or 
hepatitis C virus (HCV) whether positive or negative as assessed by HCV or HBV viral 
load.
- To investigate the pharmacodynamicactivity of nivolumab plus ipilimumabon antitumor 
immunologic biomarkers in peripheral blood and tumor tissue in subjects with advanced 
HCC.
- To explore the association of oncologic and antiviral clinical activity and safety measures 
with SNPs.
- To assess the relationship between nivolumab plus ipilimumabexposure and measures of 
hepatic dysfunction.
- To assess the subject’s overall health status using the EQ-5D-3L index and visual analog 
scale.
- To characterize the pharmacokinetics of nivolumab and ipilimumab in subjects with 
advanced HCC.
- To assess the immunogenicity of nivolumab and ipilimumab in subjects with advanced 
HCC.
.Y
,:U89&7R7AH0749&S831U4:
A summary of the nonclinical pharmacology, toxicology, pharmaceutical and metabolism data is 
provided in this section. Additional information can be found in the Investigator Brochuresfor 
nivolumab80and ipilimumab.
81
1.4.1
Pharmacology
1.4.1.1
Nonclinical Pharmacology
Nivolumab is an IgG4 antibody which binds to PD-1 (CD279) with nanomolar affinity and 
shows a high degree of specificity for PD-1, blocking binding of PD-1 to PD-L1 and PD-L2. 
nivolumab binds to human PD-1 and not to other members of the CD28 family, such as ICOS, 
CTLA-4 or BTLA. 
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1.4.1.2
Metabolism and Excretion
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals, no tissue 
distribution studies with nivolumab have been conducted in animals. However, the low volume 
of distribution in cynomolgus monkeys (0.046 to 0.060 L/kg) indicates that there is little 
extravascular distribution of the drug. 
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals no 
metabolism studies with nivolumab have been conducted in animals. The expected in vivo 
degradation of monoclonal antibodies (mAbs) is to small peptides and amino acids via 
biochemical pathways that are independent of cytochrome P450 enzymes. In accordance with 
regulatory guidelines for biotechnology-derived pharmaceuticals, no mass balance studies with 
nivolumab have been conducted in animals.
1.4.1.3
Clinical Pharmacokinetics of Nivolumab
The pharmacokinetics (PK) of nivolumab was studied in subjectsover a dose range of 0.1 to 
10mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. 
The geometric mean (% CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume 
of distribution at steady state (Vss) was 8.0 L (30.4%), and geometric mean elimination half-life
(t1/2) was 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 
12weeks when administered at 3 mg/kg Q2W, and systemic accumulation was approximately 
3-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 
10mg/kg administered every 2 weeks. The clearance of nivolumab increased with increasing 
body weight. The PPK analysis suggested that the following factors had no clinically important 
effect on the CL of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK 
analysis suggested no difference in CL of nivolumab based on age, gender, race, tumor type, 
baseline tumor size, and hepatic impairment. Although ECOG status, baseline glomerular 
filtration rate (GFR), albumin, body weight, and mild hepatic impairment had an effect on 
nivolumab CL, the effect was not clinically meaningful. When nivolumab is administered in 
combination with ipilimumab, the CL of nivolumab was increased by 24%, whereas there was no 
effect on the clearance of ipilimumab.
Full details on the clinical pharmacology aspects of nivolumabcan be found in the Investigator 
Brochure.
1.4.1.4
Clinical Pharmacokinetics of Ipilimumab
The PK of ipilimumab has been extensively studied in subjects with melanoma, at the 3 mg/kg 
and 10 mg/kg doses administered as a 1.5 h IV infusion. The PK of ipilimumab was 
characterized by population PK (PPK) analysis and was determined to be linear and time 
invariant in the dose range of 0.3 mg/kg to 10 mg/kg. The mean CL (standard deviation [SD]) 
value after IV administration of 10 mg/kg was 18.3 5.88 mL/h, and the mean steady-state 
volume of distribution (Vss) (SD) value was 5.75 1.69 L. The terminal T-HALF determined 
from PPK analysis was 15.4 days. CL of ipilimumab in subjects with mild and moderate hepatic 
impairment was similar to that of subjects with normal hepatic function. PK within Japanese 
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subjects is comparable and consistent with previous PK results reported within non-Japanese 
subjects.
1.4.2
Nivolumab Safety Summary
In clinical trials, nivolumab has demonstrated an acceptable benefit-risk across multiple tumor 
types, including advanced melanoma, RCC, NSCLC,and some lymphomas. Overall, the safety 
profile is quite similar across multiple tumor typesand is discussed further in the sections below, 
including overviews from studies CA209003 and CA20937. 
CA209003is a completed Phase 1 open label, multiple dose escalation study in 306 subjects 
with select previously treated advanced solid tumors, including melanoma, RCC, NSCLC, 
colorectal cancer, and hormone-refractory prostate cancer. Subjects received nivolumab at doses 
of 0.1, 0.3, 1, 3 or 10 mg/kg intravenously every 2weeks, up to a maximum of 2 years of total 
therapy. A total of 306 subjects were treated with nivolumab in the doserange of 0.1-10 mg/kg. 
No maximal tolerated dose was identified in CA209003. The incidence, severity and relationship 
of AEs were generally similar across dose levels and tumor types. Nivolumab related AEs of any 
grade occurred in 75.2% of subjects. Ofthe 306 treated subjects, 303(99.0%) subjects have at 
least 1 reported AE regardless of causality. The most frequently reported AEs were fatigue 
(54.9%), decreased appetite (35.0%), diarrhea (34.3%), nausea (30.1%), and cough (29.4%). 
Treatment-related AEs were reported in 230 (75.2%) of the 306subjects. The most frequently 
reported treatment-related AEs were fatigue (28.1%), rash (14.7%), diarrhea (13.4%), and 
pruritus (10.5%). Most treatment-related AEs were low grade. Treatment-related high grade 
(Grade 3-4) AEs were reported in 52 (17.0%) of subjects. The most common treatment-related 
high grade AEs were fatigue (2.3%) and diarrhea (1%). Drug-related SAEs occurred in 11.5% of 
subjects. Grade 3-4 drug-related SAEs reported in at least 2 subjects included: diarrhea 
(3subjects, 1.0%), pneumonitis (3subjects, 1.0%), pneumonia (2 subjects, 0.7%) and lipase 
increased (2 subjects, 0.7%). 
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine 
replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, and 
endocrinopathies. In addition, select AEs include a category for infusion reactions. Each 
category is composed of a discrete set of preferred terms, including those of greatest clinical 
relevance. These select AEs are considered events of interest based on the mechanism of action 
and were previously referred to as immune-related AEs or immune-mediated AEs. Most high 
grade events resolved following the treatment guidelines for the treatment of pulmonary events, 
GI events, hepatic events, renal events, and endocrine events, respectively. In conclusion, the 
safety profile at 3 mg/kg (n=54) was similar to safety profile across the dose ranges from 
0.1mg/kg to 10 mg/kg (n=306).  
Treatment-related AEs leading to discontinuation were reported in 32 (10.5%) of the 306treated 
subjects on CA209003. The most frequent of these were pneumonitis (8 subjects; 2.6%) and 
colitis (3 subjects; 1.0%). There were 3 (1%) drug related deaths; each occurred after 
development of pneumonitis. 
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CA209037is an ongoing Phase 3, open-label study of nivolumab (3 mg/kg administered by 
intravenous[IV] infusion every 2 weeks [Q2W]) vs investigator’s choice therapy in subjects 
with previously-treated advanced melanoma.As of 30-Apr-2014, 268 subjects have been treated 
with 3 mg/kg IV nivolumab in CA209037 with safety results as outlined below (source 
document interim CSR, DCN930081508)
82that are consistent with the Phase 1 experience of 
CA209003. 
In CA209037, nivolumab related AEs of any grade occurred in 67.5% of subjects. Of the 
268subjects treated with nivolumab, 255 (95.1%) subjects had at least 1 reported AE regardless 
of causality. The most frequently reported treatment-related AEs were fatigue (25.0%), pruritus 
(16.0%), diarrhea (11.2%), and nausea (9.3%). Most treatment-related AEs were low grade. 
Treatment-related high grade (Grade 3-4) AEs were reported in 24 (9.0%) of subjects. The most 
common treatment-related high grade AEs were fatigue (0.7%), anemia (0.7%), diarrhea (0.4%), 
and vomiting (0.4%). Drug-related SAEs occurred in 4.5% of subjects. Grade 3-4 drug-related 
SAEs reported in at least 2 subjects included diarrhea (2subjects, 0.7%). In addition, 
drug-related SAE of hyperglycemia occurred in 0.7%. 
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine 
replacement therapy) are:
Skin (29.1%) including pruritus (16.0%) and rash (9.3%)
GI (11.6%) including diarrhea (11.2%) and colitis (1.1%)
Endocrine (7.8%) including hypothyroidism (7.8%) and hyperthyroidism (1.9%)
Hepatic (4.5%) including AST increased (4.1%) and ALT increased (2.6%)
Pulmonary (2.2%) including pneumonitis (1.9%)
Hypersensitivity/infusion reaction (1.9%)
Renal (1.5%) including increased creatinine (0.7%), increased urea (0.4%), and 
tubulointerstitial nephritis (0.4%).
In general, these select AEs were considered by the investigator to be related to study drug, 
except for AEs in the hepatic and renal select AE categories. There were few high-grade select 
adverse events (n=20), and the majority of high-grade events (13 of 20) subsequently resolved, 
including those for which immunosuppressive therapy was not initiated. 
Treatment-related AEs leading to discontinuation were reported in 6 (2.2%) of the 268 treated 
subjects in CA209037 including single events of colitis, pancreatitis, increased ALT, increased 
lipase, autoimmune neuropathy, and demyelination. There were no deaths due to drug-related 
toxicity in CA209037. 
Taken together, these data from studies from CA209003 and CA209037 highlight the acceptable 
safety profile with similar trends in AEs in the 574 subjects treated with nivolumab in these 
2studies. Additional details on the safety profile of nivolumab, including results from other 
clinical studies, are also available in the BMS-936558 (nivolumab) IB. 
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In addition to the clinical safety data outlined above, preliminary new non-clinical safety 
findings of adverse pregnancy outcomes and infant losses in the absence of overt maternal 
toxicity have been reported.
83  The findings of increased late stage pregnancy loss and early 
infant deaths/euthanasia in nivolumab exposed pregnant monkeys suggest a potential risk to 
human pregnancy if there is continued treatment with BMS-936558 (nivolumab) during 
pregnancy.
1.4.3
Summary of Nivolumab Clinical Activity
As of July 2015, >8,600subjects have received nivolumab in single-or multiple-dose Phase 
1/2/3 studies or studies with nivolumab in combination with other therapeutics (ipilimumab, 
cytotoxic chemotherapy, anti-angiogenics, and targeted therapies). 
In CA209003, the clinical activity of nivolumab was demonstrated in a variety of tumor types, 
including melanoma, RCC, and NSCLC. Clinical activity was noted across a range of doses 
(0.1mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg). In CA209003, a total of 306subjects 
with melanoma, RCC, and NSCLC have been evaluated for clinical activity. Aresponse of either 
CR or PR, as determined by investigator assessed tumor evaluations based on RECIST1.1 
criteria,
84has been reported at all dose levels.  
In NSCLC, the most active doses were 3 and 10mg/kg. The overall ORR of 17% was reported 
with a 48-week progression-free survival rate (PFSR) of 22% (95% CI: 15-30%), and a 
24-month overall survival rate of 24% (95% CI: 16-32%). Only a single response (1/33) was 
reported at 1mg/kg. Durable responses were observed in both squamous and non-squamous 
subtypes. Historically, ORR of 5% to 10% and median PFS (mPFS) of 2 to 3months has been 
reported with docetaxel treatment in previously-treated NSCLC subjects. 
A complete response (CR) or partial response (PR) was reported in 31% (95% CI: 22%-41%) 
of the 107 response-evaluable subjects with melanoma treated with nivolumab monotherapy 
Q2W at doses ranging from 0.1 to 10 mg/kg in CA209003. The responses were durable with a 
PFSR at 24 weeks of 38% (95% CI: 28-47%) and OS at 24 months of 48% (95% CI: 38-57%). 
Of the 34 response evaluable RCC subjects in CA209003, responses were reported in both the 
1mg/kg (5 of 18 subjects, 27 %) and 10 mg/kg (5 of 16 subjects, 31%) treatment groups. PFSR 
at 24 weekswas 33% (95% CI: 14-55%) in the 1 mg/kg and 37% (95% CI: 14-61%) in the 
10mg/kg nivolumab treatment groups. OS at 24 months was 51% (95% CI: 30-64%) and 44% 
(95% CI: 20-66) in the 1 mg/kg and 10 mg/kg groups, respectively. 
In CA209037,the ongoing Phase 3 study for subjects with previously-treated advanced 
melanoma of nivolumab (3 mg/kg administered by intravenous[IV] infusion every 2weeks 
[Q2W]) vs investigator’s choice therapy, as of 30-Apr-2014, 120 nivolumab-treated and 
47subjects in the investigator’s choice arm are available for determination of the ORR using 
RECIST1.1 criteria. As determined by imaging plus clinical review by ablinded independent 
central review (BICR), the ORR for nivolumab vsthe reference arm is 31.7%vs 10.6%, 
respectively. Four subjects in the nivolumab arm had a CR, whereas no subjects in the reference 
arm had a CR. Median progression-free survival was 4.7 months (95% CI: 2.3-6.5) vs 
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4.2months (95% CI: 2.1-6.3) with a 6-month PFS rate of 48% (95% CI: 38-56)vs34% 
(95%CI: 18-51) in the nivolumab (n=122) vsreference arm (n=60), respectively.
In addition, recent clinical trial data in MEL (CA209066),and NSCLC (CA209017and 
CA209057)havedemonstrated OS benefit:
In CA209066, a Phase 3 study of 418 previously untreated metastaticmelanoma patients 
without a BRAF mutation, 1 year overall survival was 72.9% (95% CI:65.5 to 78.9) in the 
nivolumab group as compared to 42.1% (95% CI: 33.0 to 50.9) in thedacarbazine group 
(P<0.001). The median progression-free survival was 5.1 months in thenivolumab group 
versus 2.2 months in the dacarbazine group (hazard ratio for death orprogression of disease, 
0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was40.0% (95% CI, 33.3 
to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in thedacarbazine group 
(odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versusdacarbazine was 
observed across prespecified subgroups, including subgroups defined by statusregarding the 
programmed death ligand 1 (PD-L1).
85Additional supportive data for the clinicalactivity of 
nivolumab in advanced melanoma has been shown in a cohort of 107 advancedmelanoma 
subjects in an outpatient setting who enrolled between 2008 and 2012. In 107 patientswith 
advanced MEL treated with nivolumab, objective responses were observed in 31% of
patients. Median OS (62% with two to five prior systemic therapies) was 16.8 months, and
1-and 2-year survival rates were 62% and 43%, respectively. Median progression-free 
survivalwas 3.7 months (95% CI, 1.9 to 9.1 months), with 1-and 2-year progression-free 
survival ratesof 36% (95% CI, 27% to 46%) and 27% (95% CI, 17% to 36%), 
respectively.
86
In CA209017,a Phase 3 trial in 272 patients with metastatic squamous NSCLC with 
progression on or afterplatinum-based chemotherapy, subjects were randomized to 
nivolumab 3 mg/kg IV q2 week(n=135) or docetaxel (n=137) at 75 mg/m2every 3 weeks. 
Median OS was 9.2 months in thenivolumab group (95% CI: 7.3-13.3) vs 6.0 months in the 
docetaxel group (95% CI: 5.1-7.3)(HR of 0.59, P=0.00025).
A Phase 3 clinical trial of nivolumab vsdocetaxel in Non-squamous NSCLC (CA209057), 
nivolumab monotherapy demonstrated superior OS compared with docetaxel, with a 
clinically meaningful and statistically significant improvement observed (HR=0.73 [95.92% 
CI: 0.59, 0.89]; stratified log-rank test p-value = 0.0015).  The median overall survival was 
12.2 months (95% confidence interval [CI], 9.7 to 15.0) with nivolumab versus 9.4 months 
(95% CI, 8.1 to 10.7) with docetaxel.Results of secondary endpoints of ORR, DOR, and 
TTR further support the antitumor activity of nivolumab in this population.  Pre-study 
(baseline) PD-L1 expression was predictive for benefit from nivolumab for all efficacy 
endpoints.  Interaction p-values reported for PD-L1 expression subgroups by each of the 
pre-defined expression levels suggested a clinically important signal of a predictive 
association. In PD-L1 positive subjects, the nivolumab group showed improved efficacy vs 
docetaxel across all efficacy endpoints (OS, ORR, and PFS). In contrast, there were no 
meaningful differences in efficacy between the treatment groups in the PD-L1 negative 
subgroups by any expression level.
87
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1.4.4
Summary of Nivolumab plusIpilimumab Safety Data
Several doses of nivolumab and ipilimumab are currently being explored in ongoing clinical 
trials.  Although the optimal doses have not yet been defined across multiple tumor types, the 
largest studies to date have been done in melanoma at a dose of nivolumab 1 mg/kg combined 
with ipilimumab 3 mg/kg administered IV Q3W for 4 doses followed by nivolumab 3 mg/kg IV 
Q2W.  These studies include subjects with previously untreated unresectable or metastatic 
melanoma in CA209067(313 subjects) and CA209069(94 subjects) (a total of 407 subjects).  
Based on the pooled analyses, nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg
administered IV Q3W for 4 doses followed by nivolumab 3 mg/kg IV Q2W has an acceptable
safety profile, as demonstrated by the frequency, severity, and types of AEs, drug-related deaths,
SAEs, and AEs leading to discontinuationas described below.  Additional details on safety and 
clinical activity of nivolumab plus ipilimumab combinations are described in the IB.
80
The following were the key safety findings for these pooled subjects:
The most frequently reported drug-related AEs of any grade (15% of subjects) were
diarrhea (43.0%), fatigue (35.4%), pruritus (33.4%), rash (31.0%), nausea (24.8%), pyrexia
(18.7%), ALT increased (18.2%), AST increased (16.7%) and decreased appetite (16.2%).  
The most frequently reported drug-related Grade3-4 AEs (5% of subjects) were colitis
(9.6%), diarrhea (8.80%), ALT increased (8.4%), lipase increased (8.4%), and AST increased
(5.9%).
The majority of drug-related SAEs were Grade 3-4 in severity. The most frequently 
reporteddrug-related SAEs of any grade (2% of subjects) were colitis (11.1%), diarrhea 
(8.8%),pyrexia (3.7%), pneumonitis (2.7%), hypophysitis (2.2%), transaminases increased 
(2.2%),and adrenal insufficiency (2.0%). The majority of drug-related SAEs were 
Grade3-4. Themost frequently reported drug-related Grade 3-4 SAEs (2% of subjects) 
were colitis(8.8%), diarrhea (5.7%), and transaminases increased (2.2%).
Drug-related AEs leading to discontinuation occurred in 36.4% of subjects.  The majority of 
drug-related AEs leading to discontinuation of study drug were Grade 3-4 inseverity. The 
most frequently reported drug-related AEs of any grade leading todiscontinuation of study 
drug (2% of subjects) were colitis (10.1%), diarrhea (7.4%), ALTincreased (4.7%), and 
AST increased (4.2%). These were also the most frequently reporteddrug-related Grade 3-4 
SAEs leading to discontinuation of study drug (2% of subjects).
The most frequently reported drug-related select AE categories with nivolumab + ipilimumab
combination therapy were skin (61.9%), GI (46.4%), endocrine (29.7%), and hepatic
(29.0%). The majority of select AEs were considered by the investigators to be related to
study treatment.
Drug-related select AEs were mostly Grade 1-2 in all categories with the exception of
hepatic select AEs where the majority wasGrade 3-4.
Across categories, the majority of high-grade events subsequently resolved, includingthose 
for which immunosuppressive medication was not initiated.
The majority of deaths (80/105) were dueto disease progression. Study drug toxicity was
considered responsible for 2 deaths; 1 subject died of ventricular arrhythmia within 30 days
of the last dose and the other died of pneumonitis between 31 and 100 days of the last dose.
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Abnormalities in select hematology assessments and liver/kidney function tests were 
primarily Grade 1-2 in severity.
The immunogenicity of nivolumab was low and not clinically meaningful.
In general, the frequency of adverse events was lowest across AE categories in the nivolumab 
monotherapy group and highest in the nivolumab + ipilimumab group.  However, the types and 
frequency of AEs reported in the nivolumab + ipilimumab group were as expected based on the 
mechanism of action of the two agents and were consistent with previously reported data.  
Additional toxicity, including a higher frequency of Grade 3-4 AEs, was observed in the 
nivolumab+ipilimumab group relative to the ipilimumab group, leading to a higher frequency of 
discontinuation from study treatment.  The most frequently reported select AE categories were 
skin, GI, endocrine, and hepatic. Select AEs belonging to these categories were reported more 
frequently in the nivolumab+ipilimumab group than the ipilimumab group. The majority of 
events were manageable.  In summary, results to date suggest that the safety profile of 
nivolumab+ipilimumab combination therapy is consistent with the mechanisms of action of 
nivolumab and ipilimumab. The nature of the AEs is similar to that observed with either agent 
used as monotherapy; however, both frequency andseverity of most AEs are increased with the 
combination.
80
1.4.5
Summary of Nivolumab plusIpilimumab Clinical Activity
Since PD-1 and CTLA-4 use distinct mechanisms to limit T cell activation, combining 
immunotherapeutic agents with different mechanisms of action offers the possibilityof increased 
antitumor activity.   Multiple studies suggest a higher response rate and antitumor activitywith 
the combination of nivolumab plus ipilimumab:
In a Phase 1 study of the combination of nivolumab plus ipilimumab in advanced melanoma 
(CA209004), there was a 42% response rate22 of 53 subjects, including a 17% complete 
response rate (CR)in a pooled analysis of multiple doses (nivolumab 3 mg/kg and 
ipilimumab 1 mg/kg, and nivolumab 0.3 mg/kg, 1 mg/kg or 3 mg/kg combined with 
ipilimumab 3 mg/kg).
88   
A randomized Phase 2 study (CA209069) comparing nivolumab1 mg/kg plus ipilimumab 
3mg/kg q3week x 4 followed by nivolumab 3 mg/kg q2weekversus ipilimumab q3 week x 4 
showed an objective response rate of 61%, including a 22% complete response rate, in 
previously untreated, advanced melanoma patients with BRAF wild-type mutation status, 
versus 11 % for ipilimumab alone.
89  In addition, the combination regimen decreased the risk 
of melanoma progression or death compared to ipilimumab alone by 60%.  
In a randomized Phase 3 study (CA209067), 945 previously untreated subjects with 
unresectable melanoma were randomized 1:1:1 to receive nivolumab alone (3mg/kg 
Q2weeks), nivolumab plus ipilimumab (nivolumab1 mg/kg and ipilimumab3mg/kg 
Q3week x 4, followed by nivolumab 3 mg/kg Q2weeks), or ipilimumab alone (3mg/kg 
Q3weeks x 4); median PFS for the three treatment arms were 6.9 months, 11.5 months, and 
2.9 months, respectively, and demonstrated that the combination was more effective than 
either therapy alone.
90 Investigator-assessed response rates were also highest in the 
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combination arm:  nivolumab (43.7%), nivolumab plus ipilimumab (57.6%), and ipilimumab 
(19.0%).    
1.4.6
Summary of Preliminary Clinical Data from CA209040
In the current study (CA209040), as of 12-Mar-2015, 47subjects have been dosed with
nivolumab(including 43 subjects from the Dose Escalation Phaseand 4 from the Expansion 
Phase): 25uninfected, 11HCV-infected, and 11HBV-infected.
In the uninfected arm, subjects have been dosed at concentrations of 0.1 mg/kg (n = 1), 
0.3mg/kg (n = 3), 1 mg/kg (n = 3), 3 mg/kg (n = 6), and 10 mg/kg (n = 12).
In the HCV cohort, subjects have been dosed at concentrations of 0.3 mg/kg (n = 3), 1mg/kg 
(n = 4), and 3 mg/kg (n = 4).
In the HBV cohort, subjects have been dosed at 0.1 mg/kg (n = 5),0.3 mg/kg (n=3), and 
1mg/kg (n=3).
To date, there has been one DLT in a subject at 10 mg/kg in the uninfected arm (as described in 
the SAE narrative below).  No subsequent DLTs have occurred and no MTD in the uninfected 
cohort was defined.   Doseescalation to 3 mg/kg has completed in the HCV cohort without any 
safety issuesand no MTD identified.  More recently, as of the end of June 2015, 3HBV-infected 
HCC subjects have been dosedand have completed the DLT evaluation with no DLTobserved.  
Therefore, at the beginning of July 2015, the cohort of HBV-infected subjects in the Expansion 
Phasehas opened enrollment.  
As of 12-Mar-2015 (data cutoff for interim analysis), there are 17 subjects continuing 
on-treatmentin CA209040. Thirtysubjects have been discontinued including 2 subjects with a 
confirmed complete response, 26subjectswith disease progression, 1 subject with a related 
event of hepatitis and increased AST/ALT (subject 3-19 described in Section 1.4.15), and 
1subject with unrelated increased bilirubin.   
Twosubjects have experienced drug-related SAEs:
An uninfectedsubject with a Grade 2 SAE of liver decompensation who experienced a DLT 
at 10mg/kg beginning on Day 17 after a single dose of nivolumab.  The subject presented 
with new onset mild ascites and encephalopathy.  Hepatic parameters were stable, including 
G1 ALT, G2AST, and normal INR and bilirubin.  CT imaging showed no evidence of 
disease progression.  Mental status improved and the SAE resolved within 7 days; however, 
the subject experienced disease progression with increasing hip pain due to bone metastases 
and died 104 days after last study dose.  
A subject experienced a Grade 3 SAE of bullous pemphigoidin the 0.1 mg/kg HBV cohort.   
After 5 doses of study drug, the subject developed 
 without eye or oral 
involvement.  Skin biopsy revealed subepidermal blistering process rich in eosinophils, and 
immunofluorescence with strong linear deposits of IgG and C3 at the dermal-epidermal 
junction, consistent with bullous pemphigoid.  The subject was successfully managed with 
topical corticosteroids until resolution, and is now in the follow-up portion of the study. 
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There have been 17 on-treatmentdeaths (12in the uninfected cohort, 1 in the HCV-cohort,and 
4in the HBV cohort) reported after administration of nivolumab.  Ninedeaths occurred within 
100days of last dose, and 8subjectshad deaths reported > 100 days after last dose. Fifteen
subjects dieddue to disease progression; 1 subject died from GI bleeding unrelated to study drug 
129 days after the last dose; and 1 subject died from a cerebral hemorrhage unrelated to study 
drug 399 days after the last dose.  
Preliminary safety data indicate that the profile of nivolumab in subjects with advanced HCC is
generally consistent with the safety profile from other tumor types, with the exception for an 
increased frequency of asymptomatic transaminitis.  From the 47treated subjects, the most 
frequent drug-related adverse events(5% of subjects) include:  AST increased (19%), lipase 
increased (17%), rash (17%), ALT increased (15%), amylase increased (15%), pruritus (13%), 
hypoalbuminemia (9%), anemia (6%), asthenia (6%), diarrhea (6%), fatigue (6%), and 
hyponatremia (6%).  
Of note, transaminase elevationshave generally been transient, with no dose dependency, 
without accompanying changes in other hepatic parameters, and occur in both the viral and 
non-viral cohorts.  Some cases have resolved spontaneously while continuing nivolumab 
monotherapy, and only a single case required steroid intervention and improved to a Grade 1.  
Detailed narratives of drug-related hepatic events are provided in Section1.4.15.
Based on historical data, transaminase elevations are not uncommon in the setting of 
advanced HCC:
- Treatment related increased AST and ALT was observed in 26% and 18% of subjects 
treated with sorafenib,
64which is similar to nivolumab.
- As discussed in Section 1.4.7in the setting of HCV-infected HCCtreated with the 
checkpoint inhibitor, tremelimumab, a rise in serum transaminases wasobserved in more 
than half of the subjects, with nearly half of subjectsexperiencing a Grade 3 or higher 
ALT.  However, in all cases, the transaminitis was transient, not associated with a decline 
in liver function, did not require steroid management, and did not recur with subsequent 
doses. 
- Taken together, these data indicate that the overall safety profile of nivolumab (hepatic 
and non-hepatic events) is acceptable in subjects with advanced HCC.
In addition to the manageablesafety profile of nivolumab in advanced HCC, preliminary 
antitumor activity is encouraging in this patient population.  As of 12-Mar-2015, 42 subjects(all 
from the Dose Escalation Phase)have an investigator-assessed response by RECIST 1.1.  Five 
subjects are not evaluable (4 who recently started the study and 1 subject who died prior to 
disease assessment).  BOR is summarized below inTable 1.4.6-1.  Eight of 42 subjects (19%) 
have had a BOR of either CR (n=2) or PR (n=6):
Uninfected cohort (3 responders)--CR (1 mg/kg), CR (3 mg/kg), and PR (10 mg/kg)
HCV-infected cohort (4 responders)--PR at 0.3 mg/kg, 1 mg/kg, and 3 mg/kg (n=2)
HBV-infected cohort (1 responder)--PR at 0.1 mg/kg.
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Other efficacy data are also promising compared to historical data in the 2L and 1L setting:
The current median TTPin CA209040is 4.2 months which compares favorably to best 
supportive care in the 2nd line setting of 2.6-2.7months.
54,91
Preliminary analysis of survival data indicate a 1 year survival rateof 62% in CA209040, 
which compares favorably to best supportive care in the 2L setting (approximately 30%),
54,91   
and 30-44% for sorafenib in the 1L setting.
55,56,57,58,64
In summary, preliminary anti-tumor activity hasbeen observed in all 3 etiologicsubtypes of the 
Dose Escalation Phaseconfirming biological activity regardless of HCC etiology and an 
acceptable safety profile in this patient population. These results are promising given the rarity of 
CRs (<1%) across multiple Phase 3 studies with targeted agents; median TTP of < 3 months 
with best supportive care; overall survival of 30-44% with either best supportive care or 
sorafenib; and ORRswith sorafenibranging from 2% to 7% by RECIST and 9% by 
mRECIST.
54,91,92,93,94,95,96
Table 1.4.6-1:
Investigator-assessed ORR and Best Overall Response (RECIST 
v1.1) by Nivolumab Dose -Response Evaluable Subjects -
CA209040
Nivolumab Dose
0.1 mg/kg
(N = 6)
0.3 mg/kg 
(N = 9)
1 mg/kg 
(N = 10)
3 mg/kg
(N = 6)
10 
mg/kg
(N = 12)
Total
(N = 42)a
ORR, number (%) responders
1 (17)
1 (11)
2 (20)
3 (50)
1 (8)
8 (19)
Best overall response, number (%)
Complete response (CR)
-
-
1 (10)
1 (17)
-
2 (5)
Partial response (PR)
1 (17)
1 (11)
1 (10)
2 (33)
1 (8)
6 (14)
Stable disease (SD)
3 (50)
5 (56)
5 (50)
2 (33)
5 (42)
20 (47)
Progressive disease (PD)
1 (17)
3 (33)
3 (30)
1 (17)
6 (50)
14 (33)
a Fivesubjects do not have disease assessments as of the database lock on 12-Mar-2015: One subject had death 
prior to disease assessment, and 4 subjects had recently started the study and were not yet available.
1.4.7
Nivolumab Experience in Hepatitis C Infected Subjects 
A Phase 1single-ascending dose escalation trial, CA209002, of nivolumab (anti-PD-1) was 
conducted in subjects with genotype 1 active hepatitis C infection.
97Prior exposure to interferon 
was permitted.  This was a double blind randomized trial with 45 subjects receiving nivolumab 
and nine subjects receiving placebo.  Doses of 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg of nivolumab 
were administered, and subjects were followed 85 days post-dose.  
In the primary efficacy population (Per-protocol Population), 5 subjects had a clinical response 
of repeatedly demonstrated 0.5 log HCV RNA decline (1 in the nivolumab 10 mg 
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IFN-experienced group, 3 in the nivolumab 10 mg/kg IFN-naïve group, and 1 in the placebo 
group). The duration of response was 8 weeks for all subjects except for 1 subject in the 
nivolumab group who had a duration of 4 to < 8 weeks. Three subjects who manifested a 
significant clinical response, all of whom received 10 mg/kg of study drug, experienced a 4-log 
decline in HCV RNA levels; 2 of these subjects were IFN-naive while 1 was IFN-experienced.  
Of note, one of the 3 subjects, a prior INF null responder, became undetectable for HCV RNA, 
and remained undetectable for more than 1 year after study completion.  A single dose of 
nivolumab (up to 10 mg/kg) was generally well tolerated in subjects with active Hepatitis C 
infection.  There were no deaths, SAEs, or withdrawals due to AEs occurring during thecourse 
of the study.  The most commonly reported treatment-emergent AEs and treatment-related AEs 
were fatigue, headache, and diarrhea. Most were Grade 1 or 2 in severity and were evaluated as 
not related to study drug. One subject treated with 10 mg/kg of nivolumab experienced a 
transient, asymptomatic, 17 fold elevation in ALT/AST at Day 22 that coincided with peak HCV 
viral load decline.  This transaminitis spontaneously and without any intervention reverted to 
baseline within 3 weeks, and this subject maintained normal LFTs for the remainder of the study.  
In addition, changes in thyroid function were observed in a few subjects with reports both of 
hypothyroidism and hyperthyroidism.  
1.4.8
Treatment Experiences with Other Immune Checkpoint Inhibitors in 
Subjects with Chronic Hepatitis 
In addition to the safety profile of nivolumab in subjects with chronic HCV as described in 
Section 1.4.7above, there have been a few recent reports of other immune checkpoint inhibitors 
administered to oncology subjects with chronic hepatitis. 
In a Phase 2, non-controlled, open-label, multicenter trial, tremelimumab, a monoclonal antibody 
that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was administered at a dose 
of 15 mg/kg IV every 90 days was been administered to 20 subjects with HCC and chronic 
HCV.
98  A total of 46 treatment doses were administered, and 13 subjects received at least 
2doses.  Overall, there was a significant antiviral effect with a median reduction in HCV RNA 
of 0.76 log at Day 120 (P=0.11) and 2.1 log at Day 210 (P=0.017), and 3 subjects 
demonstrated a transient complete viral response during follow-up. A rise in serum 
transaminases was observed after the first dose in more than half of the subjects.  Five of 
20subjects (25%) experienced a Grade 3 or higher elevation in ALT.  However, in all cases, the 
transaminitis was transient, not associated with a decline in liver function, did not require steroid 
management, and did not recur with subsequent doses. 
Since FDA approval of ipilimumab (anti-CTLA-4 mAb) for patients with metastatic melanoma 
in 2011, there have been recent case reports that highlight ipilimumab 3 mg/kg can be 
administered IV every three weeks safely to subjects with metastatic melanoma and chronic 
HCV (n=2)
99or chronic HBV (n=1).
100  In the subject with metastatic melanoma and chronic 
hepatitis B, antiviral therapy with tenofovir was initiated to mitigate the potential risk of 
immune-mediated hepatotoxicity given the high frequency of HBV-infected hepatocytes in 
subjects with chronic HBV.  HBV DNA levels were reduced from 2950 IU/mL to 41 IU/mL 
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with tenofovir prior to administration of ipilimumab, and the subject completed treatment 
without any hepatic events or change in LFTs.   
In addition to the case report of ipilimumab administration to a single subject with melanoma 
and HBV as described above, a recent case series of 9 melanoma subjects (4 with chronic HCV 
and 5 with chronic HBV) has recently been published.  Seven subjects had no changes in LFTs 
during the ipilimumab treatment cycles, 1 subject who had a Grade 2 AST/ALT subsequently 
normalized by Cycle 4; and 1 HCV-infected subject who had a Grade1 AST/ALT at baseline 
developed a Grade 2 AST/Grade 3 ALT after Cycle 3.  In summary, these data indicate that 
ipilimumab can be well tolerated without significant hepatotoxicity in subjects with chronic 
HCV or HBV.   
Similar to the approach previously described99and reflective of guidance from an independent 
HBV/HCC expert panel (as discussed below in Section 1.4.10), subjects in the current study 
CA209040 are required to have a low HBV DNA level <100 IU/mL and be on antiviral therapy 
prior to administration of nivolumab to lower HBV viral load and reduce the risk of 
hepatotoxicity in the setting of nivolumab administration. 
Taken together, the treatment experiences of nivolumab in subjects with chronic HCV 
(Section1.4.7) and the treatment experiences of tremelimumab or ipilimumabin subjects with 
chronic hepatitis (Section 1.4.8) add to the growing safety profile of immune checkpoint 
inhibitors and suggest that nivolumab in virally-infected HCC subjects will be adequately 
tolerated.  Specifically:
Nivolumab in single ascending doses in chronic HCV is well tolerated with an acceptable 
safety profile.
High grade transaminitis may occur with immune checkpoint inhibitors (tremelimumab) in 
subjects with chronic HCV+/-HCC; however, to date, these elevations are transient, without 
decline in hepatic synthetic function or hyperbilirubinemia, resolve spontaneously, and do 
not preclude repeat dosing.
The safety profile of immune checkpoint inhibitors in the setting of chronic HCV or HBV is 
evolving; however, based on recent case reports with ipilimumab, immune checkpoint 
inhibitors can be given safely to subjects with chronic HCV or HBV.
As a result of this additional safety information, the CA209040 study team recommended in a 
previous amendment that the HBV arm initiate dosing at 0.1 mg/kg independent of the 
uninfected or HCV-infected arms (see study designFigure 3.1-1).  For additional risk mitigation, 
a sentinel dosing paradigm was utilized in the first HBV cohort of 0.1 mg/kg; therefore, two 
weeks separated the first nivolumab dose for each subject in the 0.1 mg/kg cohort.  However, in 
subsequent dose panels, a sentinel dosing strategy was not utilized.  In addition, dose escalation 
in the HBV-HCC group was not planned to exceed the MTD in the other two arms of the study.
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1.4.9
Definitions for Sorafenib Intoleranceand Progression
In theDose Escalation andExpansionPhase, ‘sorafenib intolerance’ is defined as:
CTCAE Grade 2 drug-related adverse event which 1) persisted in spite of comprehensive 
supportive therapy according to institutional standards AND 2) persisted or recurred after 
sorafenib treatment interruption of at least 7 days and dose reduction by one dose level (to 
400 mg once daily)
CTCAE Grade 3 drug-related adverse event which 1) persisted in spite of comprehensive 
supportive therapy according to institutional standards OR 2) persisted orrecurred after 
sorafenib treatment interruption of at least 7 days and dose reduction by one dose level (to 
400 mg once daily).
In the Dose Escalation and Expansion Phase subjects who failed sorafenib, ie ‘sorafenib 
progressors’ are defined as:
Documented symptomatic OR radiographic progression during or after sorafenib therapy.
In the Nivolumab plus Ipilimumab Combination Cohort, ‘sorafenib intolerance’ is defined as:
CTCAE Grade 2 drug-related adverse event which 1) persisted in spite of comprehensive
supportive therapy according to institutional standards AND 2) persisted or recurred after 
sorafenib treatment interruption of at least 7 days and dose reduction by one dose level (eg to 
400 mg once daily)
CTCAE Grade 3 drug-related adverse event which 1) persisted in spite of comprehensive 
supportive therapy according to institutional standards OR 2) persisted or recurred after 
sorafenib treatment interruption of at least 7 days and dose reduction by one dose level (eg to 
400 mg once daily).
Requires a minimum of 14 days of sorafenib exposure (not necessarily consecutive).
In the Nivolumab plus Ipilimumab Combination Cohort,subjects who failed sorafenib, ie 
‘sorafenib progressors’ are defined as:
Documented radiographic progression during or after sorafenib therapy.
A decision on temporary or permanent sorafenib treatment interruption or sorafenib-dose 
reduction should havebeen based on the recommendations outlined in the sorafenib product 
label.  Supportive therapies for sorafenib-related adverse events should have beenadministered 
according to institutional standards and may include but are not limited to treatments listed in the 
sorafenib product label:
Dermatologic Toxicities: topical therapies for symptomatic relief
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Hypertension: institution of anti-hypertensive therapy
Gastrointestinal Toxicities: with a minimal risk of severe nausea, vomiting, and diarrhea, 
supportive treatment may follow institutional standards.
Episodes of sorafenib-related toxicity (onset/end), supportive care measures, length of temporary 
sorafenib discontinuation and sorafenib dose reduction will be documented in the medical history 
sectionof the CRFs. If both disease progression and intolerance are observed at study entry, 
disease progression will be regarded as the entrycriterion.
1.4.10
Rationale for Defining Dose Limiting Hepatic Toxicityin the Dose 
Escalation Phase
An advisory board panel was convened to discuss treatment of subjects with hepatitis B infection 
with or without hepatocellular carcinoma in August 2011. The potential for hepatic flare with 
antiviral therapy such as entecavir, lamivudine or tenofovir was discussed. It was the consensus 
of the panel members that the risk for this toxicity was low in subjects with low viral DNA loads 
who were on antiviral therapy for several months. As described above in subjects with hepatitis 
C infection, transient Grade 4transaminase levels can be observed. The standard hepatic toxicity 
parameters used for BMS-936558 therapy are AST or ALT > 5 -10 x ULN for >2 weeks, AST 
or ALT > 10 x ULN irrespective of duration, T. bilirubin > 5 x ULN irrespective of duration, or 
concurrent AST or ALT > 3 x ULN and T. bilirubin > 2 ULN (potential Hy’s Law case). Due to 
the potential for hepatic inflammation that could be greater due to viral infection the panel 
recommended that these parameters be adjusted to permit a higher level of hepatic toxicity with 
AST or ALT > 10 x ULN for >2 weeks, AST or ALT > 15 x ULN irrespective of duration, 
T.bilirubin > 8 x ULN irrespective of duration for subjects with elevated bilirubin at study entry 
or > 5 x ULN for those with normal T. bilirubin at study entry, concurrent AST or ALT > 3 x 
ULN and T. bilirubin > 5 x ULN for subjects entering treatment with a normal bilirubin and up 
to 8xULN for subjects with elevated bilirubin, or clinical deterioration manifested by 
drug-related hepatic decompensation not identified above. 
1.4.11
Rationale for Nivolumab Dose in Expansion Phase
Nivolumab monotherapy at 3 mg/kg was chosen for the expansion arms in the current
amendment based on the following:
Acceptable safety profile in the current study without correlation between dose and 
frequency or severity of AEs.
Preliminary anti-tumor activity observed at dose levels of 0.1 mg/kg to 10 mg/kg in 
CA209040.
Preliminary PK analysis of a subset of samples from CA209040 that indicate exposures are 
within the expected range of subjects from other tumor types.
To align with the standard dose in the nivolumab program used in late stage studies that are
based on the safety, efficacy, and exposure-response data in multiple other tumor types.
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In the large Phase 1 CA209003 study:
- Anti-tumor activity was observed at dose levels ranging from 1 to 10 mg/kg in
melanoma, NSCLC, and RCC, as well as at dose levels of 0.1 and 0.3 mg/kg in
melanoma.
- The observed anti-tumor activity in melanoma, and NSCLC was highest at 3 mg/kg,
suggesting that anti-tumor activity approaches a plateau at dose levels of 3 mg/kg and
above.
- Results of the exposure-response analyses for these tumor types show that the probability
of a tumor response tended to approach a plateau for trough concentrations producedby
3and 10 mg/kg every 2 week dosing.
- A favorable risk/benefit profile demonstrated at 3mg/kg dose in other ongoing Phase 3 
trialsand the nivolumab label.
In addition, the uninfected HCC cohort has been safely dose escalated to the 10 mg/kg dose 
level.  The HCV cohort has safely dose escalated to 3 mg/kg, andmost recently at the end of 
June 2015, the HBV cohort has completed dose escalationto3 mg/kg.  The HCV and HBV viral 
cohorts will no longer be dose escalatedto the 10 mg/kg dose level and the dose in the 
Expansion Phasewill be 3 mg/kg for all cohorts. 
In summary, across the nivolumab program, doses up to 10 mg/kg have been adequately
tolerated, and based on the current data from CA209040 combined with CA209003 and
CA209037, a dose of 3 mg/kg Q2W was selected as the dose anticipated to achieve an
appropriate balance of efficacy and risk in the additional planned expansions of the uninfected
HCC subjects in CA209040.  
1.4.12
Rationale for Nivolumab Flat Dosingin 1L Nivolumab vs Sorafenib 
Cohortand Nivolumab plus Ipilimumab Combination Cohort(Post 
Inductionin Arms A and B)
The nivolumab dose of 240 mg every 2 weeks (Q2W) was selected based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response analyses 
of data from studies in multiple tumor types (melanoma, non-small-cell lung cancer [NSCLC], 
and renal cell carcinoma [RCC]) where body weight normalized dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and tumor types were 
observed. Nivolumab clearance and volume of distribution were found to increase as the body 
weight increases, but less than the proportionalwith increasing weight, indicating that mg/kg 
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK 
model previously developed using data from NSCLC subjects has recently been updated, using 
data from 1,544 subjects from 7 studies investigating nivolumab in the treatment of melanoma, 
NSCLC, and RCC. In this dataset, the median (minimum -maximum) weight was 77 kg 
(35kg-160 kg) and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg subject, 
nivolumab 240 mg Q2W was selected for future studies. To predict relevant summary exposures 
of nivolumab 240 mg Q2W, the PPK model was used to simulate 100 virtual trials, each 
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consisting of two arms, nivolumab 3 mg/kg Q2W and 240 mg Q2W. In the simulations, the 
simulated patient populations consisted of 1,000 subjects per treatment arm randomly sampled 
from aforementioned pooled database of cancer patients. Because no differences in PK were 
noted across ethnicities and tumor types, these simulated melanoma and NSCLC data will be 
applicable to patients with other tumor types. The simulated measure of exposure of interest, 
time-averaged concentrations (Cavgss) for 240 mg Q2W are predicted to be similar for all 
subjects in reference to 80 kg subjects receiving 3 mg/kg Q2W.Given the lower body weight in 
Japanese patients (median: 58.4 kg)
,101the exposures following 240 mg Q2W in the range of 
50to 70 kgwere also simulated, and they are predicted to be approximately 16.8% greater when 
comparedto the 3 mg/kg, 80 kg referencegroup.
Nivolumab is safe and well tolerated up to 10 mg/kg Q2W dose level. Adverse events have been 
broadly consistent across tumor types following monotherapy and have not demonstrated clear 
dose-response or exposure-response relationships. Additionally, the simulated median and 95th
prediction interval of nivolumab summary exposures across body weight range (35 -160 kg) are 
predicted to be maintained below the corresponding observed highest exposure experienced in 
nivolumab ie,95th percentile following nivolumab 10 mg/kg Q2W from clinical study 
CA209003. Thus, while subjects in the lower body weight ranges would have greater exposures 
than 80 kg subjects, the exposures are predicted to be within the range of observed exposures at 
doses (up to 10 mg/kgQ2W) used in the nivolumab clinical program, and are not considered to 
put subjects at increased risk. For subjects with greater body weights, the simulated ranges of 
exposures are also not expected to affect efficacy, because the exposures predicted following 
administration of a 240 mg Q2W are on the flat part of the exposure-response curves for 
previously investigated tumors, melanoma and NSCLC. 
Consistent with the nivolumab program and other tumor types, no MTD has been established in 
the dose escalation phase for the HCC cohorts. In addition, safety has been established up to 
10mg/kg in the uninfected-HCC cohort, and a similar safety profile has been observed 
regardless of HCC etiology at doses up to 3 mg/kg. As of 12-Mar-2015, 47 subjects had been 
treated in CA209040 as discussed in Section 1.4.6.  In addition, as of 30-June-2015, 
3HBV-infected HCC subjects have received at least 3 doses of 3 mg/kg nivolumab q2week. No 
DLT has been observed in the HBV cohort at 3mg/kg, and the safety profile remains similar 
across each etiology and dose level.  Given similar safety findings across the 3 uninfected, 
HCV-infected, and HBV-infected subjects in the Dose Escalation Phase, and similar PK 
observed from preliminary data in HCC, a flat dosing of 240 mg will be administered to all 
subjects in who will receive nivolumab monotherapyin the 1L Nivolumab vs Sorafenib Cohort
and Nivolumab plus Ipilimumab Combination Cohort.  
1.4.13
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase 
IFN-production 2-to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
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antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer 
models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies 
increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector 
cells, and dual blockade increased tumor infiltration of T effector cells and decreased 
intratumoral T regulatory cells, as compared to either agent alone.
102
The combination of nivolumab and ipilimumab was evaluated in CA209004(MDX1106-04), a 
Phase 1b multiple ascending dose study in subjects with treatment-naive and previously treated 
advanced melanoma.  Antitumor activitywas observedin 5 different combination cohorts:  
nivolumab 0.3 mg/kg and ipilimumab 3 mg/kg (Cohort 1, n=14), nivolumab 1 mg/kg and 
ipilimumab 3 mg/kg (Cohort 2, n=17), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (Cohort 2a, 
n=16), nivolumab 3 mg/kg and ipilimumab 3 mg/kg (Cohort 3, n=6), and nivolumab 1mg/kg 
and ipilimumab 3 mg/kg (Cohort 8, n=41).  From this study, it has been found that the 3 mg/kg 
nivolumab and 3 mg/kg ipilimumab combination regimen exceeded the maximum tolerated dose. 
Even though the drug-related discontinuation rates in combination cohorts were approximately 
26-27%, the ORR in these cohorts were still higher compared to nivolumab monotherapy 
(42%-44% versus 36%).
Additional studies have demonstrated the potential for IO combinations to improve antitumor 
responses across the nivolumab program.
80An ORR of 62-65% has been observed in advanced 
melanoma (CA209067 and CA209069, N=407) with a combination regimen of nivolumab 
1mg/kg plus ipilimumab 3 mg/kg q3week x 4. In RCC patients (CA209016), both nivolumab 
3mg/kg plus ipilimumab 1 mg/kg (n=21) and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
(n=23) showed antitumor activity with an ORR of 38%-40%. In NSCLC patients (CA209012), 
both combination regimens demonstrated a favorable efficacy profile with a response rate of 
20% and a median OS of 11m for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, and a response 
rate of 13% and median OS of 19.8 m for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg.  
In summary, nivolumab and ipilimumab combinationshaveshown additive or synergistic 
activitiesacross the tumor types investigated. To further improve the tolerability profile, other 
combination dosing regimens were also explored in the nivolumab development program. Less 
frequent dosing of ipilimumab at 1 mg/kg q6weekwhen givenwith nivolumab 3 mg/kg q2week 
was found to have a similar discontinuation rate to that observed in nivolumab monotherapy 
(11% vs 10%) in preliminary data from CA209012.
Based on these data, the following three dose armswill be evaluated in CA209040:
Arm A--nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q3 weeks x4,followed by nivolumab 
240 mg q2 weeks;
Arm B--nivolumab 3 mg/kg + ipilimumab 1 mg/kg, q3 weeks x4, followed by nivolumab 
240mg q2weeks;
Arm C--nivolumab 3 mg/kgq 2weeks + ipilimumab 1 mg/kgq 6weeks.
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1.4.14
Rationale for Shorter Infusion Times With 240 mg Flat Dose Nivolumab 
and Ipilimumab 
Long infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab and ipilimumab can be safely administered using shorter infusion times of 30 minutes 
duration in subjects will diminish the burden provided no change in safety profile.
Previous clinical studies of nivolumab monotherapy and ipilimumab monotherapy and the
combination of nivolumab and ipilimumab have used a 60 minute infusion duration for
nivolumab and 90-minute infusion duration for ipilimumab (1-3 mg/kg dosing for both).
However, both nivolumab and ipilimumab have been administered at up to 10 mg/kg with the
same infusion duration:
Nivolumab has been administered safely over 60 minutes at doses ranging up to10 mg/kg 
safely over long treatment duration.  In Study CA209010, (a Phase 2, randomized, double 
blinded, dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell 
RCC) a dose association was observed for infusion site reactions and hypersensitivity 
reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were 
Grade 1-2 and were manageable. An infusion duration of 30 minutes for 3 mg/kg 
nivolumab (30% of the dose provided at 10 mg/kg) is not expected to present any safety 
concerns compared to the prior experience at 10 mg/kg nivolumab dose infused over a 
60-minute duration.
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In the
CA184022 study, where ipilimumab was administered up to a dose of 10 mg/kg, on-study 
drug related hypersensitivity events (Grade 1-2) were reportedin 1 (1.4%) subject in the 
0.3mg/kg and in 2 (2.8%) subjects in the 10 mg/kg group. There were no drug-related 
hypersensitivity events reported in the 3 mg/kg group. Across the 3 treatment groups, no 
Grade 3-4 drug-related hypersensitivity events were reported and there were no reports of 
infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely administered as 
90 minute infusion in large phase 3 studies in prostate cancer (CA184043) and as adjuvant 
therapy for stage 3 melanoma (CA184029), with infusion reactions occurring in subjects. 
Administering 1 mg/kg of ipilimumab represents one-tenth of the 10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon
across nivolumab or ipilimumab clinical studies or the combination of nivolumab and
ipilimumab. Furthermore, a 30-minute break after the first infusion for the combination cohort 
willensure the appropriate safety monitoring before the start of the second infusion. Overall, a
change in safety profile is not anticipated with 30-minute infusion of nivolumab, ipilimumab or
combination.
1.4.15
Summary of Drug-related Hepatic Eventsin CA209040
Most subjects who enroll in nivolumab studies must have AST/ALT 3x ULN (Grade 1) or 
bilirubin 1.5x ULN (Grade 1).  However, given the patient population in CA209040 with 
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advanced HCC, subjects may enroll with AST/ALT 5x ULN (Grade 2) or bilirubin 3x ULN 
(Grade 2).  As a result, the CA209040 protocol when originally written made exceptions to the 
program standard DILI criteria (see Section 6.6) and dose discontinuation due to hepatotoxicity 
(see Section4.1.18).
As of 12-Mar-2015, there have been 47subjects treatedwith nivolumab and overall 19% of 
subjects have experienced a drug-related AST increase (11% Grade3) and 15% have 
experienced a drug related ALT increase (9% Grade3).  These have occurred without changes in 
other hepatic parameters, are generally transient, and occur in both viral and non viral cohorts.  
Steroid intervention was required in only 1 of 5 Grade3 elevations, and was adequately managed
(see the narrative below).
As outlined in Section1.4.8, in the setting of tremelimumab in HCC-HCV, a rise in serum 
transaminases was observed after the first dose in more than half of the HCC subjectswithfive 
of 20 subjects (25%) experiencinga Grade 3 or higher elevation in ALT.
98  However, in all 
cases, the transaminitis was transient, not associated with a decline in liver function,did not 
require steroid management, and did not recur with subsequent doses.  In addition, in advanced 
HCC subjects treated with sorafenib, all-grade transaminase elevations have been observed in 
26% of subjects with 17% Grade 3 or 4,
64which is very similar to the observedhepaticprofile of 
nivolumab to date.
Additional details for the 5 Grade3 related hepatic eventsin CA209040:
Subject 
 (uninfected) had a Grade3 event of hepatitis and AST/ALT 
increased that began on study Day 71.  At baseline, AST/ALT values were 1.2x ULN/<ULN, 
respectively, and peaked at 10x ULN/8.8x ULN,respectively.  The event was managed by 
dose delay,steroid intervention, and resolved to Grade1after 127 days.  The subject was 
discontinued permanently from nivolumab treatment.
Subject 
 (HCV infected) had a 4-day AST/ALT elevation (baseline 
3xULN/<ULN) who peaked at 6x ULN/1.6x ULN, respectively.  Onset was at Day 15 and 
was managed by dose delay.  AST/ALT remained <1.5x ULN upon rechallenge, and the 
subject continued nivolumab without further hepatic issues.
Subject 
 (HCV infected) had a Grade3 increased AST/ALT at study 
Day170.  Atbaseline, AST/ALT were 3x ULN/4.1x ULN, respectively, and the subject 
peaked at 7xULN/6.6x ULN, respectively.  The subject continued on nivolumab and LFTs 
returned to baseline after 55days.
Subject 
 (HCV infected) had a Grade3 increased AST/ALT at study Day 15.  
At screening AST/ALT were 3.5x ULN/4.3x ULN, respectively.  At baseline AST/ALT were 
4.2x ULN/5.2x ULN andpeaked at 6xULN/7.4x ULN, respectively, on Day 15.  Nivolumab 
was continuedand the event resolved after 7 days.  The subject continued nivolumab without 
further hepatic issues.
Subject 
 (Uninfected) had an 8-day event of Grade3 AST/ALT increased, 
cholangitis, and increased bilirubin that occurred at study Day 428.  AST/ALT/bilirubin at 
baseline were1.3x ULN/<ULN/<ULN, respectively, and peaked at 3.5x/3.1x/2.2x ULN.  
After dose delay and treatment with antibiotics, the event resolved; however, the subject was 
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not rechallenged due to other ongoing adverse events including anemia requiring blood 
transfusions.
.F
R7AA&*532S747659&W70749
Subjects with advanced hepatocellular carcinoma have limited therapeutic options.  Despite 
intensive efforts to develop new treatment paradigms while improving on the efficacy of current 
treatment options, the clinical management of HCC remains challenging. Systemic therapy with 
sorafenib is currently the only effective and approved first line therapy to prolong survival for 
subjects with advanced disease. For subjects progressing on or intolerant to sorafenib treatment, 
best supportive care or participation in clinical trials are the only remaining treatment options. 
The development of new approaches for the management of advanced HCC is needed.  
Nivolumab has demonstrated clinical efficacy in a renal cell carcinoma, malignant melanoma, 
non-small cell lung cancer, and some lymphomas. There is a strong preclinical rationale for 
blocking PD-1 signaling in HCC. Nivolumab appears to have a manageable safety profile across 
multiple tumor types, and has been approved for metastatic melanoma and metastatic squamous 
non-small cell lung cancer. Adverse events associated with its use include liver toxicities, 
thyroiditis, pneumonitis, and diarrhea. Liver toxicities were observed in about 2% of subjects 
treated with nivolumab. In this study, it is possible that a higher percentage of subjects will 
experience liver toxicity because of the presence of pre-existing liver damage due to viral 
infection.  A comprehensive algorithm is included in the protocol detailing the management of
pneumonitis and other immune-related adverse events associated with nivolumab therapy
(Appendix 1).  Frequent monitoring of liver function tests during the study will help to identify 
liver injury at an early time point and permit initiation of treatment.  Clinical activity with single 
agent nivolumab in other tumors that express PD-L1 support its clinical application.  
This study will permit entry of subjects with impaired hepatic function and a history of viral 
hepatitis. The maintenance of stable disease in this population may be of benefit. Due to a 
concern that the potential toxicity of nivolumab in subjects with concurrent viral hepatitis, 
particularly those with chronic HBV, could be higher than those with other risk factors for HCC, 
dose escalationwill be performed independently in each population.  As an additional safety 
measure, the initial dose level of nivolumab in the HBV cohort will be one third of the other 
arms.  Accrual to the arms of the study after that time will be independent and based on safety 
demonstration in the previous dose level for each arm.  There is some risk associated with tumor 
biopsies, including bleeding and pain. While there will be no direct benefit to individual subjects 
that undergo these procedures, it is hoped thatdata generated from the analyses of these samples 
will guide the clinical development of this compound for the treatment of cancer. Given the 
strong scientific rationale based on the biological importance of inhibiting the PD-1/PD-L1 
pathway the overall benefits far outweigh the potential clinical risks associated with this 
treatment. 
Subjects in CA209040 from the Dose Escalation Phase include sorafenib-treated (32 of 47) and 
sorafenib-naive (15 of 47), and overall suggest the potential to improve clinical outcomes in a 1L 
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or 2L setting.  However, the potential benefit of nivolumab monotherapy over sorafenib is not 
yet established.  Sorafenib is the only approved agent for advanced HCC; however, it has a 
relatively low response rate vsplacebo in the setting of frequent adverse events and drug 
discontinuations.
55,61  
  Based on the preliminary safety, tolerability, and activity of nivolumab in 
advanced HCC, the benefit-risk profile of nivolumab appearsto favor nivolumab and warrants a 
randomized comparison.  In order to assess the potential benefit and safety of nivolumab 
monotherapy over standard-of-care sorafenib, a randomized cohortcomparing nivolumab 
monotherapy to sorafenib will be conducted.  The overall risk-benefit assessment supports the 
conduct inCA209040.  A DMC will be utilized to monitor the safety and activity of the 
treatments throughout the conduct of the 1L Nivolumab vsSorafenib Cohort.
The combination of nivolumab plus ipilimumab has the potential for increased benefit compared 
to monotherapy targeting the PD-1 or CTLA-4 pathway.  Current data from CA209040 
demonstrate nivolumab has antitumor activity and an acceptable safety profilein subjects with 
advanced HCC.  Similarly, in advanced HCC-HCV subjects, blockade of CTLA-4 pathway with 
tremelimumab is tolerable and also demonstrates antitumor activity.  In addition to the potential 
for increased efficacy with a combination IO approach, there is also potential for increased 
frequencies of adverse events.  The safety profile of nivolumab andnivolumab plus ipilimumab 
is characterized by immune-related toxicities, such as diarrhea, rash, pneumonitis, liver toxicity, 
and endocrinopathies.   The frequencies and intensities of these events in the combination are 
variable and may depend on specific doses and schedules used, but may be increased over 
monotherapy.  Sequelaehave been manageable and reversible following interventionwith
existing algorithms usingdose delays and/or with systemic steroid treatment. However,these 
AEs have the potential to be fatal if not detected early and managed per the established
algorithms.
The following measures will be employed to ensuresafety of the subjects in the Nivolumab plus 
Ipilimumab Combination Cohort:
Two stage design with initial lead-in (n=12)to establish the safety and tolerability of the 
combination before enrolling the entire cohort (n=40).
Toxicity monitoring to ensure the subjects’ safety, includingfrequent safety conference calls 
during safety lead-in cohorts with investigators andrepresentatives of the sponsor.
BMS medical safety team (MST) to review ongoingsafety signals across the entire
nivolumab program, including all ongoing combinations with ipilimumab.
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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).
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
M.M
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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 (e.g., 
advertisements), and any other written information to beprovided 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 (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
M./
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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 
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.
Investigators must:
1.Provide a copy ofthe 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.
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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.
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This is a phase 1/2, dose-escalation, open-label, non-comparative study of nivolumabor 
nivolumab in combinationwithipilimumab inadvanced hepatocellular carcinoma subjects with
or without chronic viral hepatitis;and arandomized, open-labelstudy of nivolumab vssorafenib
in advanced hepatocellular carcinomasubjectswho are naive to systemic therapy.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design of CA209040 and Cohorts 1-4
Threeetiologic subtypesare included in the Dose Escalation Phase: uninfected HCC subjects, 
HCV-infected HCC subjects, and HBV-infected subjects.
The first part of the study is the Dose Escalation Phasedesigned to establish the safety of 
nivolumab at different dose levels (Section 3.1.3).  The maximum dose level for the dose 
escalation phase is 10 mg/kg in uninfected HCC subjects and 3 mg/kg in HCV andHBV infected 
HCC subjects, respectively.   
Upon activation of Amendment 4, the ExpansionPhase(200 subjects)isdesigned to generate 
additional clinical data at specified dosesin 4 cohorts (50 subjects per cohort) including 
uninfected sorafenib naive/intolerant subjects, uninfected sorafenib progressors(previously 
referred to as sorafenib failures in Amendment 4), HCV-infected, and HBV-infected subjects.
Uninfected, HCV-infected, and HBV-infected subjects will receive a dose of 3 mg/kg Q2 week 
IV over 60 minutes.  Prior to activation of amendment 8, nivolumab infusions were administered 
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over 60 minutes in the Dose Escalation Phaseand Expansion Phase; however, upon activation of 
amendment 8 and based on rationale in Section1.4.14, nivolumab infusions may be given over 
30 minutes to align with the infusion times in the 1L Nivolumab vs. Sorafenib Cohortand 
Nivolumab plus Ipilimumab Combination Cohort.    
Upon activation of Amendment 8, enrollment into the Expansion Phasewill close (if not 
already completely enrolled), and the 1L Nivolumab vsSorafenib Cohortwill begin accrual.  
This is an open-label, randomized,cohort in adult (>18 years) male and female subjects with 
advanced HCC.  Subjects must not be amenable for management with surgery or loco-regional 
therapy.  Approximately130advanced HCC subjects who are naive to systemic therapy
(uninfected, HCV-infected, or HBV-infected)will be randomized 1:1 to receiveopen labelflat 
dose nivolumab 240 mg Q2 week IV over 30 minutes(Arm A)or sorafenib 400 mg po BID 
(Arm B)until unacceptable toxicity or RECIST 1.1 radiographicprogression or study 
discontinuation for any other reason (Section 3.5).  Uninfected, HCV-infected, or HBV-infected 
subjects will be enrolled.  Subjects will be stratified by viral status (HCV vs non-HCV[HBV 
infected or uninfected]) and presence ofmacrovascular invasion (MVI) orextrahepatic spread 
(EHS).  Subjects with resolved HCV infection will be stratified into the HCV group.  
Upon activation of Amendment 8, enrollment into the Expansion Phasewill close (if not 
alreadycompletely enrolled), and the Nivolumab and Ipilimumab Combination Cohortwill 
begin accrual of up to 120 subjects.  Uninfected, HCV-infected, or HBV-infected subjects with 
advanced HCC andprevious treatment with sorafenib will be randomized 1:1:1 into 3 different 
dose arms: 
Arm A--nivolumab 1 mg/kg + ipilimumab 3 mg/kg q3 week x 4 followed by flat dose 
nivolumab 240 mg IV q2week until toxicity or disease progression(n=40)
Arm B--nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3week x 4 followed by flat dose 
nivolumab 240 mg IV q2week until toxicity or disease progression(n=40)
Arm C--nivolumab 3 mg/kgq2week+ ipilimumab 1 mg/kg q6week until toxicity or disease 
progression(n=40).
Since the use of nivolumab and ipilimumab has not been previouslystudied in subjects with 
advanced HCC, a 2 stage design will be employed for each of the 3 dose arms.  In Stage 1, 12
subjects will be enrolled in each dose arm, and will undergo a safetyand tolerability assessment 
at Week 13 (or prior to Week 13if discontinued)prior to enrollment of any additional subjects.
The safety evaluation (Section3.1.4)will be conducted independently for each dose arm in Stage 
1based on criteria described in Discontinuation Criteria (Sections4.1.18for nivolumab and4.2
for ipilimumab).  No additional subjects will be enrolled until the safety evaluation at Week 13 
occurs.  Enrollment of the first 12 subjects in each dose cohort will be limited to select sites.  
After completion ofStage 1, enrollment in Stage 2 of the subsequent 28 subjects can occur in 
each dose armandis contingent upon the results of the safety evaluation.
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Numberof Subjects:  Approximately 500subjects including the Dose Escalation Phase 
(~50subjects), Expansion Phase (200 subjects), 1L Nivolumab vs Sorafenib Cohort 
(~130subjects), and Nivolumab plus Ipilimumab Combination Cohort (120 subjects).
3.1.1
Treatment Flow 
The study will consist of 4 phases: Screening, Treatment, Follow-up and Survival Follow-up. 
ScreeningPhase:
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).
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 (for subjects in the 1L Nivolumab vsSorafenib 
Cohortand Nivolumab plus Ipilimumab Combination Cohort).
Screening assessments can be performed within 28 days of first dose.
Treatment Phase:
Nivolumab monotherapy will be given on an every two week schedule and one treatment cycle 
(42 days) is comprised of three doses in the Dose Escalation(at doses of 0.1 mg/kg to 10 mg/kg
q2week)and Expansion Phase(3 mg/kg q2week).  In the 1L Nivolumab vsSorafenib Cohort, 
nivolumab monotherapy(240 mg IV)will be given on an every two week schedule with 
1dose=1cycle; sorafenib will be given 400 mg po BID.  In the Nivolumabplus Ipilimumab 
Combination Cohort, the dosing will be asoutlined above, withno less than 19 days between
doses in Arms A and B during the q3week induction phase.  In arm C, nivolumab doses may be 
given no less than 12 days between doses, and ipilimumab doses no less than 5 weeks between 
scheduled doses
All subjects except those in the 1L Nivolumab vs Sorafenib Cohortwill undergo tumor 
assessments at every q6 week(±2 days)for the first 48 weeks, and then q12week(± 1 week)
thereafter untildisease progression.  Subjects in 1L Nivolumab vs Sorafenib Cohortwill undergo 
tumor assessmentsq8 week (± 1 week) for the first 48 weeks, and then q12week (±1week) 
thereafter untildisease progression or treatment is discontinued (whichever occurs later).  
Imaging assessments should be scheduledregardless of dose delay or missed doses in all cohorts.
Prior to activation of Amendment 8, subjects in the Dose Escalation Phasewere treated until 
either a confirmed CR, completion of 2 years of therapy, toxicity, or disease progression.  
However, upon activation of Amendment 8, all subjects are to betreated until toxicity, 
RECIST1.1 defined progression (Appendix 2), unacceptable toxicity, or study discontinuation 
for any other reason (Section3.5).  Treatment may continue beyond progression under protocol 
defined.
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Subjects will continue to receive nivolumab, sorafenib, or nivolumab plus ipilimumabuntil:
1. RECIST 1.1-defined radiographic progression or unacceptable toxicity.   
2. Clinical deterioration (Section 3.1.4) suggesting that no further benefit from treatment is 
likely.
3. Meets criteria for discontinuation of study therapy as outlined in Sections 3.1.3.1(Dose 
Limiting Toxicity), 3.5(Discontinuation of Subjects from Treatment), 4.1.18(Nivolumab 
Permanent Discontinuation Criteria), 4.1.12(Treatment Interruption or Discontinuation for 
Sorafenib Treatment) or 4.2(IpilimumabPermanent Discontinuation Criteria) 
Accumulating evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses follows delayed kinetics of weeks or months, and can be 
preceded by initial apparent radiological progression or the appearance of new lesions or some 
enlarging lesions while certain target lesions are regressing (“mixed response”). It is thus 
reasonable, in the absence of clinical deterioration, to continue to treat these subjects until 
progression is both confirmed and found to have worsened at a subsequent imaging evaluation. 
Evidence of PD will be based on a comparison with baseline (or nadir) scans or other tumor 
evaluations. Additional details on treatment beyond progression are located in Sections 3.1.8(for 
nivolumab and ipilimumab) and 4.1.13(for sorafenib).
No subject receiving nivolumab or nivolumab plus ipilimumab will be permitted dose escalations 
or de-escalations.  Sorafenib dose adjustments aredescribed in Section 4.1.8circumstances 
(Section 3.1.8).  After discontinuation from study therapy, thereare 2follow-up visits required 
(on site visits), and additional survival follow-up (on-site or phone visits).
Follow Up Phase:
Follow-Up Visit 1 to occur 35 days from the last dose (7 days) or coinciding with the date of 
discontinuation of study drug (7 days) if the date of discontinuation is greater than 42 days 
from the last dose. Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (7 days). 
Subjects who discontinue study drug for reasons other than radiographicprogression or who 
continue treatment beyond progression will continue to have tumor assessments (if clinically 
feasible) according to the schedulein Table 5.1-8and Table 5.1-9anduntil progression or 
treatment discontinuation for subjects being treated beyond 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.
Survival Follow Up Phase:
Survival Follow-Up Visits to occur approximately every 3 months from Follow-Up Visit 2. 
Survival Follow-up visits may be performed by phone contact or office visit(please refer to 
Section 3.7.
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3.1.2
Duration of Study
Thestudy is expected to accrue over a period of approximately 4years.  The study will end when 
survival follow-up collection has concluded. The last visit will be defined as the latest survival 
visit included in the final analysis of OS (ie. the latest subject death, loss to follow up, or 
withdrawal of consent).  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.
3.1.3
Dose EscalationPhase
A 3+3 design with escalating doses will be used with this Phase 1/2studystarting at a dose of 
0.3mg/kg in the non-viral HCC and HCC-HCV arms.  Escalationsto 1mg/kg, 3 mg/kg, and 
10mg/kgwere originally planned for all cohorts,if safety is demonstrated.  Accrual to the 
HCC-HBV infected arm will begin at 0.1mg/kg.  Subjects will be assigned to a dose level in the 
order of study entry.  For additional risk mitigation, a sentinel dosing strategy will be utilized in 
the first HBV cohort of 0.1mg/kg; therefore, two weeks will separate the first nivolumab dose 
for each subjectin the 0.1 mg/kg cohort.  However, in subsequent dose panels, a sentinel dosing 
strategy will not be utilized.
In Amendment 4, given the safety data for the uninfected HCC cohort atthe 10 mg/kg dose level 
and a similar safety profile observed across eachHCC etiology, 3 mg/kg dose was selected for 
Expansion Phasefor the uninfected and HCV-infected HCC subjects, whereas a dose of 3 mg/kg 
or the MTD was planned for the HBV-infected HCC subjects.  The HCV-and HBV-HCC 
cohorts in the dose escalation phase will no longerbe escalated to the 10 mg/kg dose.  More 
recently, the HBV 3 mg/kg dose escalation completed at the end of June 2015 with no DLT in 
any subject; therefore, the HBV expansion arm has opened in July 2015 at the 3 mg/kg dose.
3.1.3.1
Dose Limiting Toxicityin the Dose Escalation Phase
Dose limiting toxicity (DLT) will be determined based on the incidence and intensity of adverse 
events (AEs) occurring up to two weeks after the administration of the third dose of nivolumab 
(ie from C1D1-C1D42). 
Dose Limiting Hematologic Toxicity 
DLT will be defined as the need for platelet transfusion, platelet count <10,000/L,Grade4 
neutropenia of greater than 3 days duration or febrile neutropenia. The development of a 
transfusion requirement or an increase in transfusion requirement of more than two units of red 
blood cells every two weeks over a six week period will also be considered dose limiting unless 
an alternative cause is identified. 
Dose Limiting Non-hematologic Toxicity 
Dose limiting hepatic toxicity will be defined as 
Hepatotoxicity as evidenced by any of the following:
- AST or ALT > 10 x ULN for >2 weeks,
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- AST or ALT > 15 x ULN irrespective of duration,
- T. bilirubin > 8 x ULN irrespective of duration for subjects with elevated bilirubin at 
study entryor > 5 x ULN for those with normal T bilirubin at entry,
Clinical deterioration manifested by drug-related hepatic decompensation not identified 
above (eg, encephalopathy etc.)  
Grade 2 or greater eye pain or reduction of visual acuity that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks of starting therapy or 
requires systemic treatment (eg  encephalopathy etc.).
Clinically relevant Grade 3 or greater non-hematologic toxicity excluding lymphopenia, 
asymptomaticlipase or amylase or laboratory abnormalities that correct to Grade 1 within 
72hours after treatment. Toxicity will be graded by CTCAE v 4.03.
No dose escalations or de-escalations are permitted within each subject’s treatment. A subject 
who is withdrawn from the study before the completion of the first six weeks of treatment for a 
reason other than a DLT may be replaced. Subjects who experience dose limiting toxicity may 
resume treatment as per Section4.1.16upon resolution, providing that criteria for permanent 
discontinuation are not met (Section4.1.18).
3.1.4
Safety Evaluationof Stage 1 of the Nivolumab plus Ipilimumab 
Combination Cohort
A total of 36 subjects will be randomized 1:1:1 (n=12) into one of the following 3 dose armsin 
Stage 1:  
Arm A--nivolumab 1mg/kg + ipilimumab 3mg/kg q3week x 4(Week 1, 4, 7, and 10)
followed by nivolumab 240 mg q2week(beginning at Week 13)
Arm B--nivolumab 3mg/kg + ipilimumab 1mg/kg q3 week x 4 (Week 1, 4, 7, and 10) 
followed by nivolumab 240 mg q2week(beginning at Week 13)
Arm C--nivolumab 3 mg/kg q2 week(Week 1, 3, 5, 7, 9, 11, 13, etc)+ ipilimumab 1 mg/kg 
q6week(Week 1, 7, 13, etc).
After enrollment of 36 subjects in Stage 1, no additional subjects will be enrolled until 
completion of the safety evaluation.  Safety and tolerabilitywill be determined when subjects 
reach week 13, or have been discontinued prior to this time point.  However,tolerability beyond 
four doses may also be taken into consideration.  All subjects will continue tobe followed for 
safety, progression, and overall survival after discontinuation of studymedication. The criteria 
used to advance to Stage 2will bebased on drug relatedadverse events leading to permanent 
discontinuation in the safety lead-in cohort(Stage 1, n=12 per dose arm) (listed in Section
4.1.18for nivolumab and 4.2for ipilimumab) and include the following:
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If no more than one-third of the subjects in a given treatment arm permanently discontinue
study medication prior to Week 13 due to treatment related adverse events, thenthis dose 
cohort will be deemed as tolerableandenrollment of an additional 28 subjects may proceed 
(Stage 2).
If more than one-third of subjects in a treatment arm permanently discontinue study
medication prior to Week 13 due to treatment-related adverse events, then thesafety, 
tolerability, and efficacyof that treatment arm will be reviewed by the Sponsor and 
investigatorsprior torandomizing any additional subjects.  A decision will be made bythe 
sponsor whether to continue enrollment of an additional 28 subjects (Stage 2).
3.1.5
Evaluation of Risk/Benefit for a Cohortthat does not meet Tolerability 
Criteria in theNivolumab plus Ipilimumab Combination 
In the event that more than4 of 12 subjects (one-third) per dose arm in Stage 1 require
permanent discontinuation due to treatment related adverse events prior to completion of the 
safety lead-in, the sponsor will review the risk/benefit profile from each cohortand determine 
whether or not to advance. In this event, the Sponsorwill review allavailable data from 
ArmsA, B, and C, and recommend continuation, modification or terminationof a cohort. The 
rationale for further evaluation is that the most frequent severedrug-relatedAEs for the 
combination of nivolumab and ipilimumab have beenasymptomatic and reversible (ie, LFTs and 
lipase laboratory changes) and there is preliminaryevidence of deep and durable responses in 
advanced melanoma (CA209004, CA209067, and CA209069) despite theseevents. In 
particular, any assessment of the risk/benefit of a cohortnot meetingtolerability will be triggered 
if the following criteria are met:
A majority of subjects in the cohorthave at least stable disease or a partial tumorresponse.
All treatment related AEs leading to discontinuation are non-fatal, reversible and without
severe sequela.
A majority of the treatment related AEs are laboratory in nature, asymptomatic, and
monitorable via routine blood draws.
If a decision is made to continue with a cohortbecause of a favorable risk/benefit profile(ie. non 
fatal AEs in subjects with at least stable disease or a partial tumor response) and despitemeeting 
the ‘not tolerable’ criteria above, then the EC/IRBs must be notified.
Informed Consent forms updated, and discussion of the risk/benefit must be documented with all
current and future subjects who are randomized to this regimen.
3.1.6
Stopping Rule for Dose Escalation Cohort
During the dose escalation phase, if more than one drug-related Grade 4 toxicity or drug-related 
death occurs at a dose level for a specific cohort, new subject accrual in that cohort at that dose 
level will be held.  A discussion with investigators may be held to review the risk/benefit of this 
regimen.  This discussion will be triggered if the following criteria are met:
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Majority of subjects who discontinue due to treatment related AEs have deep tumor response 
(ie,> 80% reduction)
All treatment related AEs leading to discontinuation are non-fatal, reversible and without
severe sequela (ie,GI perforation)
Majority of the treatment related AEs are laboratory in nature, asymptomatic, and readily 
monitored with routine blood draws.
If a decision is made to continue with a dose level because of a favorable risk/benefit profile 
despite meeting the ‘not tolerable’ criteria (‘more than one drug-related Grade 4 toxicity or 
drug-related death’), then IRBs must be notified, ICFs must be updated, and discussion of the 
risk/benefit must be documented with all future subjects who enroll on this regimen.
3.1.7
Stopping Rules for Clinical Deterioration
Clinical deterioration will be assessed to have occurred after a clinical event that, in the 
Investigator’s opinion, is attributable to disease progression, is unlikely to reverse with continued 
study treatment and therefore indicates that the subject is not benefiting from study treatment and 
cannot be managed by the addition of supportive care (such as bisphosphonates and/or bone 
directed radiotherapy, thoracentesis or paracentesis of accumulating effusions). The decision to 
continue or stop treatment should be discussed with the BMS Medical Monitor and will be 
documented in the study files. 
Examples ofevents that may, in the Investigator’s opinion, indicate a lack of clinical benefit 
include, but are not limited to, the following:
Performance status decrease of at least 2 points from baseline
Skeletal related events defined by the following: 
- Pathologic bone fracture in the region of cancer involvement 
- Cancer related surgery to bone 
- Spinal cord or nerve root compression
Bladder outlet or urethral obstruction
Development of new central nervous system metastases or Grade 3 encephalopathy
Any setting where the initiation of new anti-neoplastic therapy has been deemed beneficial to 
the subject.
3.1.8
Treatment Beyond Progression for Nivolumab or Nivolumab plus 
Ipilimumab
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.  This phenomenon was observed in the Phase 1
study of nivolumab, CA209003, and confirmed in multiple Phase 3 studies (ie,lung CA209017; 
melanoma CA209037, CA209066, and CA209067). Two hypotheses explain this phenomenon. 
First, enhanced inflammation within tumors could lead to an increase in tumor size which would 
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appear as enlarged index lesions andas newly visible small non-index lesions. Over time, both 
the malignant and inflammatory portions of the mass may then decrease leading to overt signs of 
clinical improvement. Alternatively, in some individuals, the kinetics of tumor growth may 
initially outpace anti-tumor immune activity. With sufficient time, the anti-tumor activity will 
dominate and become clinically apparent.  Therefore, subjects will be allowed to continue study 
therapy after an initial investigator-assessed RECIST 1.1 (Appendix 2) defined progression as 
long as they meet the following criteria:
Investigator assessed clinical benefit
Subject is tolerating nivolumabor nivolumab plus ipilimumab
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 or 
nivolumab plus ipilimumab treatment, using an ICF describing any reasonably foreseeable 
risks or discomforts, or other alternative treatment options.
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.  The 
decision to continue treatment beyond initial investigator-assessed progression should be 
discussed with theBMS 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 in Table 5.1-4, Table 5.1-5and, Table 5.1-7.  
Subjects should discontinue study therapy upon further evidence of further progression, defined
as an additional 10% or greater increase in tumor burden SLD 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). 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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Clinical Protocol
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BMS-936558
nivolumab
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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.
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For entry into the study, the following criteria MUST be met. Eligibility criteria for this study 
have been carefully considered to ensure the safety of the study subjects and to ensure that the 
results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. No 
exceptions will be granted.
For entry into the study, the following criteria MUST be met.
3.3.1
Dose Escalation and Expansion Phase
3.3.1.1
Inclusion Criteria
1.Signed Written Informed Consent
a)The signed informed consent form prior to the performance of any study related 
proceduresthat are not considered part of standard of care.
2.Target Population
a)Subjects with advanced hepatocellular carcinoma not amenable for management with 
curative intent by surgery or local therapeutic measures.
b)Histological confirmation of hepatocellular carcinoma. Subjects with radiological 
diagnosis may be enrolled for screening in the study but histological confirmation is 
mandatory prior to initiation of study therapy.
c)Subjects must fulfill the criteria forprior therapy as follows:
i) For the dose escalation cohorts(uninfected, HCV-infected, and HBV-infected), 
subjects must have progressive disease following or be intolerant of at least one line 
of systemictherapy or refuse sorafenib treatment (refusal must be documented); 
subjects cannot be on active cancer therapy during the screening period.
ii)For theuninfected sorafenib progressors in theExpansion Phase, subjects must have 
had documented radiographic or symptomatic progression during or after sorafenib
therapy
iii)For the uninfected sorafenib naive or intolerant subjects in the Expansion Phase,
subjects must either have never received sorafenib treatment or were intolerant to 
sorafenib therapy as defined in Section1.4.9.
iv)For the HCV and HBV cohorts in the Expansion Phase, subjects must have received 
sorafenib treatment and be either intolerant or have had documented radiographic or 
symptomatic progression during or after sorafenib therapy as defined in Section 1.4.9.
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d)Subjects must have Child-Pugh scores as follows (Appendix 3):
i) Dose Escalation Phase: Child-Pugh score of 7 points or less, ie, Child-Pugh A or 
Child Pugh B7.
ii)Expansion Phase: Child-Pugh score of 6 points or less, ie, Child-PughA.
e)Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 
(Appendix4);
f) The noninfected HCC arm Dose Escalation Phase and Expansion Phasewill include 
subjects with prior HCV or HBV infection provided there is no active viral replication 
(negative for HBV DNAand/or HBV surface antigenand HCV RNA).  HBV exposed 
subjects with resolved HBV infection who have seroconverted must have detectable 
HBsAb and HBcAb titers and have undetectableHBsAgand HBV DNA.
g)In the Dose Escalation Phase and Expansion Phase, the HCV infected arm must have 
evidence of HCV RNA.  Subjects may have evidence of prior HBV infection but must 
have detectable HBsAb and HBcAb titers and have undetectable HBsAgand HBV DNA.
h)In the Dose Escalation Phase and Expansion Phase, subjects with chronic HBV infection 
must have evidence of ongoing viral replication (detectable HBsAg, HBeAg, or HBV 
DNA).  Subjects with chronic HBV infection must haveHBV DNA viral load 
<100IU/mL at screening.  In addition, they must be on antiviral therapy per regional 
standard of care guidelines prior to initiation of study therapy.  If not on antiviral therapy 
at screening, then the subject must initiate treatment per regional standard of care 
guidelines at the time of consent.  All subjects enrolled in the HBV cohort must continue 
antiviral therapy through follow-up visit 2.Both HBeAg positive and negative subjects 
will be included.
i) All subjects must have at least one measurable lesion.
j) Forsubjects in the Dose Escalation Phaseand Expansion Phase, the lesion can be 
accurately measured by CT-scan (10 mm) according to RECIST1.1(malignant lymph 
nodes must be > 15 mm on short axis) (additional details are included in Appendix 2)
i) Previously treated lesions can be considered target lesions if there is clear evidence of 
progression. 
ii)Bone metastases are not considered measurable lesions, unless there is a measurable 
soft tissue component per RECIST1.1.
iii)The measurable lesion cannot bebiopsied during treatment(if there is only one 
lesion). 
k)A formalin fixed, paraffin-embedded (FFPE) tumor tissue block or unstained slides of 
tumor sample (archival or recent) must be available for biomarker evaluation, as 
described in Section 5.6.
i) Subjects must consent to allow the acquisition of existing formalin-fixed 
paraffin-embedded (FFPE) material (block or a minimum of 15unstained slides) for 
performance of correlative studies; attempts should be made to collect at least 
20unstained slides. 
ii) If archived samples are not available, the subject must provide a fresh biopsy sample 
at screening -for this biopsy, subjects must have a soft tissue tumor lesion that can be 
biopsied at acceptable clinical risk (as judged by the investigator) at baseline. 
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Subjects must consent to the pre-treatment fresh biopsy (if no archived samples are 
available) as a condition of protocol participation. In this setting, if adequate tissue is 
not obtained during the first procedure then a repeat biopsy should be considered 
based on the investigator’s assessment of clinical risk. However, a repeat biopsy is 
not required to meet eligibility. Optional post treatment biopsy may or may not be 
obtained, depending on procedures specific at each study site.
iii)Lesions selected for biopsy should be large enough to allow for the collection of 
tumor tissue using a minimum 18 gauge or larger needle with an expected core 
sample length of 5 mm. A minimum of 2 passages of the needle core should be 
obtained. If adequate tissue is not obtained following initial passages of the needles, 
repeat passages of the needle should be performed if clinically feasible. Smaller 
lesions may be biopsied or smaller gauge needles may be used provided adequate 
tissue can be collected (similar quantity to amount collected using 18 gauge thickness 
and 5 mm core length). 
iv)The immediate confirmation (eg, touch imprint cytopathology) for presence of viable 
tumor cells from collected tissue samples is strongly recommended. 
l) Adequate organ and marrow function as evidenced by:
i) WBC
2000/µL (stable, off any growth factor within 4 weeks of study 
drug administration) 
ii)Neutrophils
1000/µL (stable, off any growth factor within 4 weeks of study 
drug administration) 
iii)Platelets 
60x103/µL (transfusion to achieve this level is not permitted)
iv)Hemoglobin
9.0 g/dL (may be transfused to meet this requirement) 
v)CreatinineCrCl >40 mL/min  (Cockcroft-Gault formula) 
vi)AST
5 X ULN 
vii)ALT
5 X ULN 
viii) Bilirubin
3 mg/dL
ix)INR 
≤ 2.3 or Prothrombin time (PT) 6 seconds above control 
x)Albumin
2.8 g/dL 
m)Ability to comply with treatment, PK and immune-monitoring sample collection (when 
indicated) and required study follow-up.
3.Age and Reproductive Status
a)Malesand Females, age 18 or older  
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 
24hours prior to the start of study drug.
c)Women must not be breastfeeding. 
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d)Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 7 
months after the last doseof study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}.
e)Azoospermic males and WOCBP who are continuously not heterosexually activeare 
exempt from contraceptive requirements.However they must still undergo pregnancy 
testing as described in this section.
f) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 5 
months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of one highly effectivemethod of contraception as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Male condoms with spermicide
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. 
Nonhormonal IUDs, such as ParaGard
Tubal ligation 
Vasectomy.
Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but female subjects 
must continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence.
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3.3.1.2
Exclusion Criteria
1.Target Disease Exceptions
a)Subjects with suspected brain metastasis are excluded, unless a brain MRI/CT is negative 
for metastasis
2.Medical History and Concurrent Diseases
a)Any history of hepatic encephalopathy 
b)Any prior (within 1 year) or current clinically significant ascites as measured by physical 
examination and that requires active paracentesis for control 
c)Active coinfection with both hepatitis B and C 
d)Hepatitis D infection in subjects with hepatitis B
e)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, prostate 
cancer without evidence of PSA progression or carcinoma in situ such as the following: 
gastric, prostate, cervix, colon, melanoma, or breast for example.
f) Subjects with any active autoimmune disease or history of known or suspected 
autoimmune disease except for subjects with vitiligo, resolved childhood asthma/atopy, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll.  
g)Uncontrolled or clinically significant cardiac disease 
h)Positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS) 
i) Known active drug or alcohol abuse 
j) Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (or any other antibody or drug specifically targeting T-cell costimulation or 
checkpoint pathways) 
k)Prior organ allograft or allogeneic bone marrow transplantation
l) All toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia and 
fatigue must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before 
administration of study drug. Subjects with toxicities attributed to prior anti-cancer 
therapy which are not expected to resolve and result in long lasting sequelae are 
permitted to enroll.  Neuropathy must have resolved to Grade 2 (NCI CTCAE version 4).
m)Active bacterial or fungal infections requiring systemic treatment within 7 days 
n)Use of other investigational drugs (drugs not marketed for any indication) within 28days 
or at least 5 half-lives (whichever is longer) before study drug administration
o)Known or underlying medical condition that, in the Investigator’s opinion, would make 
the administration of study drug hazardous to the subjects or obscure the interpretation of 
toxicity determination or adverse events.
p)Any history of clinically meaningful variceal bleeding within the last three months
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q)Subjects with a condition requiring systemic treatment with either corticosteroids 
(>10mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of study drug administration. Inhaled or topical steroids and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease.
3.Physical and Laboratory Test Findings
a)Laboratory evidence of any underlying medical conditions that, in the Investigator’s 
opinion, will make the administration of study drug hazardous or obscure the 
interpretation of toxicity determination or adverse events.
4.Allergies and Adverse Drug Reaction
a)History of severe hypersensitivity reactions to other monoclonal antibodies. 
b)History of allergy to study drug components.
5.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
6.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
c)Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4.
3.3.2
1L Nivolumab vs Sorafenib Cohort 
3.3.2.1
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 and 
inclusion/exclusion criteriareassessed.
2.Target Population
a)Subjects with advanced hepatocellular carcinoma
i) disease not eligible for surgical and/or locoregional therapies
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ii)progressive disease after surgical and /or locoregional therapies
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. 
ii)Evaluable 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 prior to randomizing a study subject. 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 2)
i) The lesion can be accurately measureduni-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 [TAI], etc.)
e)Locoregional therapy for HCC must be completed at least 4 weeks prior to the baseline 
scan. All acute toxic effects of any prior local treatment 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 3)
g)Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 
(Appendix4)
h)Subjects are eligible to enroll if they have non-viral-HCC or if they have HBV-, or 
HCV-HCC, defined as follows:
i) Chronic HBV infection as evidenced by detectable HBV surface antigen or HBV 
DNA.  Subjects with chronic HBV infection must be on antiviral therapy and have 
HBV DNA < 100 IU/mL.
ii)Active or resolved HCV infection as evidenced by detectable HCVRNA 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)
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i) Adequate hematologic function:
(1)WBC 2000/μL
(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
(3)AST and ALT 5 times the institutional upper limits of normal 
iv)Adequate renal function with a serum creatinine of < 1.5x ULN ora 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)Malesand Females, age 18 or older  
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 
24hours prior to the start of study drug.
c)Women must not be breastfeeding. 
d)Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 7 
months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}or 100 days post-treatment completion for subject receiving sorafenib.
e)Azoospermic males and WOCBP who are continuously not heterosexually activeare 
exempt from contraceptive requirements.However they must still undergo pregnancy 
testing as described in this section.
f) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 5 
months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}or 40 days post-treatment completion if receiving sorafenib.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
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the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of one highly effectivemethod of contraception as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Male condoms with spermicide
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. 
Nonhormonal IUDs, such as ParaGard
Tubal ligation 
Vasectomy.
Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but female subjects 
must continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence.
3.3.2.2
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)Any prior 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 
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within 28 days prior to the first dose of study drug administration.  (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 
(>10mg/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-infectionwith
(1)Both hepatitis B and Cas 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
(1)HBV DNA positive or HBV surface antigen positive subjects with detectable 
HCV ab, 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.
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 screening.    
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 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 
(Appendix6)
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)
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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 (Target disease exception 1.e.)
f) History of non-healing wounds or ulcers, or bone fractures within 3 months of study 
entry
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 or fine needle aspiration) 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.
i) Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy 
are permitted to enroll.
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 
(>10mg/day prednisone equivalent) or other immunosuppressive medications within 
14days of study administration.  Inhaled or topical steroids and adrenal replacement 
doses > 10 mg/day prednisone equivalents are permitted in the absence of active 
autoimmune disease.
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)Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (or any other antibody or drug specifically targeting T-cell costimulation or 
checkpoint pathways) 
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b)Prior participation in a BMS nivolumab study.
c)Prior use of systemic investigational agents for HCC.
d)Treatment with strong CYP3A4 inducers within 7 days of study entry, including rifampin 
(and its analogues) or St John’s wort.
e)Current therapeutic anticoagulation therapy. 
f) Treatment with anti-platelet therapy (aspirin at dose 300 mg/day, clopidrogrel at dose 
75 mg/day)
g)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
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.
3.3.3
Nivolumab plus Ipilimumab Combination Cohort 
3.3.3.1
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.
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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 and 
inclusion/exclusion criteriareassessed.
2.Target Population
a)Subjects with advanced hepatocellular carcinoma
i) Disease not eligible for surgical and/or locoregional therapies
ii)Documented radiographic progression during or after sorafenib therapy or sorafenib 
intolerance as defined in Section1.4.9.
b)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. 
ii)Evaluable 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 prior to randomizing a study subject. 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).
c)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).
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 [TAI], etc.)
d)Locoregional therapy for HCC must be completed at least 4 weeks prior to the baseline 
scan. All acute toxic effects of any prior local treatment must have resolved to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 Grade 1. 
e)Cirrhotic status of Child-Pugh Class A (A5 or A6) (Appendix 3)
f) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 
(Appendix4)
g)Subjects are eligible to enroll if they have non-viral-HCC or if they have HBV-, or 
HCV-HCC, defined as follows:
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i) Chronic HBV infection as evidenced by detectable HBV surface antigen or HBV 
DNA.  Subjects with chronic HBV infection must be on antiviral therapy and have 
HBV DNA < 100 IU/mL.
ii)Active or resolved HCV infection as evidenced by detectable HCVRNA or antibody.
h)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
(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 with serum albumin 2.8 g/dL, total bilirubin < 3 mg/dL, 
and AST and ALT 5 times the institutional upper limits of normal Adequate renal 
function with a creatinine clearance > 40 mL/min (Cockcroft-Gault formula) 
3.Age and Reproductive Status
a)Malesand Females, age 18 or older  
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 
24hours prior to the start of study drug.
c)Women must not be breastfeeding. 
d)Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 7 
months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time requiredfor the investigational drug to undergo approximately five half-
lives.}
e)Azoospermic males and WOCBP who are continuously not heterosexually activeare 
exempt from contraceptive requirements.However they must still undergo pregnancy 
testing as described in this section.
f) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with study drugand 5 
months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
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Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of one highly effectivemethod of contraception as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Male condoms with spermicide
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. 
Nonhormonal IUDs, such as ParaGard
Tubal ligation 
Vasectomy.
Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but female subjects 
must continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence.
3.3.3.2
ExclusionCriteria
1.Target Disease Exceptions
a)Known fibrolamellar HCC, sarcomatoid HCC,or mixed cholangiocarcinoma and HCC
b)Prior liver transplant
c)No history of hepatic encephalopathy
d)Any prior (within 1 year) or current clinically significant ascites as measured by physical 
examination and that requires active paracentesis for control 
e)Evidence of portal hypertension with bleeding esophageal or gastric varices within the 
past 3months
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 the first dose of study drug administration.  (If an MRI is 
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contraindicated, a CT scan is acceptable after discussion with the study Medical 
Monitor.)
ii)There is no requirement for immunosuppressive doses of corticosteroids 
(>10mg/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-infectionwith
(1)Both hepatitis B and Cas evidenced by detectable HBV surface antigen or HBV 
DNA and HCV RNA, OR
(2)Hepatitis D infection in subjects with hepatitis B
ii)Known history of testing positivefor human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS)  
iii)Active bacterial or fungal infections requiring systemic treatment within 7 days prior 
to study entry.
b)Interstitial lung disease that is symptomatic or may interfere with the detection and 
management of suspected drug-related pulmonary toxicity.
c)Prior organ allograft or allogeneic bone marrow transplantation
d)Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the 
normal range with medication.
e)Subjects with any active, known, or suspected autoimmune disease.
i) Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy 
are permitted to enroll.
ii)Subjects with suspected autoimmune thyroid disorders may be enrolled if they are 
currently euthyroid or with residual hypothyroidism requiring only hormone 
replacement.  
f) 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.
g) Subjects with a condition requiring systemic treatment with either corticosteroids 
(>10mg/day prednisone equivalent) or other immunosuppressive medications within 
14days 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.
h)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.
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3.Prior and Current Therapies
a)Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways.
b)Prior participation in a BMS nivolumab or ipilimumab study.
c)Radiotherapy within 2weeks prior to study drug administrationand no additional 
radiotherapy for the same lesion is planned.
d)Treatment with any chemotherapy, biologics for cancer, orinvestigational therapy within 
28days of first administration of study treatment, with the exception of sorafenib which 
requires a 14 day washout period.
4.Physical and Laboratory Test Findings
a)Positive pregnancy test
5.Allergies and Adverse Drug Reaction
a)Known or suspected allergy to nivolumab or ipilimumab or study drug components
b)History of severe hypersensitivity reaction to any monoclonal antibody
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 in 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.
3.3.4
Women of Childbearing Potential
A Woman of Childbearing Potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or is not postmenopausal. Menopause is defined as 12months of amenorrhea in a 
woman over age 45 in the absence of other biological or physiological causes.  In addition, 
women under the age of 55 must have a documented serum follicle stimulating hormone, (FSH) 
level > 40mIU/mLto confirm menopause.* 
*Women 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 periods below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels.  If the serum FSH level is >40mIU/ml at any time 
during the washout period, the woman can be considered post menopausal. 
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1 week minimum for vaginal hormonal products, (rings, creams, gels)
4 week minimum for transdermal products
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
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3.4.1
Prohibited Treatments
Locoregional therapy for HCC
Concurrent antineoplastictherapy, 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 
localtherapy described in Section3.4.1
Investigational agents for the treatment of cancer
For subjects receiving nivolumab, systemic steroids >10 mg within 14 days of dosing (with 
a few exceptions eg, steroids for adrenal insufficiency, steroids if taken as part of prophylaxis 
for CT prep[Section3.4.2]) 
Concurrent immunosuppressive agents(except to treat a drug-related adverse event).
Medications contraindicated with sorafenib treatment (refer to the package insert, summary 
of product characteristics (SmPC) or similar document).
103
3.4.2
Other Restrictions and Precautions
Subjects are permitted the use of topical, ocular, intranasal, intra-articular, and inhalational 
corticosteroids (with minimal systemic absorption). Immunosuppressive doses (eg, 
prednisone >10 mg/day or equivalent) and/or physiologic replacement doses of systemic 
corticosteroids (eg, prednisone 10 mg/day) are permitted in the context of treating adverse 
events. A brief course of corticosteroids for prophylaxis (eg, contrast dyeallergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused 
by a contact allergen) is permitted.
Hormone replacement therapy -subjects may continue to receive hormonal replacement 
therapy if initiated prior to randomization.
Bisphosphonates and RANK-L inhibitors
- For subjects receivingnivolumab or nivolumab plus ipilimumab, these are allowed for 
bone metastases
- For subjects randomized tosorafenib in the 1L Nivolumab vsSorafenib Cohort, the US-
FDA advises caution when combining bisphosphonatesand RANK-L inhibitors with 
anti-angiogenesis agents, including sorafenib.
104,105
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For subjects in the 1L Nivolumab vsSorafenib Cohort receiving sorafenib:
- Avoid concomitant use of strong CYP3A4 inducers such as carbamazepine, 
dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, or St. John’s wort because 
these drugs can decrease the systemic exposure to sorafenib.
- Therapeutic anticoagulation (eg, coumadin, warfarin, or heparin) is not permitted.  Low 
dose, non-therapeutic anticoagulation for catheter prophylaxis only will be permitted (eg, 
low dose warfarin).
- Concomitant use of QT/QTc-prolonging drugs should be avoided to the extent possible.
- Concurrent use of drugs that can disrupt electrolyte levels isdiscouraged, including, but 
not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; 
amphotericin B; high dose corticosteroids.
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) <30mL/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 anindividual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.4.3
Palliative Local Therapy
Palliative local therapyfor clinically symptomatic tumor sites (eg bone pain) including palliative 
(limited-field) radiation and palliative surgical resection may be considered if the following 
criteria are met:
The subject is considered to have progressed at the time of palliative therapy and meets 
criteria to continue with treatment beyond progression (Section3.1.8).
The lesion for palliative local therapy is a non-target lesion
The case is discussed with the BMS medical monitor. Palliative therapy must be clearly 
documented as such in the study record.
Tumor lesions requiring palliative local therapy should be evaluated for objective evidence of 
disease progression prior to the initiation of such therapy. In addition, sites must request an 
Independent Review of Progression from the third party radiology vendor prior to the 
initiation of palliative local therapy.  However, the initiation of palliative local therapy need 
not be delayed to await the assessment by the Independent Review of Progression.
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. 
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3.4.4
Treatment of HBV Virological Breakthroughand Ongoing HCV 
Subjects will have ongoing assessments of HBV DNA throughout the course of the study.  If a 
subject has an increase in HBV DNA, then virologic breakthrough should be considered.  
Adherence to current antiviral therapy should be assessed, and resistance testing performed 
according to local practices.  If a subject has documented virologic breakthrough due to antiviral 
resistance(defined as a >1 log IU/mL increase in HBV DNA), then this should be managed 
based on standardized regional guidelines and treatment with nivolumab monotherapy or 
nivolumab plus ipilimumabtemporarily held.  In the absence of a dose-limiting toxicity, or 
hepatic decompensation, the subject may resume treatment with nivolumab monotherapy or 
nivolumab plus ipilimumabonce virologic control is re-established (HBV DNA <100 IU/mL), 
provided both the PI and BMS medical monitor assess the benefit-risk ratio to be in the best 
interest of the subject.  If the subject meets the protocol defined criteria for hepatic dose limiting 
toxicity in the setting of HBV virologic breakthrough, then resumption of nivolumab 
monotherapy or nivolumab plus ipilimumabcan be reconsidered on a case-by-case basis once 
the hepatic AE has reversed and virologic control is re-established, if the subject has evidence of 
a clinical response and both the PI and BMS medical monitor assess the benefit-risk ratio to be in 
the best interest of the subject.  
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.  
/.F
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Subjects MUST discontinue investigational product (and noninvestigational product at the 
discretion of the investigator) for any of the following reasons:
Withdrawal ofinformed consent (subject’s decision to withdraw for any reason)
Any clinical adverse event (AE), abnormal laboratory test results 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
Pregnancy, except as described below
Termination of the study by BMS
Specific criteria for discontinuation of study drugs outlined for nivolumab in Section
4.1.18,ipilimumab in Section 4.2, or for sorafenib in Section 4.1.12.
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness
Protocol defined disease progressionunless subject is eligible for treatment beyond 
progression (Section3.1.8 for nivolumab or ipilimumab and Section 4.1.13 for 
sorafenib).
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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 should comply with protocol specified follow-up procedures as 
outlined inTable 5.1-8andTable 5.1-9.The only exception to this requirement is when a subject
withdraws consent for all study procedures or loses the ability to consent freely (ie, is imprisoned 
or involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
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Prior to activation of amendment 8, subjects entering the follow-up period with confirmed CR 
may be permitted to reinitiate study therapy upon disease progression after discussionand 
agreement with the BMS Medical Monitor.  Subjects reinitiating study therapy shouldcontinue 
to meet eligibility criteria at the time study drug resumes and should not haveexperienced a DLT 
that would require permanent discontinuation of study therapy. Subjects willreceive study 
therapy at the same doselevel that they received prior to entering the follow-upperiod. Subjects 
that resume study therapy in this setting may receive study therapy until toxicity or disease 
progression per RECIST 1.1.  Re-initiation of study therapy will only bepermitted once for any 
given subject.  Subjects who have completed 1 year of follow-up without evidence of disease 
progression willnot be considered eligible for re-initiation of study therapy.  Additional, 
separate, safety and efficacy summaries will be presented forthose subjects whoreinitiated study 
therapy.
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In this study, overall survival is a key endpoint of the study. 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 5until death or the conclusion of the 
study.
Follow-Up Visit 1 to occur 35 days from the last dose (7 days) or coinciding with the date of 
discontinuation of study drug (7 days) if the date of discontinuation is greater than 42 days 
from the last dose. Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (7 days). 
Survival Follow-Up Visits to occur approximately every 3 months from Follow-Up Visit 2. 
Survival Follow-up visits may be performed by phone contact or office visit.
BMS may request that survival data be collected on all randomizedsubjects outside of the 
protocol defined window(Table 5.1-8and Table 5.1-9).At the time of this request, each subject 
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will be contacted to determine their survival status unless the subject has withdrawn consent for 
all contact.
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Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
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. 
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All reasonable efforts mustbe 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 
BMS-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. If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records.
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Study drugs include both Noninvestigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
Study required premedication,and 
Other drugs administered as part of the study that are critical to claims of efficacy (eg  
backbone therapy, rescue medications)
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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Nivolumab 100 mg (10 mg/mL) will be packaged in an open-label fashion. Five or ten 
nivolumab 10mL vials will be packaged within a carton. The vials are not subject or treatment 
group specific.
Prior to activation of Amendment 8, subjects in the Dose Escalation Phasewere treated until 
either a confirmed CR, completion of 2 years of therapy, toxicity, or disease progression.  
However, upon activation of amendment 8and to align with the nivolumab program standard for 
the new cohorts, all subjects are to be treated until RECIST 1.1 defined progression 
(Appendix2), unacceptable toxicity, or study discontinuation for any other reason (Section3.5).  
Inthe Dose Escalation Phase, nivolumab will be administered as an IV infusion on treatment 
everytwo weeks until either RECIST1.1 progression(with provisions for treatment beyond 
progression as outlined in Section3.1.8)or toxicity. The period for determination of DLTs will 
be 2 weeks following the 3rd administration of nivolumabin the dose escalation phase. The 
following dose levels will be explored.  Therapy will begin as dose level 1 for the uninfected and 
HCV-infected HCC subjects and dose level 0 for the HBV-infected HCC cohortin the dose 
escalation phase. 
Table 4.1-1:
Study TreatmentDuring Dose Escalation Phase
Dose levels 
Dose of Nivolumab, Intravenous, q2 wks
0
0.1 mg/kg
1
0.3 mg/kg
2
1 mg/kg
3
3 mg/kg
4
10 mg/kg
In the Dose Escalation Phase, the maximum dose level is 10 mg/kg in uninfected HCC subjects 
and 3 mg/kg in HCV and HBV infected HCC subjects, respectively.
In the Expansion Phase, uninfected HCC, HCV-infected subjects, and HBV-infected subjects
will receive a dose of 3mg/kg.
In the 1L Nivolumab vsSorafenib Cohort, subjects will receive either open-label 240 mg
nivolumabIV q2 weeksover 30minutes(Arm A)or sorafenib 400 mg po BID(Arm B). 
In the Nivolumab + Ipilimumab Combination Cohort, subjects will be randomized 1:1:1 to 
receive:
Arm A--nivolumab 1mg/kg IV plus ipilimumab 3mg/kg IV q3 week x 4, followed by 
nivolumab 240 mg IV q2week until toxicity or disease progression
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Arm B--nivolumab 3mg/kg IV plus ipilimumab 1mg/kg IV q3week x 4, followed by 
nivolumab 240 mg IV q2week until toxicity or disease progression
Arm C--nivolumab 3 mg/kg IV q2week plus ipilimumab 1 mg/kg IV q6week until toxicity or 
disease progression 
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Table 4.1-2:
Product Description: Treatment Period
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
NivolumabSolutionfor
Injectiona
100mg(10mg/mL)
10mLvial/
Open-Label 
5or10vialspercarton/
Open-Label
Cleartoopalescent,
colorless to pale yellow 
liquid. May contain 
particles.
2°-8°C.Protectfrom
light and freezing.
Sorafenib Tabletsb
200mg
Wallet/blister card 
containing 28 film-
coated tablets/ Open-
Label
N/A
Redandroundwiththe
Bayer cross on one side 
and “200” on the other 
side.
Storeat15°-25°C.
IpilimumabSolutionfor
Injection
200mg(5mg/mL)
40mLvial/Open-Label
4vialsper
carton/Open-Label
Cleartoopalescent,
colorless to pale yellow 
liquid. May contain 
particles.
2°-8°C.Protectfrom
light and freezing.
a Nivolumab is labeled as BMS-936558-01 Solution for Injection.
b Theseproducts 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)
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and
permitted by localregulations. 
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In the Nivolumab plus Ipilimumab Combination Cohort, ipilimumab is to be administered as an 
approximately 30-minute IVinfusion. At the end of the infusion, flush the line with a sufficient 
quantity of normal saline or5% dextrose solution.When both study drugs are to be administered 
on the same day, separateinfusion bags and filters must be used for each infusion. Nivolumab is 
to be administered first.The nivolumab infusion must be promptly followed by a saline flush to 
clear the line ofnivolumab before starting the infusion. The second infusion will always be 
ipilimumab, and willstart at least 30 minutes after completion of the nivolumab infusion.
4.1.4
Sorafenib Dose and Schedule
Subjects randomized to Arm B in the 1L Nivolumab vsSorafenib Cohortwill receive treatment 
with sorafenib.  Sorafenib (Nexavar) will be self-administered orally at 400 mg (2 x 200 mg 
tablets) taken twice a day (equivalent to a total daily dose of 800 mg) without food (at least 
1hour before or 2 hours after a meal).  Sorafenib is to be swallowed with a glass of water.  
Treatment will continue until progression, unacceptable toxicity, withdrawal of consent, or study 
end, whichever occurs first.
Trained personnel will dispense study medication to subjects.  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. If the number of 
capsules 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 patient remembers.  However, if it is almost time for 
the next dose, the missed dose should be skipped and the patient should take his/her next dose as 
scheduled.  A double dose should not be administered to make up for forgotten individual doses.
Subjects will 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 (Section4.1.12).  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.
4.1.5
Nivolumab or Ipilimumab Dose Modifications
In the Dose Escalation and Expansion Phase, there will be no nivolumab dose adjustments 
allowed except for weight changes. Dosing calculations should be based on the body weight 
assessed at baseline. It is not necessary to re-calculate subsequent doses if the participantweight 
is within 10% of the weight used to calculate the previous dose. All doses should be rounded up 
or to the nearest milligramper institutional standard.
In the 1L Nivolumab vsSorafenib Cohort, all subjects will receive either a flat dose of 
nivolumab 240 mgIVq2 weekor sorafenib 400 mg po BID, and no dose adjustments regardless 
of weight change are requiredfor nivolumab.
In the Nivolumab plus Ipilimumab Combination Cohort, nivolumab weight based dosing 
calculations should be based on the body weight assessed at baseline. It is not necessary to 
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re-calculate subsequent doses if the participantweight is within 10% of the weight used to 
calculate the previous dose. All doses should be rounded up or to the nearest milligram per 
institutional standard.
4.1.6
Nivolumab or Ipilimumab Intrasubject Dose Escalation
No intrasubject nivolumab or ipilimumab dose escalation will be allowed.  
4.1.7
Nivolumab or Ipilimumab Dose Reductions
Nivolumabor ipilimumabdose reductions are not permitted in this study.  
4.1.8
Sorafenib Dose Reductions
For subjects receiving sorafenib in the 1L Nivolumab vsSorafenib Cohort, if sorafenib dose 
reduction is required for the management of an adverse event, the sorafenib dose should be 
reduced to 400 mg daily.  Further dose reductions may be done in accordance with the package 
insert.
4.1.9
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and
duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are 
consideredimmuno-oncology agent in this protocol. Early recognition and management of 
adverse eventsassociated with immuno-oncology agents may mitigate severe toxicity. 
Management algorithmshave been developed to assist investigators in assessing and managing 
the following groups ofadverse events:
Gastrointestinal
Renal
Pulmonary
Hepatic (see protocol specific updates in Section4.1.15)
Endocrinopathies
Skin
Neurological
The above algorithms are found in Appendix 1of this protocol.
4.1.10
Dose Delayfor Nivolumab Monotherapy
Dose delaycriteria apply for all drug-related adverse events. Treatment delayup to 6 weeks 
(42days) from the last dose isallowable.
Nivolumab administration should be delayedfor 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
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Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase orlipase, AST, or ALT:
- Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay. It is recommended to consult 
with the BMS Medical Monitor for Grade 3 amylase or lipase abnormalities.
- 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 asubject has baseline ASTor ALTwithin the Grade 2 toxicity range, delay dosing for 
drug-related increase in AST or ALT at 2x baselinevalue or when AST or ALT is 
8xULN (whichever is lower).
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants interruptingthe 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.
Tumor assessments for all subjects should continue as per protocol even if study drug dosing is
delayed.
4.1.11
Dose Delayfor Nivolumab plus Ipilimumab Combination Cohort
Dose delay criteria apply for all drug-related adverse events. Treatment delay up to 6weeks 
(42days) from the last doseof nivolumaband ipilimumabare allowablein Arms A and B vs
12weeks (84 days) from the last dose of nivolumab and ipilimumab in Arm C.
Study drug 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 for 
lymphopenia, asymptomatic amylase or lipase, AST, or ALT:
- Grade 3 lymphopenia does not require dose delay.
- Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay. It is recommended to consult 
with theBMS Medical Monitor for Grade 3 amylase or lipase abnormalities.
- 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).
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- If a subject has baseline AST or ALT within the Grade 1toxicity 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 
drug-related increase in AST or ALT at 2x baselinevalue or when AST or ALT is 
8xULN (whichever is lower).
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants interrupting the dose of study medication.
Tumor assessments for all subjects should continue as per protocol even if study drug dosing is 
delayed.
Subjects receiving ipilimumab in combination with nivolumab that have drug-related toxicities
that meet the criteria for dose delay, should have both drugs (ipilimumab and nivolumab)
delayed until retreatment criteria are met.Refer to Section4.1.17Criteria to Resume Ipilimumab 
Dosing for further details.
In subjectsin Arm Creceiving ipilimumab 1 mg/kg q6week:
Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab
dose is scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be
synchronized with nivolumab dosing.
Ipilimumab should be dosed at the specified interval regardless of any delays in intervening
nivolumab doses. However, in order to maintain periodic synchronized dosing of 
ipilimumaband nivolumab, the dosing days of nivolumab and ipilimumab may be adjusted 
within thepermitted 7-day window, as long as consecutive nivolumab doses are given at 
least 12days apart. Ipilimumab may be delayed beyond the 7-day window if needed to 
synchronizewith the next nivolumab dose.
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then
subsequent ipilimumab doses should rescheduled to maintain the 6 week interval between
consecutive ipilimumab doses.
A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires
ipilimumab discontinuation, with exceptions as noted in Section4.2(Ipilimumab Dose 
Discontinuation).
4.1.12
Treatment Interruption or Discontinuation 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.
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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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4.1.13
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 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 inTable 5.1-6.
Subjects should discontinue study therapy upon further evidence of further progression, defined 
as an additional 10% or greater increase in tumor burden(SPD:  sum of product of diameters) 
from time of initial progression (including all target lesions and new measurable lesions).  New 
lesions are considered measurable at the time of initial progression if the longest diameter is at 
least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15mm). Any new lesion considered non-measurable at the time of initial progression 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.
4.1.14
Management of Sorafenib Adverse Events
Toxicities attributable to sorafenib should be managed according to the locally approved product 
label or applicable Summary of Product Characteristics.
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4.1.15
Protocol-Specific Recommendation forManagement of Hepatic Events
in Nivolumab or Nivolumab plus Ipilimumab Subjects
The nivolumab program has developed a standardized algorithmfor the management of hepatic 
events based on cumulative data acrossthe program in subjects with normal hepatic function.  
Across most nivolumab studies, the eligibility criteria for inclusion are based on a maximum 
AST or ALT < 3x ULN; therefore, only subjects with normal to grade 1 LFTs have been 
enrolled.
Subjects withadvanced HCC generally have underlying cirrhosis with decreased hepatic 
function.  They may also have a concomitant chronic viral infection.  For CA209040, the upper 
limits for inclusion were therefore adjusted to account for baseline liver dysfunction.  Subjects 
with AST or ALT elevations within the CTCAE Grade 2 range.  This requires a protocol-specific 
approach for the management of hepatic events, outlined as follows:
Dose delay criteria for hepatic events are outlined in Sections4.1.10and 4.1.11.   If AST or 
ALT levels do not improve with a dose delay of 3-5 days or if the levels worsen, initiate 
steroid therapy at 0.5-2 mg/kg/day methylprednisolone or oral equivalent.
For ALT orAST levels > 8x ULN, initiate steroid therapy promptly at 1-2 mg/kg/day 
methylprednisoloneor oral equivalent.
For all subjects initiating steroids, consult the BMS Medical Monitor within 24 hours after 
initiation of steroids.  Gastroenterology consult is recommended.
If AST or ALT levels do not improve within 3-5 days or the levels worsen after the start of 
steroid therapy, discuss with the BMS Medical Monitor the possibility of adding 
mycophenolate mofetil at 1 g BID.
Tapering of steroids can start once AST or ALT levels have declined by 1 CTCAE grade.  
Taper steroids slowly over no less than 1 month.
As outlined in Sections 4.1.16and 4.1.17, nivolumab and ipilimumab therapy may resume when 
AST or ALT have returned to near baseline unless the criteria for permanent discontinuation are 
reached (Sections4.1.18and 4.2).  The BMS Medical Monitor must be consulted prior to 
resuming nivolumab for all subjects who required steroid intervention.
4.1.16
Criteria to Resume Treatment with 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.
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Subjects who require dose delays for drug-related increased AST, ALT, or bilirubin may 
resume treatment when hepatic parameters are at baselineor Grade 1 and after discussion 
with BMS MM.  
Subjects with AST, ALTor bilirubinvalues meeting discontinuation parameters (Section
4.1.18) should have treatment permanently discontinued.
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.
Subjects who delay study treatment due to any Grade 3 amylase or lipase abnormality that
is not associated with symptoms or clinical manifestations of pancreatitis, and that is assessed
by the investigator to be related to ipilimumab and not to nivolumab, may resume nivolumab
when the amylase or lipase abnormality has resolved to Grade < 3. The BMS Medical
Monitor should be consulted prior to resuming nivolumab in such subjects.
Resumingtreatmentafter a delayof up to 6 weeks from the previous dose is permitted 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 delaylasting > 6 weeks 
from the last dose, the BMS Medical Monitor must be consulted. Tumor imaging 
assessments should continue as per protocol even if dosing is interrupted.
Dosing delays > 6 weeks from the last dose that occur for non-drug-related reasons may be 
allowed if approved by the BMS Medical Monitor.
4.1.17
Criteria to Resume Treatment with Ipilimumab
Subjects may resume treatment with nivolumab and ipilimumab when drug-related AE(s)
resolve(s) 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 increased AST, ALT, or bilirubinmay 
resume treatment when hepatic parameters are at baseline or Grade 1 and after discussion 
with BMS MM.  
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before
treatment is resumed.
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Subjects who received systemic corticosteroids for management of any drug-related toxicity
must be off corticosteroids or have tapered down to an equivalent dose of prednisone
10mg/day.
Drug-related endocrinopathies adequately controlled with only physiologic hormone
replacement may resume treatment after consultation with the BMS Medical Monitor.
Dose delay of ipilimumab which results in no ipilimumab dosing for >12 weeks requires
ipilimumab discontinuation, with exceptions as noted in Section 4.2.
In subjects in Arm C receiving ipilimumab q6week:
Ipilimumab may not be resumed sooner than 6 weeks (7 days) after the prior ipilimumab
dose.
In general, subjects who meet criteria toresume ipilimumab will also have met criteria to
resume nivolumab, so it should be feasible to synchronize dosing of both drugs when
resuming ipilimumab. In order to facilitate this, the dosing days of nivolumab and
ipilimumab may be adjusted within the permitted 7-day window, as long as consecutive
nivolumab doses are given at least 12 days apart.
One exception to note is when ipilimumab and nivolumab doses are delayed due to 
drug-relatedGrade 3 amylase or lipase abnormalities not associated with symptoms or 
clinicalmanifestations of pancreatitis. If the investigator assesses the Grade 3 amylase or 
lipaseabnormality to be related to ipilimumab and not related to nivolumab, nivolumab may 
beresumed when the amylase or lipase abnormality resolves toGrade < 3 but ipilimumab 
mayonly be resumed when the amylase or lipase abnormality resolves to Grade 1 or 
baseline.  Investigator attribution of this toxicity to the ipilimumab dosing must be clearly 
noted in thesubject’s medical chart. The BMS Medical Monitor should be consulted prior to 
resumingnivolumab in such subjects.
4.1.18
Nivolumab Permanent Discontinuation Due to Adverse Event(s)
Nivolumab administration should be discontinued if at least one of the following drug-related 
adverse event(s) occurs: 
Any Grade 2 drug-related uveitis, eye pain,or reduction of visual acuity that does not 
respond to topical therapy and does not improve to Grade 1 severity within 2 weeks of 
starting therapy OR requires systemic treatment
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following
exceptions:
- Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurological toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation.
- 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:
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Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:
o AST or ALT > 10 x ULN for >2 weeks,
o AST or ALT > 15 x ULN irrespective of duration, 
o T. bilirubin > 8 x ULN irrespective of duration for subjects with elevated bilirubin 
at study entry or > 5 x ULN for those with normal T bilirubin at entry,
o Concurrent AST or ALT > 3 x ULN and T. bilirubin > 5 x ULN for subjects 
entering treatment with a normal bilirubin and up to 8 x ULN for subjects with 
elevated bilirubin
Any drug-related 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
- Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis. It is recommended to consult with the BMS Medical 
Monitor for Grade 4 amylase or lipase abnormalities
- Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72hours of their onset
- For Grade 4 endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper-or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively
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 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 
6weeks 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. Dose limiting toxicityfor Dose Escalation Phaseas defined in Section 3.1.3.1.
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For subjects in the Nivolumab plus Ipilimumab Combination Cohort:
Assessment for discontinuation of nivolumab should be made separately from the assessment
made fordiscontinuation of ipilimumab.  
If the investigator assesses the drug-related AE to be related to ipilimumabonly and not 
related to nivolumab, ipilimumab dosing alone may be discontinued whilenivolumab dosing 
is delayed until the subject meets criteria to resume nivolumab treatment(specified in 
Section4.1.16).
The relationship to ipilimumab should be welldocumented in the source documents. 
BMS medical monitor needs to be contacted prior to resuming nivolumabat 240 mg IV 
every 2 weeks.
If a subject in any of the nivolumab/ipilimumab combination arms meets criteria for
discontinuation and investigator is unable to determine whether the event is related to both or
one study drug, the subject should discontinue both nivolumab and ipilimumab and betaken 
offthe treatment phase of the study.
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Ipilimumab administration should be discontinued if at least one of the following drug-related 
adverse event(s) occurs: 
Any Grade 2 drug-related uveitis, eye pain, or reduction of visual acuity that does not 
respond to topical therapy and does not improve to Grade 1 severity within 2 weeks of 
starting therapy OR requires systemic treatment
Any Grade 3 bronchospasm or other hypersensitivity reaction
Any other Grade 3 non-skin, drug-related adverse events with the following exceptions for 
laboratory abnormalities, Grade 3 nausea and vomiting, Grade 3 neutropenia and 
thrombocytopenia, and symptomatic endocrinopathies which resolved (with or without
hormone substitution)
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o AST or ALT > 10 x ULN for >2 weeks,
o AST or ALT > 15 x ULN irrespective of duration, 
o T. bilirubin > 8 x ULN irrespectiveof duration for subjects with elevated bilirubin 
at study entry or > 5 x ULN for those with normal T bilirubin at entry,
o Concurrent AST or ALT > 3 x ULN and T. bilirubin > 5 x ULN for subjects 
entering treatment with a normal bilirubin and up to 8 x ULN for subjects with 
elevated bilirubin
Any drug-related 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
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- Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis. It is recommended to consult with the BMS Medical 
Monitor for Grade 4 amylase or lipase abnormalities.
- Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72hours of their onset
- For Grade 4 endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper-or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor.
Any treatment delay resulting in no ipilimumab dosing for > 12 weeks with the following
exceptions: Dosing delays to manage drug-related adverse events, such as prolonged 
steroidtapers, are allowed. Prior to re-initiating treatment in a subject with a dosing 
delay lasting> 12 weeks, the BMS medical monitor must be consulted. Tumor 
assessments shouldcontinue as per protocol even if dosing is delayed.
Dosing delays resulting in no ipilimumab dosing for > 12 weeks that occur for non-drug 
relatedreasons may be allowed if approved by the BMS medical monitor. Prior to 
reinitiatingtreatment in a subject with a dosing delay lasting > 12 weeks, the BMS 
medicalmonitor must be consulted. Tumor assessments should continue as per
protocol even ifdosing is delayed.
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. Dose limiting toxicity as defined in Section 3.1.3.1.
The assessment for discontinuation of ipilimumab should be made separately from the
assessment made fordiscontinuation of nivolumab. Although there is overlap among the 
discontinuation criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, 
treatment with nivolumab may continue if ipilimumab is discontinued.
If a subject in any of the nivolumab/ipilimumab combination arms meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or 
one study drug, the subject should discontinue both nivolumab and ipilimumab and be taken off 
the treatment phase of the study.
Y./
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After 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. The exact procedure 
for using the IVRS will be detailed in a separate document.
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In the Dose Escalation Phase, subjects will be entered sequentially into the dose level(ranging 
from 0.1 mg/kg to 10 mg/kg q2week)accruing up to a maximum of 6 subjects. Once the 
determination that the dose level is safe has been made, the next dose level can begin accrual.
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In the Expansion Phase, subjects will receive 3 mg/kg IV nivolumab q2week in the uninfected, 
HCV-infected, orHBV-infected cohortsuntil toxicity or RECIST 1.1 progression.
In the 1L Nivolumab vsSorafenib Cohort, subjects will be randomized to receive either 
nivolumab flatdosing 240 mg q2weeksIV over 30 minutes(Arm A)or sorafenib 400 mg po 
BID(Arm B)untiltoxicity or RECIST 1.1 progression.
In the Nivolumab plus Ipilimumab Combination Cohort, subjects will be randomized 1:1:1 to 
receive:
Arm A--Nivolumab 1mg/kg IV plus ipilimumab 3mg/kg IV q3 week x 4, followed by 
nivolumab 240 mg IV q2week until toxicity or disease progression
Arm B--Nivolumab 3mg/kg IV plus ipilimumab 1mg/kg IV q3weekx 4, followed by 
nivolumab 240mg IV q2week until toxicity or disease progression
Arm C--Nivolumab 3 mg/kg IV q2week plus ipilimumab 1 mg/kg IV q6week until toxicity 
or disease progression.
4.4.1
Treatment of Nivolumab or Ipilimumab Infusion Reactions
Infusion reactions should be graded according to CTCAE Version 4.0 allergic 
reaction/hypersensitivity.  Since nivolumab and ipilimumab contain only human 
immunoglobulin protein sequences, it is unlikely to be immunogenic and induce infusion or 
hypersensitivity reactions. However, if such a reaction were to occur, these reactions may 
manifest with signs and symptoms that may include, but are not limited to fever, chills, 
headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm or other 
symptoms. Severe infusion reactions require the immediate interruption of study drug therapy 
and permanent discontinuation from further treatment. Appropriate medical therapy including 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be 
available for use in the treatment of such reactions. Subjects should be carefully observed until 
the complete resolution of all signs and symptoms. Following an infusion reaction, subjects 
should be premedicated with acetaminophen and diphenhydramine for future treatments.  
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the BMS Medical 
Monitor and reported as an SAE if criteria are met. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated)
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30minutes before 
additional nivolumab or ipilimumab administrations.
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For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, IV fluids]; prophylactic medications 
indicated for 24 hours)
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline,and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid therapy may also be administered as appropriate. If the infusion is interrupted, 
then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur then no further nivolumabor ipilimumabwill be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and 
monitor the subject until resolution of symptoms. The amount of study drug infused must be 
recordedon the case report form (CRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 
325 to 1000 mg (acetaminophen) should be administered at least 30 minutes before additional 
nivolumab or ipilimumab administrations. If necessary, corticosteroids (up to 25 mg of 
SoluCortef or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]. Grade 4: life-threatening; pressor 
or ventilatory support indicated). 
Immediately discontinue infusion of nivolumabor ipilimumab. Begin an IV infusion of normal 
saline, and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, 
oral antihistamine, or corticosteroids). 
4.4.2
Re-Initiation of Study Therapy For Subjects from the Dose Escalation 
Phasein the Follow-up Period  (Not Applicable Post-Amendment 8)
Prior to activation of amendment 8, subjects entering the follow-up period with confirmed CR 
may be permitted to reinitiate study therapy upon disease progression afterdiscussionand 
agreement with the BMS Medical Monitor.  Subjects reinitiating study therapy shouldcontinue 
to meet eligibility criteria at the time study drug resumes and should not haveexperienced a DLT 
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that would require permanent discontinuation of study therapy. Subjects willreceive study 
therapy at the same dose level that they received prior to entering the follow-upperiod. Subjects 
that resume study therapy in this setting may receive study therapy until toxicity or disease 
progression per RECIST 1.1.  Re-initiation of study therapy will only bepermitted once for any 
given subject.  Subjects who have completed 1 year of follow-up without evidence of disease 
progression willnot be considered eligible for re-initiation of study therapy.  Additional, 
separate, safety and efficacy summaries will be presented for those subjects who reinitiated study 
therapy.
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Study drug will be administered in the clinical facility. After administration of nivolumab, 
treatment compliance will be assessed by investigator report on the case report forms and Source 
Data Verification by Site Monitors.  
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4.7.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMSor 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 BMS Study Monitor unless studydrug 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 availableand 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 reviewthroughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS 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, 
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and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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Table 5.1-1:
CA209040 Screening Procedural Outlinefor Subjects in Dose Escalationand Expansion Phase(Study 
Days -28 to -1)
Procedure
Screening
Visit 
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol specific informed consent is signed.Contact IVRS 
to obtain study subject number.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to randomization
Disease Status
Medical History
X
Include any toxicities or allergy related to previous treatments, smoking history, asthma, COPD, Child-
Pugh score determination (only Child Pugh scores of 7points or less are allowed for subjects in the 
Escalation Phase, andChild Pugh scores of 6 points or less are allowed for subjects in the Expansion 
Phase), no history ofhepaticencephalopathy.  Includes detailed medical history of potential risk factors 
for potential events such as pulmonary related events.
Archived Tumor tissue block or 
Unstained slides
X
A fresh tumor biopsy is required at baseline if there is no other recordof histological diagnosis of tumor. 
Tumor material (archived tumor paraffin blockor fresh biopsywith a minimum of 15unstainedslides) 
must be available for correlative studies. If archived material is unavailable, then tumor material from a 
fresh biopsy must be provided. Biopsied lesions must be distinct from index lesions.
Disease Assessments -Tumor 
Imaging (CTor MRI of 
Chest/Abdomen/Pelvis [including 
triphasic CT of abdomen]; Bone 
scan if clinically indicated.  Brain 
MRI if history of brain metastasis.
X
CT or MRI of the chest, abdomen and pelvis with IV contrast, including required tri-phasic 
evaluation of the liver.
MRI is acceptable if CT is contraindicated.
Modality (CT or MRI) used at baseline should be used across all imaging timepoints.
Bonescan is required if clinically indicated.
Brain MRI within 28 days prior to first dose of study therapy for subjects with a history of brain 
metastasis.
Disease Assessments -Serum
X
Serum alpha fetoprotein
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Table 5.1-1:
CA209040 Screening Procedural Outlinefor Subjects in Dose Escalationand Expansion Phase(Study 
Days -28 to -1)
Procedure
Screening
Visit 
Notes
Safety Assessments
Physical Examination (PE)
X
If the screening PE is performed within 96 hours of dosing on Day 1 then a single exam may count as 
both the screening and pre dose evaluation.
Physical Measurements
X
Includes height and weight.
ECOG Assessment
X
See Appendix4for scale
Child-Pugh Score
X
See Appendix 3for scale
Vital Signs
X
Includes body temperature, respiratory rate, seated blood pressure and heart rate. Blood pressure and 
heart rate should be measured after the subject has been seated quietly for at least 5 minutes.
Oxygen saturation
X
Collected by pulse oximetry at rest and after mild exertion
Electrocardiogram (ECGs)
X
A Single 12 lead measurement should be recorded after the subject has been supine for at least 
5minutes.
Pre-treatment Concomitant 
medication
X
30 days prior to treatment
Clinical Complaints
X
Clinical complaints must be collected from the date of subject’s written informed consent until the first 
dose of study drug.
Laboratory Tests (Hematology, 
Serum chemistry)
X
Include CBC with differential and platelets, Complete Metabolic Panel (Na, K, Cl, HCO3or equivalent
(if locally available), BUN, Cr, eGFR, AST, ALT, Alk Phos, Albumin, Total Bilirubin, Total Protein, 
Calcium, glucose), direct bilirubin, lipase, amylase, magnesium, phosphorous, LDH andurinalysis (dip). 
If screening labs are drawn within 4 days of first treatment then these labs will also qualify as Day 1 
(pre-dose) labs.
Thyroid Function Panel
X
TSH, free T3 and free T4. Total T3/T4 are acceptable if free T3/T4 are not available.  Subjects with 
suspected autoimmune thyroid disorders will also be tested for thyroglobulin and thyroid peroxidase 
antibodies and thyroid stimulating immunoglobulin. If screening labs are drawn within 4days of first 
treatment then these labs will also qualifyas Day 1 (pre-dose) labs.
Serology (HepB, HepC, HIV)
X
HepB surface antigen, HepB surface antibody, Hep B Core antibody, Hep Beantigenand e antibody,
HBV DNA, HDV testingfor subjects with HBV, HepC viral load (PCR) and Hep C Ab, HIV 1/2
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Table 5.1-1:
CA209040 Screening Procedural Outlinefor Subjects in Dose Escalationand Expansion Phase(Study 
Days -28 to -1)
Procedure
Screening
Visit 
Notes
CoagulationPanel
X
Including PT/INR, aPTT and fibrinogen. If screening labs are drawn within 4 days of first treatment then 
these labs will also qualify as Day 1 (pre-dose) labs.
HLA typing
X
Blood samples will be collected to explore single nucleotide polymorphisms (SNPs) in specific genes, 
and HLA typing
Serum/Urine  Pregnancy Test
X
For WOCBP within 24 hours of Study Drug Administration. The minimum sensitivity of the pregnancy 
test must be 25 IU/L or equivalents of HCG. If the pregnancy test is positive, the subject must not 
receive study drug.
Adverse Event Reporting
Monitor for Serious Adverse Events
X
All SAEs must be collected from the date of the subject’s written consent.
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Table 5.1-2:
Screening Procedural Outline for 1L Nivolumab vs Sorafenib Cohort
Procedure
Pre-Treatment Visit 
(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 an enrollment 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
Child Pugh A5 or A6 only
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 for valve and LVEF evaluation is to be done at baseline and as clinically 
indicated.
Laboratory Tests
X
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
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 Ab, Hep D antibody
Testing to be completed at the Central Laboratory.
Local laboratory Hep D result can be used to assess subject eligibility if central laboratory 
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Table 5.1-2:
Screening Procedural Outline for 1L Nivolumab vs Sorafenib Cohort
Procedure
Pre-Treatment Visit 
(Baseline)
Notes
resultnotavailableintime.
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/HLASample
X
Urinary analysis
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 or MRI of the chest, abdomen and pelvis with IV contrast, including required tri-
phasic evaluation of the liver.
MRI isacceptable if CT is contraindicated.
Modality (CT or MRI) used at baseline should be used across all imaging timepoints, if 
possible.
Bone scan is required if clinically indicated.
MRI brain within 28 days prior to first dose of study therapy 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 a minimum 
of 15 unstained slides of tumor tissue (archival or recent) for biomarker evaluation will be 
obtained prior to subject randomization.
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 a H &E stain (100tumor 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.
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Table 5.1-2:
Screening Procedural Outline for 1L Nivolumab vs Sorafenib Cohort
Procedure
Pre-Treatment Visit 
(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.  Central 
lab must provide IVRS with confirmation of receipt of evaluable tumor tissue prior to subject 
randomization
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Table 5.1-3:
Screening Procedural Outline for Nivolumab plus Ipilimumab Combination Cohort
Procedure
Pre-Treatment Visit 
(Baseline)
Notes
Eligibility Assessments
Informed Consent
X
Original informed consent in screening for protocol participation. Study allows