Clinical trial NCT03439891
Conditions: Stage III Hepatocellular Carcinoma AJCC v8 Stage IIIA Hepatocellular Carcinoma AJCC v8 Stage IIIB Hepatocellular Carcinoma AJCC v7 Stage IIIC Hepatocellular Carcinoma AJCC v7 Stage IV Hepatocellular Carcinoma AJCC v8 Stage IVA Hepatocellular Carcinoma AJCC v8 Stage IVB Hepatocellular Carcinoma AJCC v8
Sponsor: Robin Kate Kelley
Start date: 2018-04-16; Completion date: 2023-11-30
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase II trial studies the best dose and side effects of sorafenib tosylate and nivolumab in treating patients with liver cancer that cannot be removed by surgery (unresectable), has spread to nearby tissues or lymph nodes (locally advanced) or to other places in the body (metastatic). Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sorafenib tosylate and nivolumab may work better in treating patients with liver cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Maximum tolerated dose (MTD) of sorafenib tosylate (sorafenib) in combination with standard dose nivolumab with Child Pugh A-B7 liver function. (Part 1: Escalation Cohort).

II. Safety in participants with Child-Pugh B liver function. (Part 2: Child-Pugh B Escalation Cohort)

SECONDARY OBJECTIVES:

I. Safety and tolerability of combination overall. (Parts 1 and 2).

II. Rate of immune-related adverse event (irAE) for combination overall and in participants with Child-Pugh B liver function. (Parts 1 and 2).

III. Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in participants with Child-Pugh B liver function. (Parts 1 and 2).

IV. Duration of response (DOR), progression free survival (PFS), and overall survival (OS) for escalation cohort and Child-Pugh B expansion cohort and overall. (Parts 1 and 2).

EXPLORATORY OBJECTIVES:

I. Relationship between peripheral blood mononuclear cell (PBMC) immune cell subset frequencies, baseline liver function, and clinical outcomes.

II. Relationship between PBMC T cell receptor (TCR) clonotype frequency and diversity, baseline liver function, and clinical outcomes.

III. Tumor tissue immune cell subsets and TCR clonotype frequency and diversity in pre-treatment archival tumor tissue samples.

IV. Tumor and immune cell programmed death-ligand 1 (PD-L1) status in pre-treatment archival tumor tissue samples and relationship to clinical outcomes.

V. Changes in hepatitis B virus (HBV) and/or hepatitis C virus (HCV) viral load on treatment.

VI. Alpha-fetoprotein (AFP) changes on treatment and relationship to clinical outcomes.

VII. Relationship between clinical outcomes and clinicopathologic features including race/ethnicity, etiology of liver disease including HBV/HCV status, baseline liver function, presence of cirrhosis, macrovessel invasion, extrahepatic spread, site(s) of metastatic disease, prior treatment history including prior radiation and arterial therapies.

OUTLINE: This is a dose-escalation and expansion study of sorafenib tosylate.

DOSE-ESCALATION (Part 1):

Between 3-12 participants will be enrolled in Part 1. Participants receive sorafenib tosylate orally (PO) once daily (QD) or twice daily (BID) on days 1-28, and nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

EXPANSION COHORT (Part 2).

Participants receive nivolumab IV over 30 minutes on days 1 and 15, and sorafenib tosylate once daily (QD) or twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 and 100 days, then every 3 months for up to 2 years after the last dose.

Arms: arm 1: Participants with Child-Pugh A or B7 receive a daily dose of 400mg sorafenib on days 1-28, and 240mg of nivolumab IV over 30 minutes beginning on day 15 of course 1, then on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Course will continue until 1 dose-limiting toxicity occurs to establish maximum tolerated dosing schedule. arm 2: Participants with Child-Pugh A or B7 receive a daily dose of 400mg sorafenib twice a day on days 1-28, and 240mg of nivolumab IV over 30 minutes beginning on day 15 of course 1, then on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Course will continue until 1 dose-limiting toxicity occurs to establish maximum tolerated dosing schedule. arm 3: Participants with Child-Pugh B7-9 receive sorafenib at the maximum tolerated dose (MTD) established in Part 1 on days 1-28, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Nivolumab intervention 2: Sorafenib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
Multicenter Pilot Study of the Safety, Efficacy, and Immune Cell 
Profiling in Advanced Hepatocellular Carcinoma (HCC) Patients 
Treated with the Combination of Sorafenib plus Nivolumab as First-
Line of Systemic Therapy
Protocol Number:  CC # 174523
Study Drug(s):  Sorafenib, nivolumab
Version Number:   7.0
Version Date:  03/09/2022
IND Number:  137033
NCT Number:  NCT03439891
Principal Investigator (Sponsor-Investigator)
R. Kate Kelley, MD
University of California San Francisco
San Francisco, CA 94143
Telephone:  
Fax:  
E-mail: 
Statistician
Paige Bracci, PhD, MPH
Revision History
Version 7.0
Version 6.0
Version 5.0
Version 4.0
03/09/2022
12/15/2021
08/11/2021
03/12/2021
Version 3.0
11/26/2019
Version 2.0
03/27/2019
Version 1.0
10/19/2017
Version 0.2
06/30/2017


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Protocol Signature Page
Protocol No.: CC# 174523
Version Date: 03/09/2022
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date


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Protocol Signature Page – Participating Sites
Protocol No.: CC# 174523
Version Date: 03/09/2022
Participating Site(s)
Principal Investigator Name: 
Dr. Edward Kim, MD 
Institution Name:
University of California, Davis
Address:  
Telephone: 
1
E-mail: 
Principal Investigator Name: 
Institution Name:
Address:  
Telephone:  
E-mail:  
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 
1572), Institutional Review Board regulations, and all national, state and local laws and/or 
requirements of the pertinent regulatory requirements. 
Principal Investigator
Site
Printed Name
Institution Name
Signature
Date


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Abstract
Title
Multicenter Pilot Study of the Safety, Efficacy, and Immune Cell Profiling in 
Advanced Hepatocellular Carcinoma (HCC) Patients Treated with the 
Combination of Sorafenib plus Nivolumab as First-Line of Systemic Therapy 
Patient 
population
Unresectable HCC with no prior systemic therapy and Child Pugh A or B liver 
function
Rationale for 
Study
The multikinase inhibitor sorafenib, whose principal targets include VEGFR2, 
VEGFR3, and RAF kinases, is the only approved first-line therapy with 
established survival benefit in patients with HCC not amenable to curative 
therapies.1,2  Though the survival benefit of sorafenib has been consistent 
across multiple studies, the overall magnitude of benefit is small, and 
generally fewer than 5% of patients demonstrate response by conventional 
Response Evaluation Criteria in Solid Tumors (RECIST) across studies.1-3 
Recently, the anti-programmed death-1 receptor (PD-1) inhibitor, nivolumab, 
demonstrated a preliminary signal of efficacy in the CheckMate 040 Phase 
I/II trial in advanced HCC patients, including a dose escalation cohort of 48 
patients and a dose expansion cohort of 214 additional patients, across 
etiologic subtypes.4  In the dose expansion cohort, tumor responses occurred 
in 20%, median duration of response has not yet been reached but was over 
17 months for the dose escalation cohort. Results of CheckMate 040 have 
led to an ongoing multinational Phase III trial, CheckMate 459 
[NCT02576509] comparing the efficacy of sorafenib versus nivolumab as 
first-line therapy for advanced HCC.  
Primary 
Objective
Part 1: Escalation Cohort: Maximum tolerated dose (MTD) of sorafenib in 
combination with standard dose nivolumab in patients with Child Pugh A-B7 
liver function
Part 2: Child Pugh B Expansion Cohort: Safety in patients with Child Pugh B 
liver function 
Secondary 
Objectives
1.
Safety and tolerability of combination overall
2.
Rate of irAE for combination overall and in patients with Child Pugh B 
liver function
3.
Objective response rate (ORR) by RECIST 1.15 for overall study
4.
ORR by RECIST 1.1 in patients with Child Pugh B liver function
5.
Duration of response (DOR), progression free survival (PFS), and overall 
survival (OS) overall and in Child Pugh B Expansion Cohort


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Study Design
This is an open-label, dose-escalation and expansion pilot study to examine 
the safety and efficacy of sorafenib combined with the PD-1 checkpoint 
inhibitor, nivolumab, in patients with unresectable HCC not amenable to 
curative therapies, with no prior systemic treatment. The study is divided into 
two parts: Dose Escalation Cohort (Part 1, in patients with Child Pugh A-B7 
liver function) and Child Pugh B Expansion Cohort (Part 2, in patients with 
Child Pugh B liver function). There are 2 planned study sites: UCSF and a 
sub-site which was activated after completion of Part 1: Dose Escalation 
Cohort. Immune profiling of PBMC will be performed in UCSF patients only; 
PBMCs will not be collected for sub-site participants. 
Number of 
patients
6-24 patients. Part 1: 6-12 patients; Part 2: 12 patients.
Duration of 
Therapy
Sorafenib will be administered continuously and nivolumab will be 
administered every 14 days until progression, unacceptable toxicity, 
withdrawal of consent, criteria for discontinuation are met, or study end, 
whichever comes first. 
Duration of 
Follow up
Patients will be followed for survival every 3 months after last dose of study 
drug for up to 2 years.
Duration of 
study
The study is expected to complete accrual approximately 48 months from the 
time the study opened to accrual, based upon expected enrollment of 
approximately 1-2 subjects per month and enrollment holds for protocol 
amendment. Accrual will be closed after 12 patients are enrolled to Child 
Pugh B Expansion Cohort or on 30 April 2022, whichever occurs first.
Study Drugs
Sorafenib is a multikinase inhibitor which inhibits specific targets that are 
imperative for tumor cell proliferation including the serine/threonine kinases 
c-Raf and B-Raf (IC50 6 and 25 nM respectively) and the receptor tyrosine 
kinase RET, Flt-3 and c-Kit (IC50 47, 33 and 68 nM respectively).6  Sorafenib 
has potent activity against receptor tyrosine kinases important in tumor 
angiogenesis including the vascular endothelial growth factor receptor family 
(VEGFR1, -2, -3; IC50 26, 90 and 20 nM respectively) and platelet derived 
growth factor-beta (PDGFR-ί; IC50 57 nM). In cellular mechanistic (on target) 
assays, sorafenib was found to be a potent inhibitor of VEGFR-2, VEGFR-3, 
and PDGFR and Flt-3 receptor phosphorylation.6  The anti-tumor activity of 
sorafenib in vivo is driven by its direct effects on tumor growth through its 
inhibition of the Raf/MEK/ERK pathway and on the anti-angiogenic activity of 
the compound.  Sorafenib demonstrates broad anti-tumor activity in human 
tumor xenograft models of liver, kidney, lung, prostate, breast and leukemia. 
In human hepatocellular tumor cell lines, sorafenib potently inhibited cellular 
proliferations, Raf/MEK/ERK signaling and induced apoptosis. Sorafenib has 
potent activity against human tumor xenograft model of hepatocellular 
carcinoma with tumor stabilization seen at moderate doses and partial tumor 
regressions observed at higher doses. For further information about 
preclinical pharmacology, please refer to the current version of the sorafenib 
IB.
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets 
the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell 
surface membrane receptor. PD-1 is a negative regulatory molecule 


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expressed by activated T and B lymphocytes.7 Binding of PD-1 to its ligands, 
programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-
regulation of lymphocyte activation. Inhibition of the interaction between PD-1 
and its ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens. Nivolumab is 
expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification 
technologies.


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Table of Contents
Protocol Signature Page...................................................................................................2
Protocol Signature Page – Participating Sites..................................................................3
Abstract.............................................................................................................................4
1.
Introduction...............................................................................................................16
1.1
Background .......................................................................................................16
1.2
Rationale of the study........................................................................................16
1.3
Sorafenib ...........................................................................................................17
1.3.1
Sorafenib preclinical data ...........................................................................17
1.3.2
Sorafenib clinical experience in HCC .........................................................17
1.4
Nivolumab..........................................................................................................18
1.4.1
Nivolumab preclinical data..........................................................................18
1.4.2
Nivolumab clinical experience in HCC........................................................19
1.5
Combination of multikinase inhibition and checkpoint inhibition........................20
1.5.1
Combination multikinase inhibition and checkpoint inhibition preclinical 
rationale......................................................................................................20
1.5.2
Combination multikinase inhibition and checkpoint inhibition clinical 
experience ..................................................................................................21
1.6
Rationale for selected correlative analyses.......................................................21
1.6.1
PD-L1 expression .......................................................................................21
1.6.2
Peripheral Blood Mononuclear Cell (PBMC) Immune Cell Subsets and TCR 
Clonotype Frequency and Diversity............................................................22
1.6.3
Tumor immune cell infiltration and subsets ................................................22
1.6.4
Alpha fetoprotein (AFP) tumor marker........................................................23
1.7
Rationale for expansion of eligibility to include Child Pugh B hepatic dysfunction
23
1.8
Rationale for protocol amendment to change Expansion Cohort primary 
objective to study safety and tolerability in patients with Child Pugh B hepatic 
function..............................................................................................................24
2.
Study objectives .......................................................................................................24
2.1
Primary objectives .............................................................................................24
2.2
Secondary objectives for Parts 1 and 2.............................................................24
2.3
Exploratory objectives for Parts 1 and 2............................................................25
3.
Investigators and other study participants................................................................25


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4.
Study design.............................................................................................................25
4.2
Duration of Therapy...........................................................................................26
4.3
Duration of Follow Up........................................................................................26
4.4
Study schema....................................................................................................26
4.5
Study Timeline...................................................................................................26
4.5.1
Primary Completion ....................................................................................26
4.5.2
Study Completion .......................................................................................26
5.
Study population.......................................................................................................27
5.1
Eligibility.............................................................................................................27
5.1.1
Inclusion criteria..........................................................................................27
5.1.2
Exclusion criteria.........................................................................................28
5.2
Inclusion and Recruitment of Women and Minorities ........................................30
5.3
Withdrawal of subjects from study.....................................................................30
5.3.1
Screen failures/dropouts.............................................................................30
5.3.2
Replacement...............................................................................................31
5.3.3
Withdrawal..................................................................................................31
6.
Treatments ...............................................................................................................32
6.1
Treatments to be administered..........................................................................32
6.2
Part 1: Dose Escalation Cohort .........................................................................32
6.2.1
Part 1 dose levels .......................................................................................32
6.2.2
3+3 dose escalation rules...........................................................................32
6.2.3
Dose limiting toxicity (DLT) window and definitions....................................33
6.2.3.1
Hematologic DLT .................................................................................33
6.2.3.2
Non-hematologic DLT including immune-related AE (irAE).................34
6.2.3.3
DLT exceptions....................................................................................34
6.3
Part 2: Child Pugh B Expansion Cohort ............................................................35
6.3.1
Dose Levels for Part 2 Child Pugh B Expansion Cohort.............................35
6.4
Sorafenib ...........................................................................................................35
6.4.1
Sorafenib dosage and administration .........................................................36
6.4.1.1
Sorafenib missed doses.......................................................................36
6.4.2
Sorafenib drug supply and handling ...........................................................36
6.5
Nivolumab..........................................................................................................37


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6.5.1
Nivolumab dosage and administration........................................................37
6.5.1.1
Nivolumab schedule modifications and definition of delay...................38
6.5.1.2
Nivolumab premedication ....................................................................38
6.5.2
Nivolumab drug supply and handling..........................................................38
6.6
Blinding..............................................................................................................38
6.7
Dose modifications and delays..........................................................................38
6.7.1
Sorafenib dose modifications and delays for toxicity..................................39
6.7.2
Nivolumab dose modifications and delays..................................................40
6.7.2.1
Criteria to resume nivolumab dosing after delay for toxicity ................41
6.7.3
Dose delays for reasons other than treatment-related toxicity ...................41
6.8
Supportive care for toxicity ................................................................................42
6.8.1
Sorafenib supportive care...........................................................................42
6.8.1.1
Hand-foot skin reaction (HFSR)...........................................................42
6.8.1.2
Diarrhea ...............................................................................................42
6.8.1.3
Treatment-emergent hypertension.......................................................42
6.8.2
Nivolumab supportive care .........................................................................43
6.8.2.1
Immune-related adverse events (irAE) on nivolumab..........................43
6.8.2.2
Infusion reactions during nivolumab infusion.......................................43
6.9
Unacceptable toxicity requiring treatment discontinuation ................................45
6.9.1
Unacceptable toxicity from sorafenib..........................................................45
6.9.2
Unacceptable toxicity related to nivolumab ................................................45
6.10 Discontinuation of therapy.................................................................................46
6.11 Treatment beyond progression..........................................................................46
6.12 Drug logistics and accountability .......................................................................47
6.12.1
Drug accountability .....................................................................................47
6.12.2
Destruction and return of unused study drug..............................................47
6.13 Treatment compliance.......................................................................................48
6.14 Concomitant therapy .........................................................................................48
6.14.1
Permitted concomitant therapies and medications.....................................48
6.14.2
Prohibited concomitant therapies and medications ....................................49
7.
Procedures and variables.........................................................................................49
7.1
Schedule of procedures.....................................................................................49


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7.1.1
Schedule for Part 1: Dose Escalation Cohort .............................................50
7.1.2
Schedule for Part 2: Child Pugh B Expansion Cohort ................................53
7.2
Administrative procedures and data collection..................................................56
7.2.1
Informed consent........................................................................................56
7.2.1
Registration.................................................................................................56
7.2.1.1
Sub-site registration.............................................................................56
7.2.2
Eligibility determination...............................................................................56
7.2.3
Prior and concomitant medications.............................................................56
7.2.4
Demographics and medical history.............................................................56
7.2.5
HCC staging and disease history ...............................................................57
7.2.5.1
Prior treatments for HCC .....................................................................57
7.2.5.2
Liver disease history ............................................................................57
7.2.5.3
Subsequent therapy.............................................................................57
7.2.6
Enrollment...................................................................................................57
7.2.6.1
Sub-site enrollment..............................................................................58
7.3
Clinical procedures and assessments...............................................................58
7.3.1
Adverse event (AE) monitoring...................................................................58
7.3.2
Compliance with oral study drug.................................................................58
7.3.3
Vital signs ...................................................................................................58
7.3.4
Complete physical examination..................................................................58
7.3.5
Eastern Cooperative Oncology Group (ECOG) performance scale ...........58
7.3.6
Liver function assessment ..........................................................................59
7.3.7
Tumor imaging and response assessment.................................................59
7.3.8
Laboratory procedures/assessments..........................................................59
7.3.9
Tumor and blood sample collection and banking for correlative analyses .60
7.3.9.1
Archival tumor sample collection .........................................................60
7.3.9.2
Peripheral blood mononuclear cell (PBMC) collection.........................60
7.3.9.3
Optional specimen banking..................................................................61
7.3.10
Electrocardiogram.......................................................................................61
7.4
Assessing and reporting adverse events (AE) ..................................................61
7.4.1
AE and SAE definitions...............................................................................62
7.4.1.1
Definition of adverse event (AE) ..........................................................62


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7.4.1.2
Definition of serious adverse event (SAE) ...........................................62
7.4.2
Reporting of SAE to Bayer..........................................................................63
7.4.3
Reporting of SAE to BMS for protocol versions 1.0-3.0..............................64
7.4.3.1
SAE Reconciliation Reports.................................................................64
7.4.4
SAE follow up reports .................................................................................65
7.4.5
IND safety reporting....................................................................................65
7.4.6
Expected adverse events ...........................................................................65
7.4.7
Pregnancies................................................................................................66
8.
Statistical methods and determination of sample size .............................................66
8.1
Analysis sets......................................................................................................66
8.1.1
DLT population (Part 1) ..............................................................................66
8.1.2
Safety population (Parts 1 and 2) ...............................................................66
8.1.3
Efficacy population (Parts 1 and 2).............................................................67
8.2
Statistical and analytical plans...........................................................................67
8.2.1
Primary endpoints.......................................................................................67
8.2.1.1
Part 1: Dose Escalation Cohort primary endpoint................................67
8.2.1.2
Part 2: Child Pugh B Expansion Cohort primary endpoint...................67
8.2.2
Secondary endpoints..................................................................................68
8.2.2.1
Safety and tolerability...........................................................................69
8.2.2.2
Rate of irAE for combination overall and in Child Pugh B patients......69
8.2.2.3
ORR by RECIST 1.1 for overall study and in Parts 1 and 2 individually
.............................................................................................................69
8.2.2.4
Duration of response (DOR), PFS, and OS for Child Pugh B Expansion 
Cohort and overall study population ....................................................69
8.2.3
Exploratory endpoints.................................................................................70
8.2.3.1
PBMC immune cell subset frequencies and relationship to treatment 
and clinical outcomes...........................................................................70
8.2.3.2
PBMC T cell receptor (TCR) clonotype frequency and diversity and 
relationship to treatment and clinical outcomes...................................71
8.2.3.3
Tumor immune infiltrates, T cell subsets, and TCR profiling ...............71
8.2.3.4
Tumor and immune cell PD-L1 expression..........................................71
8.2.3.5
AFP response ......................................................................................72
8.3
Planned interim analyses ..................................................................................72


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8.3.1
Part 1: Dose Escalation Cohort DLT analyses ...........................................72
8.4
Determination of sample size ............................................................................72
8.4.1
Part 1: Dose Escalation Cohort sample size ..............................................72
8.4.2
Part 2: Child Pugh B Expansion Cohort sample size..................................72
9.
Data handling and quality assurance .......................................................................73
9.1
Pre-study documentation...................................................................................73
9.2
Institutional Review Board approval ..................................................................73
9.3
Informed consent...............................................................................................73
9.4
Changes in the protocol.....................................................................................73
9.5
Handling and documentation of clinical supplies...............................................74
9.6
Case report forms (CRFs) .................................................................................74
9.7
Oversight and monitoring plan...........................................................................75
9.8
Multicenter communication................................................................................75
9.9
Record keeping and record retention ................................................................75
9.10 Coordinating Center documentation of distribution ...........................................76
9.11 Regulatory documentation.................................................................................76
9.12 Audit and inspection ..........................................................................................77
10. Protection of Human Subjects..................................................................................77
10.1 Protection from Unnecessary Harm ..................................................................77
10.2 Protection of Privacy..........................................................................................77
11. Premature termination of the study ..........................................................................77
12. Ethical and legal aspects..........................................................................................78
12.1 Ethical and legal conduct of the study...............................................................78
12.2 Subject information and consent .......................................................................79
12.3 Publication policy...............................................................................................79
12.4 Confidentiality....................................................................................................79
13. Reference list ...........................................................................................................80
APPENDIX 1: RECIST 1.1 .............................................................................................84
APPENDIX 2: ECOG performance status ......................................................................85
APPENDIX 3: Child Pugh score .....................................................................................86
APPENDIX 4: AJCC staging for HCC.............................................................................87
APPENDIX 5: BCLC staging for HCC ............................................................................88


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APPENDIX 6: irAE management....................................................................................89
APPENDIX 7: Sorafenib drug diary ................................................................................96
APPENDIX 8: Biospecimen acquisition and handling ....................................................98
APPENDIX 9: MedWatch 3500A form..........................................................................100
APPENDIX 10: BMS SAE Reconciliation Reports........................................................101
APPENDIX 11: UCSF Data and Safety Monitoring Plan (DSMP) for Multicenter 
Institutional Study...................................................................................................102


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List of Abbreviations
ADL
Activities of daily living 
AFP
Alpha fetoprotein
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BCLC
Barcelona Clinic Liver Cancer
BID
bis in die, twice daily
B-Raf
B isoform of Rapidly Accelerated Fibrosarcoma protein
BUN
Blood Urea Nitrogen
c-KIT
Stem Cell Factor Receptor Tyrosine Kinase
CR
Complete Response
CRC
Clinical Research Coordinator
C-RAF
C isoform of Rapidly Accelerated Fibrosarcoma protein
CTCAE
Common Terminology Criteria for Adverse Events
DHPD
Dihydropyrimidine dehydrogenase
DSMC
Data Safety Monitoring Committee
DSMP
Data Safety Monitoring Plan
DOR
Duration of response
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
ERK
Extracellular Signal-regulated Kinases
FDA
Food and Drug Administration (US)
FLT3
FMS-like tyrosine kinase 3
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCC
Hepatocellular carcinoma
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HFSR
Hand foot skin reaction
IB
Investigator’s Brochure


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ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IR
Immediate release
IRB
Institutional Review Board
MAPK
Mitogen Activated Protein Kinase
MEK
MAP Kinase / ERK Kinase 1
NM
Nano molar
NYHA
New York Heart Association
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PR
Partial response
PDGFR
Platelet Derived Growth Factor Receptor
PFS
Progression free survival
PTT
Partial thromboplastin time
RCC
Renal cell carcinoma
SAE
Serious adverse event
SUSARs
Suspected unexpected serious adverse reactions
UCSF CIL
UCSF Cancer Immunotherapy Laboratory
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor


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1.
Introduction
1.1
Background
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide 
with an estimated incidence of over 750,000 new cases and almost as many deaths 
annually.8  The incidence and mortality of HCC are rising significantly in the United 
States.9  Advanced stage of disease at diagnosis precludes curative treatments in the 
majority of cases, and there are limited treatment options for patients with unresectable 
HCC after failure of liver-directed therapies.  In 2008, publication of the Sorafenib 
Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) phase III trial 
demonstrated a significant improvement in overall survival (OS) in patients with 
advanced HCC treated with the biologic agent, sorafenib.2  The SHARP trial will be 
discussed in detail below. After progression on sorafenib, another multikinase inhibitor 
regorafenib showed significant improvement in 2nd line OS along with modest 
improvement in progression-free survival (PFS).10  Despite improvements in outcome 
with sorafenib and regorafenib, however, the median OS for patients starting first line 
therapy for advanced HCC remains less than a year.  Multiple recent randomized phase 
3 trials of other anti-angiogenic multikinase inhibitors in HCC have failed to show 
benefit, underscoring the challenges of toxicity, comorbidity, and chemoresistance in 
this treatment-refractory disease.11  Recently, a Phase I/II trial has shown preliminary 
activity of the immune checkpoint inhibitor, nivolumab in HCC as discussed below.4 New 
active drugs and combinations are urgently needed.
1.2
Rationale of the study
The multikinase inhibitor sorafenib, whose principal targets include VEGFR2, VEGFR3, 
and RAF kinases, is the only approved first-line therapy with established survival benefit 
in patients with HCC not amenable to curative therapies.1,2  Though the survival benefit 
of sorafenib has been consistent across multiple studies, the overall magnitude of 
benefit is small, and generally fewer than 5% of patients demonstrate response by 
conventional Response Evaluation Criteria in Solid Tumors (RECIST) across studies.1-3 
Recently, the anti-programmed death-1 receptor (PD-1) inhibitor, nivolumab, 
demonstrated a preliminary signal of efficacy in the CheckMate 040 Phase I/II trial in 
advanced HCC patients, including a dose escalation cohort of 48 patients and a dose 
expansion cohort of 214 additional patients, across etiologic subtypes.4  In the dose 
expansion cohort, tumor responses occurred in 20%, median duration of response has 
not yet been reached but was over 17 months for the dose escalation cohort.     Results 
of CheckMate 040 have led to an ongoing multinational Phase III trial, CheckMate 459 
[NCT02576509] comparing the efficacy of sorafenib versus nivolumab as first-line 
therapy for advanced HCC.  


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1.3
Sorafenib
1.3.1 Sorafenib preclinical data
Sorafenib is a multikinase inhibitor which effects specific targets that are imperative for 
tumor cell proliferation including the serine/threonine kinases c-Raf and B-Raf (IC50 6 
and 25 nM respectively) and the receptor tyrosine kinase RET, Flt-3 and c-Kit (IC50 47, 
33 and 68 nM respectively).6  Sorafenib has potent activity against receptor tyrosine 
kinases important in tumor angiogenesis including the vascular endothelial growth factor 
receptor family (VEGFR1, -2, -3; IC50 26, 90 and 20 nM respectively) and platelet 
derived growth factor-beta (PDGFR-ί; IC50 57 nM). In cellular mechanistic (on target) 
assays, sorafenib was found to be a potent inhibitor of VEGFR-2, VEGFR-3, and 
PDGFR and Flt-3 receptor phosphorylation.6  The anti-tumor activity of sorafenib in vivo 
is driven by its direct effects on tumor growth through its inhibition of the Raf/MEK/ERK 
pathway and on the anti-angiogenic activity of the compound.  Sorafenib demonstrates 
broad anti-tumor activity in human tumor xenograft models of liver, kidney, lung, 
prostate, breast and leukemia. In human hepatocellular tumor cell lines, sorafenib 
potently inhibited cellular proliferations, Raf/MEK/ERK signaling and induced apoptosis. 
Sorafenib has potent activity against human tumor xenograft model of hepatocellular 
carcinoma with tumor stabilization seen at moderate doses and partial tumor 
regressions observed at higher doses. For further information about preclinical 
pharmacology, please refer to the current version of the sorafenib IB.
1.3.2 Sorafenib clinical experience in HCC
Sorafenib as a single agent has been evaluated globally in multiple trials in various 
malignancies. Three pivotal international multi-institutional, single agent, randomized, 
placebo-controlled trials led to sorafenib’s approval for the treatment of patients with 
advanced renal cell carcinoma (RCC, 2005), hepatocellular carcinoma (HCC, 2007) and 
locally advanced or metastatic differentiated thyroid carcinoma refractory to radioactive 
iodine (DTC2013). 
Clinical results in Phase I studies of sorafenib as a single agent were suggestive of a 
therapeutic effect in HCC and led to the design of a single arm Phase II study, in which 
137 subjects with advanced, inoperable HCC Child-Pugh classes A and B were 
treated.12  The results of this study (median TTP of 5.5 months by independent 
assessment and median overall survival of 9.2 months), provided the basis for the 
randomized, placebo-controlled Phase III study in subjects with advanced HCC Child-
Pugh class A (SHARP, Sorafenib HCC Assessment Randomized Protocol).  This large 
(602 subjects) Phase III study was the first international, randomized, double-blind, 
placebo-controlled study to demonstrate a statistically significant and clinically 
meaningful improvement in OS in advanced HCC subjects treated with sorafenib over 
placebo.2 Of the 299 sorafenib subjects valid for ITT analysis, the median OS was 10.7 
months in the sorafenib group and 7.9 months in the 303 subjects randomized to the 
placebo group (hazard ratio (HR) in the sorafenib group, 0.69; 95% confidence interval, 
0.55 to 0.87; p<0.001.  The nominal alpha for this analysis was 0.0077 according to the 
pre-specified O'Brien-Fleming-type alpha spending function.  Therefore, sorafenib had a 


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statistically significant effect on prolonging overall survival.  This significant survival 
benefit represented a 31% reduction in risk of death (or 44% improvement in OS) in 
subjects treated with sorafenib versus those treated with placebo.  
Similar improvements in OS and TTP were observed in a Phase III trial of sorafenib 
versus placebo in 271 Asian patients with advanced HCC randomized 2:1 to sorafenib 
versus placebo.1 In the Asian study, the median OS for sorafenib was 6.5 months for 
sorafenib compared to 4.2 months for placebo (HR 0.68), and median TTP was 2.8 
months for sorafenib versus 1.4 months for placebo (HR 0.57). 
In the SHARP study, treatment-related adverse events occurred in 80% of patients in 
the sorafenib group by comparison with 52% in the placebo group.2  Grade 3 toxicities 
included diarrhea (8%), hand-foot skin reaction (8%), hypertension (2%), and abdominal 
pain (2%) in the treatment group.  Grade 3 or 4 hypophosphatemia (4%) and 
thrombocytopenia (4%) were also more common in patients treated with sorafenib. In 
the Asian randomized, placebo-controlled Phase III study, the most common Grade 3 
and 4 toxicities were hand-foot skin reaction (10.1%), diarrhea (6%), hyperbilirubinemia 
(3.4%), and fatigue (3.4%) with the use of sorafenib.1  The preceding Phase II study of 
sorafenib in HCC included 28% of patients with Child-Pugh class B cirrhosis; subgroup 
analysis in this cohort with greater degree of hepatic impairment showed higher rates of 
hyperbilirubinemia and encephalopathy developing on study by comparison with 
patients with Child-Pugh class A.12,13
As of 31-December 2015 approximately 70,897 patients have been exposed to 
sorafenib in company-sponsored interventional clinical trials, non-interventional studies 
and investigator-sponsored studies for which Bayer has provided grants. The 
cumulative post-marketing exposure, excluding above mentioned clinical studies, since 
2005 is estimated to be 440,109 patients.
Please refer to the current version of the sorafenib IB for the complete list of observed 
adverse events seen in Phase III studies. 
1.4
Nivolumab
1.4.1 Nivolumab preclinical data
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed 
death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. 
PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes.7 
Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), 
results in the down-regulation of lymphocyte activation. Inhibition of the interaction 
between PD-1 and its ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens. Nivolumab is expressed in 
Chinese hamster ovary (CHO) cells and is produced using standard mammalian cell 
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Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to 
related members of the CD28 family (nivolumab IB).  Nivolumab inhibits the interaction 
of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and 
interferon-gamma (IFN-γ) release in vitro (nivolumab IB).14 Nivolumab binds with high 
affinity to activated human T-cells expressing cell surface PD-1 and to cynomolgus 
monkey PD-1. In a mixed lymphocyte reaction (MLR), nivolumab promoted a 
reproducible concentration-dependent enhancement of IFN-γ release.15 In intravenous 
(IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well 
tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 
50 mg/kg, administered twice weekly for 27 doses. While nivolumab alone was well 
tolerated in cynomolgus monkeys, combination studies have highlighted the potential for 
enhanced toxicity when combined with other immunostimulatory agents (nivolumab IB).  
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant 
cynomolgus monkeys with nivolumab was conducted (nivolumab IB).  Administration of 
nivolumab at up to 50 mg/kg 2QW was well tolerated by pregnant monkeys; however, 
nivolumab was determined to be a selective developmental toxicant when administered 
from the period of organogenesis to parturition at ≥ 10 mg/kg (area under the 
concentration-time curve [AUC] from time zero to 168 hours [AUC(0-168 h)] 117,000 
µg●h/mL). Specifically, increased developmental mortality (including late gestational 
fetal losses and extreme prematurity with associated neonatal mortality) was noted in 
the absence of overt maternal toxicity. There were no nivolumab-related changes in 
surviving infants tested throughout the 6-month postnatal period. Although the cause of 
these pregnancy failures was undetermined, nivolumab-related effects on pregnancy 
maintenance are consistent with the established role of PD-L1 in maintaining 
fetomaternal tolerance in mice.16
Please refer to the current version of the nivolumab IB for additional data from 
preclinical studies.
1.4.2 Nivolumab clinical experience in HCC
The anti-programmed death-1 receptor (PD-1) inhibitor, nivolumab, has been studied in 
multiple tumor types, including HCC.  Nivolumab has been approved for treatment of 
multiple malignancies, including unresectable or metastatic melanoma, as monotherapy 
or in combination with ipilimumab; metastatic non-small cell lung cancer (NSCLC); 
advanced renal cell carcinoma (RCC); and relapsed or progressive classical Hodgkin’s 
lymphoma.  
In HCC, the Phase I/II clinical trial CheckMate 040 reported on 262 patients with 
advanced HCC treated with nivolumab in a dose escalation cohort (n=48) and a dose 
expansion cohort (n=214).4  In the dose escalation phase, a maximum tolerated dose 
was not reached; the dose of 3 mg/kg IV every 2 weeks was selected for dose 
expansion.  Grade 3-4 treatment-related adverse events (AE) occurred in 25%, 
including rash (23%), AST and/or ALT elevation in 21% and 15% respectively, elevated 
amylase and/or lipase in 21% and 19% respectively, and pruritus in 19%.  Three of 48 
patients experienced serious adverse events (SAE): pemphigoid, adrenal insufficiency, 
and liver disorder in 1 each.  There were no deaths attributed to treatment-related 


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toxicity. The objective response rate (ORR) in dose escalation phase was 15% with 3 
complete responses (CR) and 4 partial responses (PR), with prolonged median duration 
of response (DOR) approximately 17 months.4,17  The median OS for the dose 
escalation cohort was 15.0 months. 
In the CheckMate 040 dose expansion cohort, 214 additional patients with advanced 
HCC were treated with nivolumab at dose of 3 mg/kg IV every 2 weeks.  Safety was 
similar to the dose escalation cohort with Grade 3-4 treatment-related AE occurring in 
19%.  There were no events of reactivation HBV.  The ORR for the dose expansion 
cohort was 20%, similar across subgroups defined by positive for hepatitis C virus 
(HCV), positive for hepatitis B virus (HBV), and uninfected without HBV or HCV; the 
response rates were also similar for patients without prior sorafenib therapy as for those 
enrolled after progression on sorafenib.  The median OS has not been reached for the 
overall dose expansion cohort, but the median OS for the uninfected, sorafenib 
progressor cohort (n=57) was 13.2 months.4  Among patients with evaluable tumor 
samples in the CheckMate 040 expansion cohort (81%), tumor responses were not 
significantly associated with tumor PD-L1 expression which was present in 20%.  
Results of CheckMate 040 have led to an ongoing multinational Phase III trial, 
CheckMate 459 [NCT02576509] comparing the efficacy of sorafenib versus nivolumab 
as first-line therapy for advanced HCC.  Please refer to the nivolumab IB for the 
complete list of observed adverse events seen in Phase III studies.
1.5
Combination of multikinase inhibition and checkpoint inhibition
1.5.1 Combination multikinase inhibition and checkpoint inhibition 
preclinical rationale
One potential mechanism for primary or secondary resistance to checkpoint inhibition is 
immunosuppression by factors within the tumor microenvironment, such as by FOXP3+ 
regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSC).18  
Several preclinical studies suggest that multikinase inhibitors such as sorafenib may 
reduce the number of tumor infiltrating Tregs and myeloid derived suppressor cells 
(MDSC) as well as inhibiting their function, thereby promoting an immune antitumor 
response.19-21 In a syngeneic mouse model, the combination of the multikinase inhibitor, 
lenvatinib, plus anti-mouse PD-1 mAb showed greater growth inhibition in combination 
than with either agent as monotherapy, with complete tumor regressions in a subset of 
mice treated on combination.22  Re-inoculation with tumor cells did not grow any tumors 
in the mice with complete tumor regression, while all naïve animals grew tumors. The 
combination was associated with synergistic upregulation of interferon signaling-related 
genes; lenvatinib was associated with increased memory T cell and TH1 population 
compared with vehicle treatment.
In a small study of peripheral blood mononuclear cells (PBMC) derived from 20 HCC 
patients as well as 11 control patients, ex vivo incubation with sorafenib elicited dose-
dependent Treg inhibition and effector T cell (Teff) activation at low doses, with Teff 
suppression at higher doses.23  In PBMC samples from 19 HCC patients, sorafenib 


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treatment was associated with decreased frequency and absolute number of FOXP3+ 
Tregs along with significantly increased ratio of Teff to Treg by FACS analysis after 4 
weeks of sorafenib therapy compared to baseline.24 Conflicting data in human renal cell 
carcinoma blood samples have been reported, and the timing of these effects has not 
been well characterized.25,26 
Sorafenib therapy may also be associated with increased PD-L1 expression on tumor-
infiltrating immune cells.  In a study of 23 HCC patients with pre-treatment baseline 
tumor samples compared to tumor biopsies after progression on sorafenib, immune cell 
PD-L1 expression by IHC was significantly increased post sorafenib therapy.27  These 
findings suggest PD-L1 expression as a possible mechanism of sorafenib resistance 
and support investigation of the combination of sorafenib plus PD-1 inhibition.
1.5.2 Combination multikinase inhibition and checkpoint inhibition 
clinical experience
Other multikinase inhibitors combined with nivolumab indicate preliminary favorable 
response rates but are notable for Grade 3-4 hepatotoxicity rates of approximately 18-
20% (unpublished data, BMS). CA209-016 is an ongoing phase 1 study of nivolumab 
plus sunitinib, pazopanib, or ipilimumab in patients with advanced renal cell carcinoma 
(RCC).  Interim data from 33 patients enrolled on CA209-016 (n=14 with prior systemic 
therapy) treated with combination of nivolumab plus sunitinib shows a promising overall 
response rate of 52%, with median duration of response of 54 weeks. No DLT were 
identified at full doses of both sunitinib and nivolumab in combination. Toxicity profile 
was notable for Grade 3-4 ALT elevation and hypertension, each occurring in 
approximately 18%, with Grade 3-4 AST elevation and diarrhea in approximately 9% 
each.  For the combination of nivolumab and pazopanib on CA209-016, the overall 
response rate in previously treated patients was 45%, though study expansion was not 
pursued due to occurrence of 4 DLT among 20 patients. Grade 3-4 toxicity included 
elevated ALT and AST each in 20% (requiring treatment discontinuation in 3 patients), 
diarrhea in 20%, hypertension in 10%, and fatigue in 15%. 
1.6
Rationale for selected correlative analyses
1.6.1 PD-L1 expression
Tumor PD-L1 expression by IHC predicts an increased likelihood of response to 
immune checkpoint inhibition with PD-1 inhibitors in some cancer types.28  A pooled 
analysis of 20 trials including 1475 patients with melanoma, non-small cell lung cancer 
(NSCLC), and genitourinary cancer showed a significant interaction between PD-L1 
expression and response overall, with overall RR 34.1% vs. 19.9% (p<0.0001).28  
Response rates were significantly higher in PD-L1+ melanoma and NSCLC but no 
significant difference in response rate was observed according to PD-L1 status for 
genitourinary cancers, and a significant proportion of patients with PD-L1-negative 
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In HCC patients enrolled on CheckMate-040, 81% of patients in dose expansion had 
evaluable tumor samples for PD-L1 expression.4  Among these, approximately 20% of 
cases exhibited tumor staining positive for PD-L1, defined as membrane expression of 
PD-L1 on at least 1% of tumor cells.   In this study, positive tumor PD-L1 expression 
was not significantly associated with response to nivolumab therapy. 
Tumor and immune cell PD-L1 expression will be analyzed by immunohistochemistry 
(IHC) from pre-treatment baseline archival tumor samples in all patients and any post-
treatment samples if obtained as part of standard clinical care.  PD-L1 IHC analyses will 
be performed in the UCSF Cancer Immunotherapy Laboratory (CIL) or other laboratory 
approved by Study Chair dependent upon funding and sample availability.
1.6.2 Peripheral Blood Mononuclear Cell (PBMC) Immune Cell Subsets 
and TCR Clonotype Frequency and Diversity
Research blood samples will be collected from all patients enrolled at UCSF at time 
points listed in Section 7.1. Research blood samples will not be collected from patients 
enrolled at the sub-site.
Whole blood will be processed into PBMC and cryopreserved at the UCSF Cancer 
Immunotherapy Laboratory (CIL) for future analyses in batch after completion of study.
PBMC samples will be analyzed for immune cell subsets by flow cytometry and may 
also be profiled for T cell receptor (TCR) genotype by next generation sequencing 
technologies.  Dr. Fong’s laboratory has demonstrated that treatment with the 
combination of CTLA-4 blockade plus GM-CSF results in expansion of activated effector 
CD8+ T cells as well as expansion of tumor antigen-specific T cells in patients with 
advanced prostate cancer.29,30  Dr. Fong’s laboratory and collaborators also have 
shown that checkpoint blockade by treatment with CTLA-4 inhibition in patients with 
metastatic prostate cancer and melanoma can increase T cell clonotype repertoire and 
diversity.29,31  
Immune cell subsets will be measured using flow cytometry as has been previously 
described.29,30  The frequency of individual clonotypes, and the diversity of overall 
clonotype repertoire, will be measured by next-generation sequencing.31  Baseline and 
changes on treatment in PBMC T cell subsets and TCR clonotype frequency and 
diversity will be explored for relationship to clinical outcomes including ORR, DOR, PFS, 
OS, and AFP response.
1.6.3
Tumor immune cell infiltration and subsets
Preexisting tumor immune infiltration has shown association with increased likelihood of 
tumor response to checkpoint inhibition.32,33  This association between tumor immune 
infiltration and increased response to immunotherapy may be due to preexisting tumor-
specific T cell clones within the tumor which have been primed by tumor antigens but 
attenuated by checkpoint signaling, which are then activated upon checkpoint inhibition.  
To explore the impact of tumor immune infiltration in HCC treated with the combination 
of sorafenib plus nivolumab, archival pre-treatment tumor core biopsy or resection 


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samples (primary and/or non-nodal metastatic site depending on availability) will be 
obtained from all patients.  The samples will be examined for immune cell infiltrates and 
T cell subset composition in batch at study completion in the UCSF CIL as has been 
previously described.29,30,34  The presence of tumor immune infiltrates and T cell subset 
composition will be explored for association with clinical outcomes including ORR, DOR, 
PFS, OS, and AFP (Alpha fetoprotein) response.  
On-treatment or post-treatment tumor samples will also be analyzed in comparison to 
the baseline/pre-treatment specimen when available, such as in cases for which an on-
treatment or post-treatment tumor resection or biopsy is required for clinical care (e.g. 
palliative metastatectomy/debulking, biopsy of an equivocal lesion, or if fiducial 
placement is required for palliative radiotherapy). 
The immune cell subsets in tumor tissue will be compared descriptively to paired PBMC 
from the same patient (Section 1.6.2).29
1.6.4 Alpha fetoprotein (AFP) tumor marker
The most commonly measured blood tumor marker of HCC is AFP, a glycoprotein 
highly expressed during hepatocyte development.   AFP is secreted by approximately 
70% of HCC. Elevated baseline AFP levels have been shown to correlate with worse 
prognosis after hepatic resection, transplant, and local therapies. A study of patients 
enrolled in a phase III randomized trial comparing two palliative cytotoxic chemotherapy 
regimens showed that patients with AFP decline by at least 20% (designated as AFP 
responders) demonstrated markedly improved survival by comparison with AFP non-
responders, with overall survival 13.5 versus 5.6 months, respectively (p < 0.0001).35 
AFP changes are also associated with response to sorafenib and may be an early 
surrogate marker of response.36,37  
1.7
Rationale for expansion of eligibility to include Child Pugh B 
hepatic dysfunction
The CheckMate 040 trial enrolled a cohort of 49 advanced HCC patients with Child 
Pugh B7 or B8 liver dysfunction which showed objective response rate of 10.2%, with 
median duration of response 9.9 months.38 The safety of nivolumab appeared similar to 
Child Pugh A patients, with discontinuation for toxicity in 2 patients (4.1%). Four patients 
(8.2%) experienced treatment-related hepatic adverse events, similar to proportion in 
Child Pugh A patients in CheckMate 040. Similar results were demonstrated in a 
retrospective case series of patients with Child Pugh B7-B9 hepatic function treated with 
nivolumab at UCSF, with treatment related discontinuation required in 4 of 18 patients 
(22%) and objective responses occurring in 17%.39 Sorafenib also has demonstrated 
acceptable safety in Child Pugh B patients and similar adverse event and 
pharmacokinetic profiles to Child Pugh A,13,40 with no dose modifications recommended 
in the FDA prescribing information, though a phase 1 and pharmacokinetic study of 
sorafenib in setting of hepatic dysfunction recommended empiric starting dose reduction 
according to baseline bilirubin and albumin levels.41  There are few treatment options 
with prospective data for safety and efficacy in Child Pugh B patients, noting that the 


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first-line treatment options of bevacizumab plus atezolizumab as well as lenvatinib have 
only been studied prospectively in Child Pugh A populations to date, without established 
safety in Child Pugh B populations.42,43 Thus, inclusion of carefully-selected Child Pugh 
B patients provides a treatment option for a subgroup of HCC patients without any 
established first line treatment options beyond sorafenib alone.
1.8
Rationale for protocol amendment to change Expansion Cohort 
primary objective to study safety and tolerability in patients with 
Child Pugh B hepatic function
After completion of Part 1: Escalation Cohort, the results of the IMbrave150 trial were 
reported demonstrating the superiority of the combination of atezolizumab plus 
bevacizumab over standard sorafenib in patients with advanced HCC and Child Pugh A 
liver function, becoming a new global standard of care in this population.42 Atezolizumab 
plus bevacizumab has not been studied in patients with Child Pugh B liver dysfunction, 
however, and is contraindicated in patients with esophageal varices at high risk for 
upper gastrointestinal bleeding or patients with recent history of gastrointestinal 
bleeding, complications which are associated with Child Pugh B liver dysfunction. 
Due to the changing treatment landscape with new first-line treatment options for 
patients with advanced HCC and Child Pugh A liver function, and the lack of established 
combination immunotherapy options for patients with Child Pugh B liver function, the 
previous version Expansion Cohort (Part 2) of this protocol has been amended and 
renamed as the Child Pugh B Expansion Cohort (Part 2), in order to study the safety 
and tolerability of the combination of sorafenib plus nivolumab in patients with both 
Child Pugh B liver dysfunction and advanced HCC, a population with urgent unmet 
medical need for safe and efficacious therapies.  
2. Study objectives
2.1
Primary objectives
1. Part 1: Escalation Cohort:   Maximum tolerated dose (MTD) of sorafenib in 
combination with standard dose nivolumab with Child Pugh A-B7 liver function
2. Part 2: Child Pugh B Expansion Cohort: Safety in patients with Child Pugh B liver 
function
2.2 Secondary objectives for Parts 1 and 2
1. Safety and tolerability of combination overall
2. Rate of irAE for combination overall and in patients with Child Pugh B liver 
function
3. Objective response rate (ORR) by RECIST 1.15 for overall study
4. ORR by RECIST 1.1 in patients with Child Pugh B liver function
5. Duration of response (DOR), progression free survival (PFS), and overall survival 
(OS) for Escalation Cohort and Child Pugh B Expansion Cohort and overall


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2.3 Exploratory objectives for Parts 1 and 2
1. Relationship between PBMC immune cell subset frequencies, baseline liver 
function, and clinical outcomes 
2. Relationship between PBMC T cell receptor (TCR) clonotype frequency and 
diversity, baseline liver function, and clinical outcomes 
3. Tumor tissue immune cell subsets and TCR clonotype frequency and diversity in 
pre-treatment archival tumor tissue samples 
4.
5. Tumor and immune cell PD-L1 status in pre-treatment archival tumor tissue 
samples and relationship to clinical outcomes
6. Changes in HBV and/or HCV viral load on treatment
7. AFP changes on treatment and relationship to clinical outcomes
8. Relationship between clinical outcomes and clinicopathologic features including 
race/ethnicity, etiology of liver disease including HBV/HCV status, baseline liver 
function, presence of cirrhosis, macrovessel invasion, extrahepatic spread, 
site(s) of metastatic disease, prior treatment history including prior radiation and 
arterial therapies
3. Investigators and other study participants
Principal Investigator: 
Robin K. Kelley, MD
Associate Professor of Clinical Medicine
University of California, San Francisco (UCSF)
A second study site, University of California, Davis (UCD) was activated after 
completion of Part 1: Dose Escalation Cohort.
4. Study design
This is an open-label, dose-escalation and expansion pilot study to examine the safety 
and efficacy of sorafenib combined with the PD-1 checkpoint inhibitor, nivolumab, in 
patients with unresectable HCC not amenable to curative therapies, with no prior 
systemic treatment. The study is divided into two parts: Dose Escalation Cohort (Part 1) 
and Child Pugh B Expansion Cohort (Part 2). Immune profiling of PBMC will be 
performed in all patients enrolled at UCSF. There are 2 planned study sites: UCSF and 
a sub-site UCD which was activated after completion of Part 1: Dose Escalation Cohort.  


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4.2
Duration of Therapy
Sorafenib will be administered continuously and nivolumab will be administered every 
14 or 28 days until progression, unacceptable toxicity, withdrawal of consent, criteria for 
discontinuation are met, or study end, whichever comes first.
4.3
Duration of Follow Up
Patients will be followed for survival every 3 months after completion of treatment or 
removal from study, or until death, whichever occurs first, for up to 2 years.  Patients 
removed from study for unacceptable treatment related adverse event(s) will be 
followed until resolution or stabilization of all treatment related adverse events to Grade 
2 or lower, or determination of chronic/irreversible by treating investigator and Study 
Chair.
4.4
Study schema
4.5
Study Timeline
4.5.1 Primary Completion
The study is expected to complete accrual within approximately 48 months after 
enrolment of first patient, based upon expected accrual rate of 1-2 subjects per month 
and transition time required for protocol amendment. Accrual is expected to be 
completed by 30 April 2022; no subsequent patients will be enrolled after 30 April 2022 
unless approved by Study Chair and Bayer.
4.5.2 Study Completion
The study is expected to complete primary and secondary endpoint measurements and 
survival follow up approximately 60 months after enrolment of first patient, based upon 
expected 48 month accrual period, median time on treatment of 4 months, and 24 
months of survival follow up from the last dose for last patient on study. 


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5. Study population
5.1
Eligibility
5.1.1
Inclusion criteria
1. Histologic or cytologic diagnosis of unresectable, locally advanced and/or 
metastatic HCC not amenable to curative surgery, transplantation, or ablative 
therapies based upon assessment of treating investigator
a. For patients without prior histologic or cytologic diagnosis, radiographic 
diagnosis is allowed provided patients meet American Association for the 
Study of Liver Diseases (AASLD) criteria for radiographic diagnosis 44 
2. Radiographically measurable disease by RECIST version 1.1 in at least one site 
not previously treated with chemoembolization, radioembolization, radiation, or 
other local/liver-directed procedures (i.e. must have at least one measurable 
target lesion, either within the liver or in a measurable metastatic site); a new 
area of tumor progression within or adjacent to a previously-treated lesion, if 
clearly measurable by a radiologist, is acceptable
3. Untreated/pretreatment archival tumor tissue must be available for correlative 
analyses
4. Age at least 18 years at enrollment
5. ECOG 0 or 1 at enrollment
6. At least 4 weeks after any prior chemoembolization, radioembolization, local 
ablative therapies, or hepatic radiation and recovery to ≤ grade 1 treatment-
related toxicity
7. At least 6 weeks after any major surgery including prior hepatic resection and 
recovery to ≤ grade 1 treatment-related toxicity 
8. At least 7 days after minor surgery (such as central venous access) or biopsy 
and recovery to ≤ grade 1 treatment-related toxicity
9. At least 2 weeks after any prior palliative radiation (e.g. to focal metastatic lesion 
such as bone metastases) and recovery to ≤ grade 1 treatment-related toxicity 
10.Blood pressure ≤140/90 mm Hg with or without anti-hypertensive therapy
a. Patients may be rescreened after initial ineligibility if due to elevated blood 
pressure, if adequately medically managed within approximately 30 days
11.Adequate baseline organ and marrow function as defined below:
a. adequate bone marrow function:
absolute neutrophil count at least 1,200/mcL
platelets at least 50,000/mcL
hemoglobin at least 9 g/dL
b. adequate hepatic function:
Part 1: total bilirubin less than 2.6 mg/dL or 2 times ULN, whichever is 
higher, and albumin at least 2.5 g/dL if otherwise meets criteria for Child 
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Part 2: total bilirubin less than 3.9 mg/dL or 3 times ULN41, whichever is 
higher, and albumin at least 2.0 g/dL, if otherwise meets criteria for Child 
Pugh B 
Part 1: AST(SGOT) and ALT (SGPT) less than 5 X ULN, INR less than 1.7
Part 2: AST(SGOT) and ALT (SGPT) less than 8 X ULN, INR less than 1.7
c. creatinine less than 1. 5 X ULN and/or creatinine clearance ≥ 60 mL/min
12.Child Pugh A or B7 (Part 1); Child Pugh B7-9 (Part 2) (See Appendix 14.3)
13.If HBV sAg and/or core Ab positive, must be treated with appropriate antiviral 
therapy according to institutional practice with HBV DNA by PCR less than 500 
IU/mL
14.If clinical or histologic diagnosis of cirrhosis and/or clinical or radiographic 
evidence esophageal or gastric varices, must have had EGD surveillance and 
adequate endoscopic therapy according to institutional standards 
15.Able to swallow and retain oral medications
16.Women of child-bearing potential (WOCBP) must have a negative pregnancy test 
within 28 days before study enrollment
17.WOCBP and male partners of WOCBP must agree to use two methods of 
contraception until at least 5 months after last dose of each study drug for 
WOCBP subjects, and 7 months for male partners of WOCBP  
18.Able to understand and willingness to provide informed consent, and the 
willingness to comply with the requirements of the protocol 
a. Subjects must have signed and dated an IRB/IEC approved written 
informed consent form in accordance with regulatory and institutional 
guidelines and before the performance of any protocol related procedures 
that are not part of standard of care 
5.1.2 Exclusion criteria
1. Any prior systemic therapy for HCC
2. Known fibrolamellar or mixed HCC-cholangiocarcinoma histology
3. Requirement for paracentesis to control ascites within 6 months before 
enrollment 
a. Ascites which is not clinically detectable or mild on stable doses of 
diuretics during screening is allowed provided meets criteria for Child 
Pugh A or B7 (Part 1) or B7-9 (Part 2)
4. Symptomatic hepatic encephalopathy requiring medication (such as lactulose or 
rifaximin) (Part 1) or any hospitalization for encephalopathy within 6 months 
before enrollment (Part 1 or 2)
a. Hepatic encephalopathy that is adequately controlled on stable doses of 
lactulose and/or rifaximin per assessment of treating investigator is 
allowed in Part 2, provided no hospitalization for encephalopathy within 6 
months before enrollment
b. Medications such as lactulose used for other indications (e.g. constipation) 
are allowed in both Part 1 and 2
5. History of upper GI bleeding from esophageal and/or gastric varices within 12 
months before enrollment


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6. Requirement for systemic corticosteroids unless used for adrenal replacement, 
acute therapy for asthma or bronchitis exacerbation (≤ 2 weeks), or 
premedication for contrast allergy 
a. Topical, intranasal, or inhaled steroids are not excluded
7. Active autoimmune condition requiring systemic immunosuppressive medication
8. Known HIV infection
9. Active coinfection with HBV plus HDV or HCV:
a. Both hepatitis B and C as evidenced by detectable HBV surface antigen or 
HBV DNA and detectable HCV RNA
b. Hepatitis D infection (HDV antibody positive) in subjects with detectable 
hepatitis B surface antigen or HBV DNA
10.Prior allogeneic transplant of any solid organ or bone marrow/stem cells
11.Symptomatic hypothyroidism without replacement
a. Patients may be rescreened after initiating adequate replacement therapy
12.History of seizure disorder requiring antiepileptic medication or brain metastases 
with seizures
13.Non-healing wound, ulcer, non-healing traumatic bone fracture, or abscess within 
30 days of enrollment
a. Nondisplaced, uncomplicated pathologic fracture due to tumor may be 
eligible provided adequately treated with radiation, surgery or other 
treatments with full recovery based upon investigator assessment 
14.Central or necrotic lung metastases 
15.Known brain or leptomeningeal metastases
16.Uncontrolled hypertension (systolic pressure >140 mm Hg and/or diastolic 
pressure > 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite 
optimal medical management
17.Active or clinically significant cardiac disease including:
a. Congestive heart failure – New York Heart Association (NYHA) > Class II
b. Active coronary artery disease including unstable or newly diagnosed 
angina or myocardial infarction within 6 months prior to study entry
c. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin
d. QTc (Fridericia) > 450 msec on two consecutive ECGs (baseline ECG 
should be repeated if QTc is found to be > 450 msec)
18.Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 
Grade 2 or higher within 6 months before first dose of study treatment any other 
hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within 6 
months before first dose of study treatment
19.Subjects with arterial or venous thrombotic or embolic  events, such as 
cerebrovascular accident (including transient ischemic attacks), myocardial 
infarction, or deep venous thrombosis (DVT) within 6 months of informed consent
a. Tumor or bland thrombus in hepatic vasculature is not an exclusion 
provided hepatic function criteria are met
b. Asymptomatic thromboembolic events such as incidentally-detected 
subsegmental pulmonary emboli or superficial thromboses are not an 


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exclusion provided the patient does not require treatment with therapeutic 
anticoagulation
20.Subjects who have used strong CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort [Hypericum perforatum], 
dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], 
and/or rifabutin) within 28 days before first dose of study treatment
21.Subjects who require therapeutic anticoagulation or anti-platelet therapy
a. Low dose aspirin (≤100 mg/day) is allowed
b. Prophylactic doses of low molecular weight heparin (LMWH) are allowed if 
approved by Study Chair or designee
22.Subjects with any previously untreated and concurrent cancer that is distinct in 
primary site or histology from HCC except cervical cancer in-situ, treated non-
melanoma skin cancers, localized prostate cancer not requiring systemic therapy 
undergoing surveillance, or superficial bladder tumor; subjects surviving a cancer 
that was curatively treated and without evidence of disease for more than 2 years 
before enrollment are allowed provided that cancer therapy was completed at 
least 2 years prior to study entry (date of the informed consent form)  
23.Any uncontrolled intercurrent illness including, but not limited to: Ongoing or 
active infection requiring antibiotic therapy, pulmonary disease impairing 
functional status or requiring oxygen, impairment in gastrointestinal function that 
may affect or alter absorption of oral medications (such as malabsorption or 
history of gastrectomy or bowel resection), or uncontrolled diarrhea  
24.Known or suspected allergy or hypersensitivity to any of the study drugs, study 
drug classes, or excipients of the formulations given during the course of this trial
25.Women who are pregnant or breast-feeding at enrollment
26.Inability to comply with the protocol and/or not willing or not available for follow-
up assessments
27.Any condition which, in the investigator’s opinion, makes the subject unsuitable 
for trial participation
5.2
Inclusion and Recruitment of Women and Minorities
Individuals of any sex/gender, race, or ethnicity may participate.
5.3
Withdrawal of subjects from study
5.3.1 Screen failures/dropouts
A subject who discontinues study participation prematurely (without meeting a study 
defined safety or efficacy endpoint) for any reason is defined as a “dropout” if the 
subject has already received at least one dose of either study drug. A subject who, for 
any reason (e.g. failure to satisfy the selection criteria), terminates the study before 
receiving dose of either study drug is regarded a “screen failure”.


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5.3.2 Replacement
Patients enrolled to Part 1 or Part 2 who are determined ineligible after enrollment 
and/or who are not evaluable for the endpoints of DLT or safety will be replaced. See 
“Statistical methods and determination of sample size” in Section 8.0.   
5.3.3 Withdrawal
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons: 

Subject withdraws consent from study treatment and study procedures.  A 
subject must be removed from the trial at his/her own request or at the request 
of his/her legally acceptable representative.  At any time during the trial and 
without giving reasons, a subject may decline to participate further.  The subject 
will not suffer any disadvantage as a result.

Subject is lost to follow-up.

Death.
Subjects may be withdrawn from the study for the following reasons:

The subject is non-compliant with study drug, trial procedures, or both; including 
the use of anti-cancer therapy not prescribed by the study protocol.

Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who have 
been withdrawn from treatment with study drug because of pregnancy should 
not undergo CT scans [with contrast]/MRI or bone scans while pregnant.)

If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being.

Severe allergic reaction or unacceptable toxicity to both study drugs (see 
Section 6.9).

The development of a second cancer. 

Development of an intercurrent illness or situation which would, in the judgment 
of the investigator, significantly affect assessments of clinical status and trial 
endpoints.

Deterioration of ECOG performance status to greater than 2 despite best 
supportive care and attributed as at least possibly related to protocol therapy.

Use of illicit drugs or other substances that may, in the opinion of the 
investigator, have a reasonable chance of contributing to toxicity or otherwise 
skewing trial result.


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
Administrative or safety reasons requiring study closure.
Any subject removed from the trial will remain under medical supervision until discharge 
or transfer is medically acceptable. In all cases, the reason for withdrawal must be 
recorded in the CRF and in the subject's medical records. Details for the premature 
termination of the study as a whole are provided in Section 10 (Premature termination of 
the study).
6. Treatments
6.1
Treatments to be administered
All patients will be treated with the combination of sorafenib plus nivolumab.  Patients 
will be enrolled to one of two sequential cohorts: the Dose Escalation Cohort (Part 1) or 
the Child Pugh B Expansion Cohort (Part 2). Patients enrolled to the Dose Escalation 
Cohort (Part 1) will be enrolled starting at Dose Level -1 according to Table 6.2.1-1 
below, following standard 3+3 dose escalation rules as outlined in Section 6.2.2 below.  
Patients enrolled to the Child Pugh B Expansion Cohort (Part 2) will be enrolled to the 
maximum tolerated dose (MTD) of sorafenib identified in Part 1 along with standard 
dose nivolumab, as described below in Section 6.2.2.  
6.2
Part 1: Dose Escalation Cohort
Between 3-12 patients will be enrolled in Part 1 starting at Dose Level (DL) -1.  See 
Table 6.2.1-1 for dose levels and Table 6.2.2-1 for dose escalation decision rules. 
Standard dose nivolumab 240 mg IV every 14 days will be used for both dose levels 
based upon absence of established dose-relationship for toxicities attributed to this 
agent in advanced HCC patients.4 
6.2.1 Part 1 dose levels
Table 6.2.1-1. Part 1 Dose Levels
Dose Level -2
Dose Level -1
(starting dose)
Dose Level 1
Drug
n =3-6 patients
n = 3-6 patients
n = 0-6 patients
Sorafenib
400 mg PO QOD
400 mg PO daily
400 mg PO BID
Nivolumab
240 mg IV Q2 weeks over 30 minutes
6.2.2 3+3 dose escalation rules 
Table 6.2.2-1. Dose Escalation Decision Rules


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Number of Patients with DLT at a 
Given Dose Level
Escalation Decision Rule
0 out of 3
Dose escalate to next higher dose level. If already at DL 1, enroll 3 
additional patients at DL 1.
≥ 2 out of 3*
Dose escalation will be stopped.  This dose level will be declared the 
maximally administered dose (highest dose administered).  The next 
lower cohort will be expanded to 6 patients. If no DLTs are seen consider 
an intermediate dose level between this dose and the MAD dose. 
1 out of 3
Enter 3 more patients at this dose level.
If 0 of these 3 patients experience a DLT, proceed to the next dose level.  
If already at DL 1, then DL 1 is the MTD.
If 1 or more of these 3 patients suffer a DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered dose. 
≤ 1 out of 6 at highest dose level below 
the maximally administered dose
This is the MTD and recommended Expansion Cohort dose. 
Note: Dose escalation will stop at Dose Level 1 which is the FDA-labeled dose of sorafenib as monotherapy for HCC.  
If >1 DLT occur at DL-2 a decision will be made whether to amend or terminate the study. 
6.2.3 Dose limiting toxicity (DLT) window and definitions
The DLT window will be 28 days (1 cycle).  Subjects must receive 2 doses of nivolumab 
and at least 75% of sorafenib doses within 28 days (1 cycle), or experience a qualifying 
DLT event, to be evaluable for DLT. DLT will be defined as clinically-significant toxicities 
which are at least possibly treatment-related and meet criteria listed in the sections 
below.
Toxicity will be graded by NCI CTCAE v.4.03 (https://ctep.cancer.gov/). Toxicity grade 
should be determined after standard, optimal supportive care treatments have been 
provided when appropriate. Optimal supportive care is defined as standard of care 
measures (such as electrolyte supplementation, the use of loperamide for diarrhea or 
antiemetics for nausea, or topical skin care for rash) that the treating physician deems 
appropriate and sustainable over multiple cycles of therapy.  Clinically significant toxicity 
is defined as requiring therapeutic intervention beyond standard supportive care and/or 
placing the patient at risk for other toxicity by the judgment of the treating investigator.   
After experiencing a DLT, a subject may resume treatment with dose reduction and/or 
optimal supportive care according to protocol guidance on dose modification and delay, 
once criteria for retreatment have been met and provided criteria for discontinuation 
have not been met.
6.2.3.1 Hematologic DLT
1. Grade 4 hematologic toxicity (limited to neutrophil, hemoglobin, and platelet counts)
1. Lymphopenia is excluded
2. Prolonged Grade 3 thrombocytopenia > 7 days, requiring dose modifications during 
Cycle 1, requiring platelet transfusion, or associated with clinically relevant bleeding 
(as defined by bleeding requiring hospitalization, transfusion, or an invasive procedure 
such as endoscopy) 


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3. Grade 3 neutropenia with fever (ANC < 1000 and T ≥ 38.5°C)
6.2.3.2 Non-hematologic DLT including immune-related AE (irAE)
1. Any treatment-related Grade ≥ 3 non-hematologic toxicities with exceptions listed 
below in Section 6.2.3.3
2. Treatment-related hepatotoxicity as evidenced by any of the following is considered a 
DLT:
a. AST and/or ALT > 5 x ULN (Grade 3) for patients with normal or grade 1 AST 
and/or ALT at baseline, if bilirubin ≤ 2 x ULN
b. AST and/or ALT > 8 x ULN for patients with grade 2 AST and/or ALT at 
baseline, if bilirubin ≤ 2 x ULN
c. T. bilirubin > 5 x ULN irrespective of baseline  
d. AST and/or ALT > 3 x ULN with concurrent increase in bilirubin > 2 x ULN 
without evidence for other cause (e.g. cholangitis, obstruction, viral hepatitis, 
tumor progression, etc.) (Hy’s Law)
e. Clinical deterioration manifested by drug-related hepatic decompensation not 
identified above (e.g., new onset Grade >2 ascites or encephalopathy 
attributed to treatment)
3. Any Grade ≥ 3 irAE during DLT window that does not downgrade to ≤ Grade 2 within 
7 days after onset of the event despite optimal medical management including 
systemic corticosteroids and/or hormone replacement and/or does not downgrade to 
≤ Grade 1 or baseline within 14 days, with exceptions of pneumonitis and eye toxicity 
as below:
a. Any Grade ≥ 2 pneumonitis irAE that does not improve to ≤ Grade 1 within 7 
days of initiation of maximal supportive care
b. Any Grade ≥ 2 ophthalmologic irAE such as uveitis causing eye pain or 
reduction of visual acuity that does not improve to Grade ≤ 1 severity within 14 
days of starting topical therapy or requires systemic treatment
4. Any Grade ≥ 2 toxicity despite optimal supportive care that requires sorafenib dose 
reduction during the DLT window (with exceptions for hand-foot skin reaction (HFSR) 
and hypertension as detailed below) or results in a treatment delay or discontinuation 
of either drug for > 7 days
5. Removal from study due to toxicity attributable to treatment during DLT window
6.2.3.3 DLT exceptions
The following AE will not be considered DLT:
1. Asymptomatic Grade 3 non-hepatic laboratory values, with the following 
specifications: 
a. Asymptomatic Grade 3 laboratory values are only considered DLT if 
determined treatment-related and clinically significant (e.g. requiring 
therapeutic intervention)
b. Liver function test abnormalities will be determined DLT according to DLT 
definitions in Section 6.2.3.


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2. Grade 3 hypertension that resolves to ≤140/90 within 7 days of adjustment or addition 
of oral blood pressure medication(s)
3. Grade 3 HFSR attributed to sorafenib
4. Grade 3 infusion reactions which resolve within 6 hours of supportive therapy are not 
considered DLT but require nivolumab discontinuation (see Section 6.9)
5. Grade 3 fatigue
6. Toxicity attributed to hepatocellular carcinoma (e.g. AE due to mass effect, 
obstruction, or pain caused by tumor growth or new lesions)
6.3
Part 2: Child Pugh B Expansion Cohort
After identification of MTD for sorafenib in combination with standard dose nivolumab in 
Part 1, approximately 12 additional patients with  liver function will be enrolled to the 
Child Pugh B Expansion Cohort on combination therapy with sorafenib at MTD from 
Part 1 (400 mg PO daily) and nivolumab 240 mg IV every 14 days both starting on 
C1D1.  
6.3.1 Dose Levels for Part 2 Child Pugh B Expansion Cohort
Drug
Dose
Part 2  (n =12 patients)
Sorafenib 
400 mg PO daily
Start on C1D1
Nivolumab
240 mg IV Q14 days*
Start on C1D1
*Option to switch nivolumab dosing to 480 mg IV Q28 days on or after C4D1 (see 
Section 6.5.1) with Study Chair approval in eligible patients.
 
6.4
Sorafenib
Sorafenib (BAY 43-9006) is an oral multi-kinase inhibitor targeting both tumor cells and 
the tumor vasculature. The chemical name for sorafenib tosylate is 4
Chloro-3-trifluoromethyl-phenyl)-ureido] -phenoxy}-pyridine-2
carboxylic acid methylamide-4-methylbenzene-sulfonate, and its molecular weight is 
637 daltons.  The structure of sorafenib is depicted in Figure 6.4-1.
Sorafenib (as Nexavar™) is approved for use in multiple countries including the United 
States (US), the European Union (EU), and many other countries for multiple oncology 
indications including renal cell carcinoma, HCC, and differentiated thyroid cancer. 
Figure 6.4-1: Structure of sorafenib (BAY 43-9006)


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6.4.1 Sorafenib dosage and administration
Subjects will be instructed on the proper administration of sorafenib.  Sorafenib tablets 
should be taken approximately 12 hours apart if assigned to BID dose level or 
approximately 24 hours apart if assigned to QD dose level, at approximately the same 
time(s) each day.  Sorafenib tablets should be taken without food, at least 1 hour before 
or at least 2 hours after a meal, and with up to 240 mL (approximately 1 cup or 8 oz.) of 
water.  Consumption of grapefruit and grapefruit juice should be avoided while receiving 
study drug.
6.4.1.1 Sorafenib missed doses
Missed doses of sorafenib should be taken as soon as the subject remembers. 
However, if it < 12 hours before next dose due, the missed dose should be skipped and 
the subject should take his/her next dose as scheduled. A double dose should not be 
administered to make up for missed individual doses.
6.4.2 Sorafenib drug supply and handling
For Part 1 of study, sorafenib tablets were obtained locally from commercial supplies 
with prescription from treating investigator, as a standard therapy for HCC.  For Part 2 
of study after amendment to restrict to Child Pugh B7-9 liver dysfunction, sorafenib 
tablets will be supplied by Bayer HealthCare.  The 200-mg tablet formulation contains 
sorafenib tosylate and the excipients croscarmellose sodium, microcrystalline cellulose, 
hypromellose, sodium lauryl sulfate, and magnesium stearate.  The tablets have a film 
coating comprised of hypromellose, polyethylene glycol, titanium dioxide, and red ferric 
oxide, which has no effect on the release rate of the active ingredient, sorafenib 
tosylate.  The tablets are un-debossed, salmon colored, weigh approximately 350 mg 
each, and are 10 mm (millimeter) round in shape. Sorafenib tablets do not need to be 
protected from light.  They are sufficiently stable with regard to light, oxidation, thermal 
stress, and hydrolytic degradation.  The formulation is presented as an immediate 
release (IR) dosage form, i.e., the active ingredient is completely dissolved under in 


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vitro test conditions within a short period of time. Additional information on prepared 
drug storage and administration are available in the sorafenib Investigator Brochure.
6.5
Nivolumab
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed 
death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. 
PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes. 
Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), 
results in the down-regulation of lymphocyte activation. Inhibition of the interaction 
between PD-1 and its ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens.  Nivolumab is a soluble 
protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 
identical light chains. Nivolumab is expressed in Chinese hamster ovary (CHO) cells 
and is produced using standard mammalian cell cultivation and chromatographic 
purification technologies. The clinical study product is a sterile solution for parenteral 
administration.
Nivolumab (as OPDIVO™) is approved for use in multiple countries including the United 
States (US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014) for 
multiple oncology indications. OPDIVO™ is not approved for use in HCC as of 1 June 
2017.
6.5.1 Nivolumab dosage and administration
Nivolumab 240 mg flat dose will be administered as an IV infusion over 30 minutes 
through a 0.2-micron to 1.2-micron pore size, low-protein binding (polyethersulfone 
membrane) in-line filter. It is not to be administered as an IV push or bolus injection. 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low 
as 0.35 mg/mL. During drug product preparation and handling, vigorous mixing or 
shaking is to be avoided. Nivolumab infusions are compatible with polyvinyl chloride 
(PVC) or polyolefin containers and infusion sets, and glass bottles. At the end of the 
infusion, the line should be flushed with a sufficient quantity of dextrose or normal 
saline.
For patients enrolled to Part 2, nivolumab may be switched to monthly infusion of 480 
mg Q28 days on or after C4D1 with Study Chair approval in patients with investigator-
assessed clinical benefit and without any uncontrolled or grade >2 immune-related 
toxicity, based upon established safety and efficacy of the monthly dosing regimen 
across tumor types.44  A note to file will be placed in the subject’s study chart to 
document Study Chair or designee approval. 


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6.5.1.1 Nivolumab schedule modifications and definition of delay
Subjects may be dosed no less than 12 days between nivolumab doses at 240 mg dose 
Q14 days, and no less than 24 days between nivolumab doses at 480 mg monthly 
dose. Subjects may be dosed up to 3 days (for Q14 day dosing) or 6 days (for Q28 day 
dosing) after the scheduled date if necessary. A dose given more than 3 or 6 days after 
the intended dose date will be considered a delay for each respective dosing interval. 
Subsequent dosing should be based on the actual date of administration of the previous 
dose of drug.
6.5.1.2 Nivolumab premedication
Premedication for nivolumab is not required unless a subject has experienced prior 
infusion reaction. See Section 6.8.2.2.  In subjects who have experienced a prior 
infusion reaction (< Grade 3) and who are determined eligible for retreatment, the 
following prophylactic premedications are recommended: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional 
nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 
mg of IV hydrocortisone or equivalent) may be used. 
6.5.2 Nivolumab drug supply and handling
Nivolumab was supplied by Bristol-Myers Squibb to each study site for Part 1 and 
beginning of Part 2 patient enrollment.  Starting after protocol amendment (version 4.0) 
requiring Child Pugh B7-9 liver dysfunction for eligibility to Part 2, nivolumab will be 
prescribed as a standard therapy option for patients with Child Pugh B liver dysfunction 
from commercial supplies and administered according to package insert instructions.  
Additional information on prepared drug storage and administration are available in the 
nivolumab Investigator Brochure and package insert.
6.6
Blinding
This is an open-label study.  No blinding will be performed.
6.7
Dose modifications and delays
Toxicity will be assessed according to NCI CTCAE v.4.03 (https://ctep.cancer.gov/). 
Dose modifications, interruptions, and treatment discontinuation for one or both study 
drugs will be determined according to the system showing the greatest degree of 
toxicity and according to the treating investigator’s assessment of cause of toxicity.  
Toxicity will be formally assessed at protocol-defined safety assessment time points well 
as by investigator review of weekly laboratory testing and, in the interim, by any 
unscheduled patient contact with the study team.  
General principles of dose modification and delay are listed below:

Optimal supportive care should be provided for all clinically relevant toxicities. 


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
See Section 6.8 for guidance on supportive care/rescue medications for specific 
toxicities.

For any toxicity (regardless of grade), despite optimal supportive care, that is felt 
by the treating investigator to represent a risk to the patient’s safety, additional 
dose reduction, treatment delay, and/or treatment discontinuation (beyond per 
protocol dose modifications) are permitted at the discretion of the treating 
investigator.

Scheduled safety and tumor assessments for all subjects should continue as per 
protocol even if dosing is delayed.
o
Safety assessments may be required more often if treatment delay for 
toxicity.

No dose re-escalation is permitted after dose reduction for toxicity.

If a treatment-related toxicity requiring treatment delay has not recovered to ≤ 
Grade 1 after treatment delay ≥ 6 weeks (42 days) for toxicity, treatment will be 
discontinued.
o
Exceptions allowing longer treatment delay up to approximately 12 weeks 
for recovery of treatment-related toxicity in subjects who have 
demonstrated previous treatment benefit (e.g. radiographic regression 
and/or clinical improvement such as reduced pain or tumor marker) are 
permitted with documented approval from Study Chair or designee.
6.7.1 Sorafenib dose modifications and delays for toxicity
Sorafenib doses will be delayed or reduced for clinically significant hematologic and 
non-hematologic toxicities that are determined to be related to sorafenib therapy 
according to the guidelines in the sections below, according to types of toxicity.
Sorafenib dose reduction will follow predefined dose levels in Table 6.2.1-1 in Section 
6.2.1. Subjects requiring dose reduction at current dose should be treated at next lower 
dose level until Dose Level -2.  If additional toxicity attributed to sorafenib occurs 
despite reduction to Dose Level -2, sorafenib will be discontinued.  
Table 6.7.1-1  Sorafenib dose modifications and delays for hematologic toxicity
Toxicity
ANC (x 109/L)
Hemoglobin (g/dL)
Platelets (x 109/L)
Sorafenib
Grade 1
 1.5
 LLN – 10.0
75
Treat on time
No change
Grade 2
 1.0  to < 1.5
 10.0 – 8.0
 50 to < 75
Treat on time
No change
Grade 3
 0.5  to < 1.0
 8.0 – 6.5
 25 to < 50
Treat on time
Reduce by one dose level
Grade 4
 0.5
Life-threatening 
consequence; urgent 
intervention indicated
25
Discontinue  from study


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Febrile 
Neutropenia
Delay sorafenib until toxicity 
has resolved to Grade 2 or 
less; when sorafenib is 
restarted, reduce by one dose 
level
Table 6.7.1-2: Sorafenib dose modifications and delays for non-hematologic toxicity 
Grade
Dose interruption
Dose modification
Grade 0-2* (except for 
HFSR or diarrhea)
Treat on time
No change
Grade 2 HFSR* or diarrhea
1st occurrence: Continue treatment with augmented HFSR 
skin care and/or antidiarrheal regimen
If no improvement within 7 days or ≥ 2nd occurrence: 
Interrupt until < Grade 2
Decrease one dose 
level
Grade 3
Interrupt until ≤ Grade 2
Decrease one dose 
level
Grade 4
Discontinue from study  
Discontinue from 
study
*See Table 6.8.1-1 and Sections 6.8.1.1 through 6.8.1.3 for HFSR, diarrhea, and HTN supportive care guidance.
6.7.2 Nivolumab dose modifications and delays
No dose reductions for nivolumab are permitted under this protocol.  Nivolumab 
administration will be delayed for the following: 
1. Any Grade ≥ 2 non-skin drug-related adverse event, with the following exceptions:
a. Grade 2 drug-related fatigue or asymptomatic laboratory abnormalities do not 
require a treatment delay.
2. Any Grade ≥ 3 skin drug-related adverse event.
3. Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions:
a. Grade 3 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis do not require a dose 
delay.
4. Dose delay for changes in AST or ALT as follows:
a. 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).
b. If a subject has baseline AST or ALT within the Grade 1 toxicity range, delay 
dosing for drug-related increase to ≥ 8x ULN.
c. If a subject has baseline AST or ALT within the Grade 2-3 toxicity range, 
delay dosing for two-fold drug-related increase in AST or ALT or for AST or 
ALT values 10x ULN (whichever is lower).
5. Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication.


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See Section 6.8.2 and Appendix 14.5 for guidance on management of toxicity attributed 
to nivolumab including initiation of immunosuppression for possible immune-related 
toxicity.  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 at least weekly until levels peak or begin to decline. Nivolumab dosing can be 
resumed when the following re-treatment criteria are met.   
6.7.2.1 Criteria to resume nivolumab dosing after delay for toxicity
Subjects may resume treatment with a study drug after treatment hold for toxicity if the 
drug-related AE(s) resolve to Grade ≤ 1 or baseline within 6 weeks (42 days), with the 
following exceptions:
1. Subjects may resume treatment in the presence of Grade 2 fatigue.
2. Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.
3. 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.
4. Subjects who require dose delays for drug-related elevations in AST, ALT, or total 
bilirubin may resume treatment when these values have returned to their baseline 
CTCAE Grade or normal, provided the criteria for unacceptable toxicity requiring 
permanent discontinuation are not met (Section 6.9).
5. Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed.
6. Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement are acceptable for resuming treatment.
7. A longer treatment delay up to approximately 12 weeks for recovery of treatment-
related toxicity in subjects may be permitted in subjects who have demonstrated 
previous treatment benefit (e.g. radiographic regression and/or clinical improvement 
such as reduced pain or tumor marker), with approval from Study Chair or designee.
If the criteria to resume treatment are met, the subject should restart treatment at the 
next scheduled time point per protocol.
6.7.3 Dose delays for reasons other than treatment-related toxicity
Dosing interruptions in either or both drugs are permitted in the case of unrelated 
medical or surgical events or logistical reasons not related to study therapy (e.g., 
elective surgery, unrelated medical events, administrative reasons, patient vacation or 
personal reasons, and/or holidays). Subjects should be placed back on study therapy 
within approximately 4 weeks (28 days, 1 cycle) of the scheduled interruption if within 
the first 6 months (6 cycles) of protocol therapy, or within approximately 8 weeks (56 
days, 2 cycles) if the delay occurs after the first 6 months (6 cycles) of protocol therapy.  
Scheduled safety and tumor assessments for all subjects should continue per protocol 


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even if dosing is delayed.
Longer delays may be permitted on a case-by-case basis if approved in writing by Study 
Chair. 
The reason for interruption should be documented in the patient's study record.  Before 
resuming treatment, patients must demonstrate adequate clinical and laboratory 
parameters to resume treatment without indication for dose modification or delay 
according to Section 6.8. 
6.8
Supportive care for toxicity
6.8.1 Sorafenib supportive care
Standard supportive care should be provided to all patients according to institutional 
practice for sorafenib therapy. The following tables provide guidance on supportive care 
to prevent and/or mitigate toxicity related to sorafenib, to be employed at discretion of 
treating investigator.  The treating investigator may employ different or additional 
interventions according to institutional practice and clinical judgment.
6.8.1.1 Hand-foot skin reaction (HFSR)
Table 6.8.1.1-1 Guidance on prevention and supportive care for HFSR on sorafenib
Toxicity Grade
Practical Prevention / Management Strategies for HFSR 
Grade 0 (Preventive 
strategies)
Maintain frequent contact with trial physician to ensure early diagnosis of 
HFSR.
Practical prevention strategies
o Subjects should avoid hot water, tight clothing, or activities that can cause 
friction on the skin.
o Moisturizing cream should be applied frequently.
Padded gloves and open shoes with padded soles should be worn to relieve 
pressure points.
Grade 1 
Any occurrence

Continue preventive strategies and in addition:
o Soak hands and feet in cool water.
o Apply petroleum jelly to moist skin.
Grade 2 Any occurrence or 
Grade 3 Any occurrence

Continue supportive/management measures and add analgesic(s) for pain.
6.8.1.2 Diarrhea
Diarrhea is a common side effect of sorafenib.  The preventive and supportive care 
strategies for diarrhea should be consistent with local standard of care on sorafenib 
(e.g., anti-diarrheals, optimized hydration status for diarrhea, dietary modifications).
6.8.1.3 Treatment-emergent hypertension
Hypertension is a known and potentially serious AE associated with sorafenib 
treatment. Subjects will undergo brief physical examinations, including blood pressure 
monitoring, approximately every other week per Section 7.1.  Blood pressure 
measurements that are out of the normal range must be reported to the treating 


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physician.  Blood pressure measurements considered out of the normal range are 
diastolic pressure > 90 mm Hg and/or systolic pressure > 140 mm Hg.
The choice of anti-hypertensive medication to be used in cases of treatment-emergent 
hypertension will be at the investigator's discretion and based on site-specific treatment 
guidelines as applicable.  All anti-hypertensive medications used for the management of 
treatment-emergent hypertension should be recorded in the subject’s records.
6.8.2 Nivolumab supportive care
6.8.2.1 Immune-related adverse events (irAE) on nivolumab
For potential immune-related adverse events (irAE) attributed to nivolumab, 
immunosuppressive therapy should be promptly initiated at discretion of treating 
investigator.  General guidelines for immunosuppressive therapy are provided below.  
Specific guidance for common irAE are provided in Appendix 14.6.  
Note that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased. For each disorder, attempts should be 
made to rule out other causes such as metastatic disease or bacterial or viral infection, 
which might require additional supportive care. These treatment guidelines are intended 
to be applied when the investigator determines the events to be related to nivolumab.
Suggested steroid regimens include:
1. Systemic steroids equivalent to prednisone 1-2 mg/kg/day for severe immune-
related toxicity requiring immunosuppressive therapy.
2. Oral prednisone 0.5 mg/kg/day or other equivalent steroid regimen for mild-
moderate immune-related toxicity requiring immunosuppressive therapy.
3. Topical corticosteroids for mild-moderate dermatitis.
4. Corticosteroid eye drops for ocular immune-related toxicity.
Supportive care on prolonged steroid therapy including blood pressure and blood 
glucose monitoring, gastroprotection with proton pump inhibition, and antibacterial 
prophylaxis (e.g. trimethoprim-sulfamethoxazole prophylactic doses) should be 
employed at discretion of treating investigator according to institutional standards.
Once symptoms resolve or return to Grade 1/baseline, initiate slow steroid taper over at 
least 4 weeks, with close monitoring. It may be necessary to perform conditional 
procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event.
6.8.2.2 Infusion reactions during nivolumab infusion
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 


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pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
Infusion reactions should be graded according to NCI CTCAE (version 4.03) guidelines.
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate:
1. For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; 
intervention not indicated)
o
Remain at bedside and monitor subject until recovery from symptoms.
o
For future infusions, the following prophylactic premedications are 
recommended: Diphenhydramine 50 mg (or equivalent) PO and 
acetaminophen 325 to 1000 mg PO at least 30 minutes before additional 
nivolumab administrations.
2. 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, bronchodilators, IV fluids]; 
prophylactic medications indicated for  24 hours).
o
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and 
acetaminophen 325 to 1000 mg PO; remain at bedside and monitor subject 
until resolution of symptoms. Corticosteroid or bronchodilator therapy may 
also be administered as appropriate. If the infusion is interrupted, then restart 
the infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate. The amount of study drug infused must be 
recorded on the electronic case report form (eCRF). Monitor subject closely. If 
symptoms recur, then no further nivolumab will be administered at that visit.
o
For future infusions, the following prophylactic premedications are 
recommended: Diphenhydramine 50 mg PO (or equivalent) and 
acetaminophen 325 to 1000 mg PO should be administered at least 30 
minutes before additional nivolumab administrations.  If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used.
3. For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae [e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; presser or ventilator support indicated).
o
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the subject as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg 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. 


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o
Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. 
o
Nivolumab will be permanently discontinued. 
o
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms.
4. In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids).
6.9
Unacceptable toxicity requiring treatment discontinuation
If one study drug is discontinued for unacceptable toxicity, treatment with the other 
agent will also be discontinued. 
6.9.1 Unacceptable toxicity from sorafenib
The decision to discontinue sorafenib for toxicity should follow local standards of care 
as guided by the FDA label for sorafenib in HCC.  Grade ≥ 4 AE attributed to sorafenib 
require discontinuation of sorafenib.   
6.9.2 Unacceptable toxicity related to nivolumab
Treatment with nivolumab should be permanently discontinued for the following 
toxicities attributed to nivolumab therapy:
1. Any Grade ≥ 2 ophthalmologic irAE such as uveitis causing eye pain or reduction of 
visual acuity that does not improve to Grade ≤ 1 severity within 14 days of starting 
topical therapy or requires systemic treatment
2. Any Grade ≥ 3 non-skin, drug-related adverse event that does not downgrade to 
Grade ≤ 2 within 7 days with optimal medical management including systemic 
corticosteroids and/or hormone replacement and/or does not downgrade to ≤ Grade 
1 or baseline within 14 days, with the following exceptions:
a. Any Grade ≥ 2 pneumonitis irAE that does not improve to ≤ Grade 1 within 7 
days of initiation of maximal supportive care requires discontinuation
b. Any event of Grade ≥ 3 drug-related uveitis, bronchospasm, pneumonia or 
pneumonitis, hypersensitivity reaction, or infusion reaction regardless of 
duration requires discontinuation
c. Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation
d. Asymptomatic/uncomplicated Grade 3 drug-related laboratory abnormalities 
do not require treatment discontinuation
3. Hepatotoxicity as evidenced by the following lab values requires discontinuation:


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a. AST or ALT > 8 x ULN for > 2 weeks, irrespective of baseline
b. AST or ALT > 15 x ULN irrespective of baseline or duration
c. Total bilirubin > 5 x ULN, irrespective of baseline or duration
4. Any Grade 4 drug-related adverse event or laboratory abnormality requires 
discontinuation, except for the following events which do not require discontinuation:
a. Grade 4 neutropenia < 7 days
b. Grade 4 lymphopenia or leukopenia
c. Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis including no evidence of 
pancreatitis on CT or MRI imaging
d. Isolated Grade 4 electrolyte imbalances or abnormalities that are not 
associated with clinical sequelae and are corrected with supplementation and 
appropriate management within 7 days of their onset
e. Grade 4 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation
5. Any dosing delay for treatment-related toxicity lasting > 6 weeks (42 days) with the 
following exceptions: 
a. Dosing delays up to 12 weeks to allow for prolonged steroid tapers to manage 
drug-related irAE are allowed with approval from Study Chair.  
6.10
Discontinuation of therapy
Protocol treatment will be discontinued if criteria for withdrawal are met (Section 5.2) or 
for the following reasons:
1. Unacceptable toxicity attributed to either study drug (see Section 6.9)
2. Radiographic disease progression by RECIST 1.1
o
Subjects meeting criteria for treatment beyond progression may continue 
treatment until progression confirmed on one follow up imaging study, 
according to Section 6.11 below
3. Complete response after 24 months of protocol treatment
Follow up for protocol endpoints including safety and survival will continue per Section 
7.1 after discontinuation. 
6.11
Treatment beyond progression
A subject may be granted an exception by Study Chair to continue on treatment with 
both sorafenib plus nivolumab until the next scheduled scan time point (approximately 8 
more weeks, or earlier if clinically indicated by signs or symptoms of progression) if 
scans within first 6 months of treatment demonstrate radiographic progression by 


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RECIST 1.1, in order to account for possible delayed responses on immunotherapy, 
provided the patient meets criteria below:
1.
No significant symptoms of progression
2.
No evidence of impending complication due to tumor progression (such as 
radiographic evidence of impending obstruction or mass effect, bleeding, 
or liver failure) by treating investigator and Study Chair assessment
3.
No other criteria for drug discontinuation are met (Section 6.10)
Subjects meeting criteria for treatment beyond progression will have note to file 
documenting appropriate to continue treatment post progression signed by Study Chair 
or designee and treating investigator signed in study chart.  Subjects will be informed by 
the treating Investigator and in the main consent form for the study, of the risks and 
benefits of continuing treatment beyond progression. Subjects will be informed the 
choice of continuing treatment is ultimately their decision. Treatment with both study 
drugs will continue according to schedule of procedures for originally assigned study 
cohort (Section 7.1).  If progression is confirmed at a follow up imaging time point, the 
subject will be discontinued from protocol therapy.  
6.12
Drug logistics and accountability
Nivolumab will be stored at the investigational sites in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the 
instructions given by the clinical supplies department of the Institution and will be 
inaccessible to unauthorized personnel.  Sorafenib will be prescribed and provided by 
local Pharmacy to patients according to standard practice.
6.12.1
Drug accountability
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form.  (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.)
6.12.2
Destruction and return of unused study drug
At the end of the study, unused supplies of nivolumab should be destroyed according to 
institutional policies. Destruction will be documented in the site Investigational 
Pharmacy drug accountability records according to institutional Standard Operating 
Procedures (SOP). The certificates of destruction should be sent to Bayer and BMS for 
sorafenib and nivolumab, respectively.


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6.13
Treatment compliance
An adequate record of receipt, distribution, and return of all study drugs (if applicable) 
must be kept in the form of a Drug Accountability Form according to site Investigational 
Pharmacy SOP. 
Subject compliance with protocol therapy includes willingness to comply with all aspects 
of the protocol, including safety and efficacy evaluations.  At the discretion of the 
principal investigator, a subject may be discontinued from the trial for non-compliance 
with follow-up visits, procedures, or study drug administration.
6.14
Concomitant therapy
All concomitant medications starting within 28 days of first dose and last dose of 
protocol therapy (including start/stop dates and indication) must be recorded in the 
subject’s source documentation.
6.14.1
Permitted concomitant therapies and medications
1. For patients with active HBV infection or prior HBV exposure, antiviral therapy and 
monitoring viral load should be administered per institutional standards.
2. Subjects may receive standard of care treatment for any underlying illness or 
infection.
3. Bisphosphonates or denosumab are permitted as supportive care for bone 
metastases and/or hypercalcemia at discretion of treating investigator.
4. Steroid and other immunosuppressive therapy is permitted for treatment of 
treatment-related irAE per Section 6.9.
5. Supportive care on steroid or immunosuppressive therapy such as proton pump 
inhibitor for gastroprotection or prophylactic antibacterial agents such as 
trimethoprim-sulfamethoxazole are permitted according to institutional practice.
6. Treatment with non-conventional therapies (e.g., herbs [with the exception of St. 
John’s Wart], acupuncture) and vitamin/mineral supplements is acceptable 
provided that, in the opinion of the investigator, such treatment will not interfere 
with the trial endpoints.
7. If AE of neutropenia, anemia, or thrombocytopenia, subjects may receive 
appropriate supportive care (e.g., transfusion, prophylactic antibiotics, antifungals 
and/or antivirals, hematopoietic growth factors).  This supportive care should not 
substitute a recommended dose modification.
8. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 
with sorafenib.  Systemic exposure to substrates of CYP2B6 and CYP2C8 is 
expected to increase when these are co-administered with sorafenib.


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6.14.2
Prohibited concomitant therapies and medications 
1.
Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than sorafenib and 
nivolumab
2.
Patients who require palliative radiation for worsening symptoms related to 
underlying malignancy must be removed from study
a. Requirement for radiation may be considered a clinical progression event 
depending on judgment of treating investigator and clinical context
3.
Concurrent use of another investigational drug or device therapy (i.e., outside of 
study treatment) during, or within 4 weeks of trial entry (signing of the informed 
consent form)
4.
Antiviral therapy for active HCV is not allowed during protocol therapy unless 
approved by the Study Chair due to potential for overlapping toxicity
5.
Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with 
heparins and heparinoids are prohibited 
a. Low dose aspirin (≤ 100 mg daily) is allowed
b. Prophylactic doses of heparin are allowed with written approval from Study 
Chair
c. Requirement for therapeutic anticoagulation requires removal from study
7. Procedures and variables
7.1
Schedule of procedures
The schedule of procedures including allowed time windows are provided in Tables 7.1-
1 and 7.1-2 for Part 1: Dose Escalation Cohort and Part 2: Child Pugh B Expansion 
Cohort.


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7.1.1 Schedule for Part 1: Dose Escalation Cohort
Study Event
Screening
Treatment Cycle
Safety Follow Up
Survival 
Follow Up
Time point
(Cycle (C) & Day (D) or 
days after last dose)
C1D1
C1D15
C2D1
C2D15
C3+D1
C3+D15
30 days after 
last dose 
(SFUV1)
100 days after 
last dose 
(SFVU2)
Every 3 
months after 
last dose
Window (days)
-28 to 1
-2 to 
+3
-2 to 
+3
-2 to 
+3
-2 to 
+3
-2 to +3
-2 to +3
±14
±28
±28
Administrative Procedures
Informed consent & 
registration on OnCore®
X
Eligibility determination
X
Prior & concomitant 
medication review
X
X
X
X
X
X
X
X
X
Demographics & medical 
history
X
HCC staging & liver 
disease history
X
Confirmation of 
appropriate antiviral 
therapy if HBV+
X
Enrollment
X
Subsequent Therapy
X
X
Survival status
X
Treatment
Sorafenib1
X
X
X
X
X
X
Nivolumab2
X
X
X
X
X
X
Clinical procedures and assessments
AE monitoring
X
X
X
X
X
X
X
X
X
Compliance with oral 
study drug
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
ECG
X


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Study Event
Screening
Treatment Cycle
Safety Follow Up
Survival 
Follow Up
Time point
(Cycle (C) & Day (D) or 
days after last dose)
C1D1
C1D15
C2D1
C2D15
C3+D1
C3+D15
30 days after 
last dose 
(SFUV1)
100 days after 
last dose 
(SFVU2)
Every 3 
months after 
last dose
Window (days)
-28 to 1
-2 to 
+3
-2 to 
+3
-2 to 
+3
-2 to 
+3
-2 to +3
-2 to +3
±14
±28
±28
Complete physical 
examination
X
X
X
X
X
X
X
X
ECOG
X
X
X
X
X
X
X
X
Liver function assessment 
(by Child Pugh Score)
X
X
X
X
X
X
X
X
Tumor imaging3 
X3
X3 (every 8 weeks ±14 
days)
X3
(±28 days)
Laboratory procedures performed at local laboratory
CBCD, CMP, PT/INR4
X  
X5
X
X
X
X
X
X
X
T3, fT4, TSH
X
X5
X
X
X
X
Urinalysis
X
X5
X
X
X
X
Pregnancy test in WOCBP 
only6
X
X
X
X
X
X
X
X
X
Viral hepatitis viral load & 
serologic testing7
X7
AFP10
X
X5
X
X
X 
X
Archival tumor sample8
X
X8
X8
PBMC sample9
X
X
X
X
X
X (C3D1 & 
C7D1 only)
X
Footnotes:
1.
Sorafenib dose and schedule (QD or BID) will be determined according to Section 6.2.1 and administered continuously.
2.
Nivolumab will be administered at flat dose of 240 mg IV over 30 minutes every 14 days (-2 to +3 days) on D1 and D15 each cycle. 
3.
Cross-sectional imaging with CT or MRI abdomen plus pelvis (including triphasic/multiphase liver) and CT chest with or without contrast is required at screening and every 8 
weeks ±14 days until end of treatment; at SFFUV1, imaging does not need to be repeated if performed within 28 days prior (±28 day window). Imaging may be performed more 
frequently if clinically indicated to evaluate for progression or toxicity.  RECIST 1.1 measurements should be performed by a radiologist or qualified investigator at each time point.
4.
Complete blood count and differential (CBCD), metabolic panel including liver and kidney function and electrolytes (see Section 7.3.6 for individual tests required), and PT/INR 
should be obtained as standard of care safety monitoring before every nivolumab infusion. 
5.
C1D1 blood tests and urinalysis do not need to be repeated if performed within 3 days before C1D1 during screening.
6.
Perform on women of childbearing potential only at screening within 28 days, 24 hours prior to each nivolumab infusion (including C1D1), and at safety follow up visits. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.
7.
Baseline hepatitis screening should be performed in all patients including HCV Ab, HBcAb total, HBsAg, and in patients positive for HBcAb, HDV Ab.  Prior serologic values 
collected within approximately 2 years may be used for screening if available. If HBcAb and/or HBsAg is positive, HBV DNA level by PCR should be monitored on treatment 
according to institutional standards (recommended is every 4 weeks according to treating investigator discretion) and patient should be treated with antiviral prophylaxis according 


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to institutional practice. HCV RNA PCR should be monitored on treatment according to institutional practice.  HBV DNA and HCV RNA should be checked and monitored in all 
cases of hepatotoxicity on treatment according to institutional standard practices.
8.
Archival tumor samples (FFPE block when available and/or at least 10 unstained slides of approximately 10 µm thickness plus at least 10 unstained slides of approximately 5 µm 
thickness plus a paired H&E slide) should be obtained from prior tumor sampling/diagnostic procedure(s) such as prior resection, core biopsy, or cytology/cell button when 
available.  FFPE block or slides should also be obtained from any subsequent tumor sampling which occurs during or after protocol therapy (such as repeat biopsy to confirm 
progression or palliative metastatectomy surgery). See Appendix 14.8.
9.
Blood samples will be obtained in all patients enrolled at UCSF for PBMC immune profiling at Screening, on Day 1 and 15 of Cycles 1 and 2, Day 1 of Cycles 3 and 7, then at 
SFUV1. See Appendix 14.8.
10.
AFP will be performed at screening, all cycles D1, at disease progression, SFUV1, and SFUV2.


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7.1.2 Schedule for Part 2: Child Pugh B Expansion Cohort
Study Event
Screening
Treatment Cycle
Safety Follow Up
Survival 
Follow Up
Time point
(Cycle (C) & Day (D) or 
days after last dose)
C1D1
C1D15
C2D1
C2D15
C3+D1
C3+D15
30 days after 
last dose 
(SFUV1)
100 days 
after last 
dose (SFVU2)
Every 3 
months after 
last dose
Window (days)
-28 to 1
-2 to 
+3
-2 to +3
-2 to 
+3
-2 to 
+3
-2 to +3
-2 to +3
±14
±28
±28
Administrative Procedures
Informed consent & 
registration on OnCore®
X
Eligibility determination
X
Prior and concomitant 
medication review
X
X
X
X
X
X
X
X
X
Demographics & medical 
history
X
HCC staging & liver 
disease history
X
Confirmation of 
appropriate antiviral 
therapy if HBV+
X
Enrollment
X
Subsequent Therapy
X
X
Survival status
X
Treatment
Sorafenib1
X
X 
X
X
X
X
Nivolumab2
X
X 
X
X
X
X2
Clinical procedures and assessments
AE monitoring
X
X
X
X
X
X
X
X
X
Compliance with oral 
study drug
X
X
X
X
X
X
ECG
X
Vital signs
X
X
X
X
X
X
X
X
X
Complete physical 
examination
X
X
X
X
X
X
X
X
ECOG
X
X
X
X
X
X
X
X
Liver function 
assessment (by Child 
Pugh Score)
X
X
X
X
X
X
X
X


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Study Event
Screening
Treatment Cycle
Safety Follow Up
Survival 
Follow Up
Time point
(Cycle (C) & Day (D) or 
days after last dose)
C1D1
C1D15
C2D1
C2D15
C3+D1
C3+D15
30 days after 
last dose 
(SFUV1)
100 days 
after last 
dose (SFVU2)
Every 3 
months after 
last dose
Window (days)
-28 to 1
-2 to 
+3
-2 to +3
-2 to 
+3
-2 to 
+3
-2 to +3
-2 to +3
±14
±28
±28
Tumor imaging3 
X3
X3 (every 8 weeks 
±14 days)
X3
(±28 days)
Laboratory procedures performed at local laboratory
CBCD, CMP, PT/INR4
X  
X5
X
X
X
X
X
X
X
T3, fT4, TSH
X
X5
X
X
X
X
Urinalysis
X
X5
X
X
X
X
Pregnancy test in 
WOCBP only6
X
X
X
X
X
X
X
X
X
Viral hepatitis viral load & 
serologic testing7
X7
AFP11
X
X5
X
X
X 
X
Archival tumor sample8
X
X8
X9
PBMC sample9
X
X5
X
X
X
X (C3D1 
and C7D1 
only)
X
Footnotes:
1.
Sorafenib dose and schedule will be MTD from Part 1: Dose Escalation cohort and will be administered continuously.  For patients enrolled to Part 2: Arm 1, sorafenib will start on 
C1D15.  For patients enrolled to Part 2: Arm 2, sorafenib will start on C1D1. 
2.
Nivolumab will be administered at flat dose of 240 mg IV over 30 minutes every 14 days (-2 to +3 days) on D1 and D15 each cycle starting on C1D1.  In Part 2 and with Study 
Chair approval, patients meeting criteria in Section 6.5  may switch to monthly dosing of nivolumab starting on or after C4D1 (-4 to +6 days) provided no uncontrolled or grade >2 
immune related toxicity.  A note to file must be included in study chart documenting Study Chair or designee approval. For patients who switch to monthly dosing on or after C4D1, 
the D15 visit and other assessments may be omitted if not clinically-indicated.
3.
Cross-sectional imaging with CT or MRI abdomen plus pelvis (including triphasic/multiphase liver) and CT chest with or without contrast is required at screening and every 8 
weeks ±14 days until end of treatment; ; at SFFUV1, imaging does not need to be repeated if performed within 28 days prior (±28 day window). Imaging may be performed more 
frequently if clinically indicated to evaluate for progression or toxicity.  RECIST 1.1 measurements should be performed by a radiologist or qualified investigator at each time point.
4.
Complete blood count and differential (CBCD), metabolic panel including liver and kidney function and electrolytes (see Section 7.3.6 for individual tests required), and PT/INR 
should be obtained as standard of care safety monitoring before every nivolumab infusion.
5.
C1D1 blood tests and urinalysis do not need to be repeated if performed within 3 days before C1D1 during screening.
6.
Perform on women of childbearing potential only at screening within 28 days, 24 hours prior to each nivolumab infusion (including C1D1), and at safety follow up visits. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.
7.
Baseline hepatitis screening should be performed in all patients including HCV Ab, HBcAb total, HBsAg, and, in patients positive for HBcAb, HDV Ab.  Prior serologic values 
collected within approximately 2 years may be used for screening if available.  If HBcAb and/or HBsAg is positive, HBV DNA level by PCR should be monitored on treatment 
according to institutional standards (recommended is every 4 weeks according to treating investigator discretion) and patient should be treated with antiviral prophylaxis according 
to institutional practice. HCV RNA PCR should be monitored on treatment according to institutional practice.  HBV DNA and HCV RNA should be checked and monitored in all 
cases of hepatotoxicity on treatment according to institutional standard practices.
8.
Archival tumor samples (FFPE block when available and/or at least 10 unstained slides of approximately 10 µm thickness and at least 10 unstained slides of approximately 5 µm 
thickness plus a paired H&E slide) should be obtained from prior tumor sampling/diagnostic procedure(s) such as prior resection, core biopsy, or cytology/cell button when 


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available.  FFPE block or slides should also be obtained from any subsequent tumor sampling which occurs during or after protocol therapy (such as repeat biopsy to confirm 
progression or palliative metastatectomy surgery). See Appendix 14.8.
9.
Blood samples will be obtained in UCSF patients only for PBMC immune profiling at Screening, on Day 1 and 15 of Cycles 1 and 2, Day 1 of Cycles 3 and 7, then at SFUV1. See 
Appendix 14.8.
10. Removed. 
11.
AFP will be performed at screening, all cycles D1, at disease progression, SFVU1, and SFVU2.


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7.2
Administrative procedures and data collection
7.2.1 Informed consent
The treating investigator must obtain documented consent from each potential subject 
prior to participating in a clinical trial.
7.2.1 Registration
All patients who consent will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  
7.2.1.1 Sub-site registration
The sub-site must notify the UCSF Clinical Research Coordinator (CRC) and Study 
Chair of patient consent(s) at sub-site within 3 business days of consent.  A study ID will 
be provided as confirmation of receipt which will enable registration on OnCore®.
7.2.2 Eligibility determination
All inclusion and exclusion criteria (see Section 5.1) will be reviewed and signed off on 
by the investigator or qualified designee at study site, and site study coordinator to 
ensure that the subject qualifies for the trial.  For patients in screening at sub-site, the 
UCSF Study Chair or designee must review and confirm eligibility to prior to enrollment 
(see Section 7.2.6.1).
7.2.3 Prior and concomitant medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
subject within 28 days before starting the trial.  Prior treatments for the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as 
a prior medication. 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial treatment until approximately 100 days after last dose of study drug at 
the Safety Follow Up Visits (SFUV1 and SFUV2).  All medications related to reportable 
SAEs should be recorded.
7.2.4 Demographics and medical history
Standard demographic information (e.g. age, gender, race/ethnicity) will be collected 
from medical records. Medical history findings (i.e. previous diagnoses, diseases or 
surgeries) meeting all criteria listed below will be collected:

Not pertaining to the study indication


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
Start before signing of the informed consent 

Considered relevant to the study.
Detailed instructions on the differentiation between medical history and adverse events 
can be found in Section 7.4.1.
7.2.5 HCC staging and disease history
The investigator or qualified designee will obtain prior and current details regarding 
disease status, including HCC stage at enrollment, stage at diagnosis, diagnostic 
test(s), and site(s) of disease.  Staging will be captured by both American Joint 
Committee on Cancer (AJCC) TNM staging (Appendix 14.4) and Barcelona Clinic Liver 
Cancer (BCLC) staging (Appendix 14.5). 
7.2.5.1 Prior treatments for HCC
The investigator or qualified designee will review all prior cancer treatments including 
surgery, ablative treatments, arterial therapies (such as transarterial chemoembolization 
(TACE) or transarterial radioembolization (TARE)), or radiation.  No prior systemic 
therapy for HCC is permitted by this protocol.
7.2.5.2 Liver disease history
The investigator or qualified designee will review liver disease history including risk 
factors for HCC (including viral hepatitis, alcohol use, non-alcoholic steatohepatitis or 
fatty liver disease diagnosis or risk factors, cirrhosis/fibrosis, autoimmune disease, any 
other prior liver injury).  History of and any new episodes of esophageal varices, ascites, 
or encephalopathy will be documented at baseline, during treatment, and until the 
SFUV.
7.2.5.3 Subsequent therapy
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment until approximately 100 days after last dose of 
protocol therapy at the SFUV1 and SFVU2.  Once new anti-cancer therapy has been 
initiated or if transition to palliative/end of life care such as Hospice enrollment occurs, 
the subject will transition to the Survival Follow-Up Phase.
7.2.6 Enrollment
Once screening is completed, eligibility documents and checklist for all patients will be 
reviewed by and confirmed by investigator and/or Study Chair, CRC, and lead or senior 
CRC following UCSF HDFCCC SOP.  Once eligibility is confirmed, approval to treat 
documentation indicating Cohort and dose level assignment as applicable will be 
provided to treating investigator and placed in study chart as confirmation of enrollment 
to proceed with protocol therapy.


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7.2.6.1 Sub-site enrollment
The sub-site coordinator will send by secure e-mail or fax de-identified HIPAA-compliant 
copies of all consent and screening source documents to UCSF study team for eligibility 
confirmation.  Once eligibility is confirmed by the Study Chair or designee, a document 
of approval to treat indicating Cohort and dose level assignment as applicable will be 
provided by secure e-mail by the UCSF CRC to the sub-site coordinator and treating 
investigator as confirmation of enrollment to proceed with protocol therapy.
7.3
Clinical procedures and assessments
7.3.1 Adverse event (AE) monitoring
The investigator or qualified designee will assess each subject to evaluate for potential 
new or worsening AEs as specified in the Schedule of Procedures (Section 7.1) and 
more frequently if clinically indicated.  Adverse experiences will be graded and recorded 
throughout the study according to NCI CTCAE Version 4.03.  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. Please refer to Section 7.4 for further information on 
AE assessment and reporting.
7.3.2 Compliance with oral study drug
Patients will be provided a sorafenib drug diary to record time and dose of sorafenib 
administration each cycle (Appendix 14.7).  
7.3.3 Vital signs
The investigator or qualified designee will obtain vital signs at the time points specified 
in the Schedule of Procedures (Section 7.1).   Vital signs should include temperature, 
pulse, respiratory rate, oxygen saturation (pulse oximetry), weight and blood pressure.  
Height will be measured at screening only.
7.3.4 Complete physical examination
The investigator or qualified designee will perform a complete physical examination 
according to institutional practice for the management and monitoring of patients with 
liver cancers. Complete physical exams are required at screening, C1D1, C1D15, 
C2D1, C2D15, C3D1, and every D1 after Cycle 3. They are also required at Safety 
Follow-up 30 days and 100 days after lase dose (SFUV1 and SFVU2). Clinically 
significant abnormal findings during Screening should be recorded as medical history.  
7.3.5 Eastern Cooperative Oncology Group (ECOG) performance scale
The investigator or qualified designee will assess ECOG status (see Appendix 14.2) at 
the time points specified in the Schedule of Procedures (Section 7.1). 


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7.3.6 Liver function assessment
The investigator or qualified designee will assess liver function by Child Pugh score 
(see Appendix 14.3) at the time points specified in the Schedule of Procedures (Section 
7.1). 
7.3.7 Tumor imaging and response assessment
Cross-sectional imaging with CT (preferred) or MRI abdomen plus pelvis and CT chest 
with/without or without contrast is required at screening then every 8 weeks (±14 days) 
until end of treatment.  Multiphase/triphasic liver imaging should be included as 
appropriate.  Additional baseline imaging such as PET scan, bone scan, or MRI brain 
are only required if clinically indicated by symptoms and/or to assess known bone 
metastases or other sites of known metastatic disease.  All baseline evaluations will be 
performed as close as possible to the beginning of treatment and ≤ approximately 28 
days before C1D1. The same imaging modality/modalities should be used if possible 
throughout study unless there is a clinical indication to use a different modality (i.e. 
based upon Radiology recommendation to better assess a target lesion, an event of 
new contrast allergy, etc.).  RECIST 1.1 measurements will be performed by a 
radiologist or qualified investigator.
7.3.8 Laboratory procedures/assessments
The specific laboratory procedures/assessments to be performed in this trial are 
provided in Table 7.3.6-1 below, at time points listed in Schedule of Procedures 
(Section 7.1).  Scheduled laboratory procedures and assessments should be performed 
at the study site of treatment.
Table 7.3.6-1 Laboratory procedures and assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
Urine β-human chorionic gonadotropin†
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
PT (INR)
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Thyroid stimulating hormone (TSH)
Red Blood Cell 
Count
Creatinine
Microscopic exam 
(If abnormal) 
Total triiodothyronine (T3)
Absolute 
Neutrophil Count
Carbon dioxide (C02 or 
bicarbonate)
Urine pregnancy 
test †
Free thyroxine (T4)
Calcium
AFP tumor marker 
Chloride
Hepatitis B or C viral load and serology (including 
Hepatitis D) as clinically indicated (see Tables 
7.1-1 and 7.1-2 footnote 7)
Glucose
Phosphorus
Blood samples for correlative studies*


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Table 7.3.6-1 Laboratory procedures and assessments
Hematology
Chemistry
Urinalysis
Other
Potassium
Archival tumor sample accessioning*
Sodium
Magnesium
Total bilirubin
Direct bilirubin
Blood urea nitrogen 
(BUN)
† Perform urine pregnancy test on WOCBP only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test is required. 
*See Section 7.3.7 and Appendix 14.8 for further information on research sample collection. 
7.3.9 Tumor and blood sample collection and banking for correlative 
analyses
Archival tumor samples for all patients and peripheral blood samples for patients 
enrolled at UCSF will be obtained and stored for planned future exploratory and 
correlative analyses (see Sections 1.6 and 2.3) which will be performed in batch after 
completion of study and pending funding.   
7.3.9.1 Archival tumor sample collection
In all patients, left-over diagnostic tumor block and/or slides from any tumor sampling 
procedure(s) (e.g. biopsy, fine needle aspiration, and/or resection specimens) 
performed prior to enrollment, during study treatment, and/or after treatment 
discontinuation due to progression will be obtained to determine tumor PD-L1 
expression status, to characterize tumor immune infiltrates/T cell subsets, and (optional 
for UCSF patients only) to bank for future correlative analyses as part of the UCSF 
Hepatobiliary Tissue Bank and Registry (CC#124512) as a companion protocol to this 
study.  
Formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks will be accessioned 
whenever available.  In addition to blocks or if a block is not available, at least 10 
unstained slides (prefer 10 µm) plus 1 H&E slide from a tumor tissue block may be 
accessioned.  Corresponding pathology reports from initial diagnosis and/or subsequent 
tumor sampling will be obtained.  Specimens will be obtained from the Pathology 
Department for banking as soon as possible after consent and/or occurrence of post-
enrollment tumor sampling and stored in the UCSF Biorepository.  Correlative analyses 
using archival tissue samples will be performed in batch at completion of study and 
pending funding.  See Appendix 14.8 for correlative specimen procurement and 
handling instructions.
7.3.9.2 Peripheral blood mononuclear cell (PBMC) collection
In all patients enrolled at UCSF, approximately 60 mL of whole blood will be collected 
into green top tubes (e.g. six 10 cc tubes filled approximately to 10 mL) at the time 


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points listed in the Schedule of Procedures (Section 7.1).  The tubes will be delivered 
directly to the UCSF Cancer Immunotherapy Lab for PBMC isolation then freezing for 
future analysis in batch at end of study and pending funding.  See Appendix 14.8 for 
correlative specimen procurement and handling instructions.
 
7.3.9.3 Optional specimen banking
For patients enrolled at UCSF who consent to optional specimen banking as part of 
companion protocol CC#124512, all left-over blood and/or tumor samples will be 
banked under the UCSF Hepatobiliary Tissue Bank and Registry protocol. See 
Appendix 14.8 for correlative specimen procurement and handling instructions.
7.3.10
Electrocardiogram
A baseline electrocardiogram (ECG) should be obtained during screening at the study 
site per Section 7.1 in all patients.
7.4
Assessing and reporting adverse events (AE)
All subjects who receive at least one dose of study treatment will be evaluable for safety 
from the time of informed consent until 100 days after last dose of protocol therapy or 
the start of a new anti-cancer therapy after study discontinuation, whichever is earlier. 
Any serious adverse events (SAE) occurring later than 100 days after the last dose of 
protocol therapy or after start of new anti-cancer therapy also should be recorded and 
reported if assessed as at least possibly related to study drug or a protocol-specified 
procedure.  All observations pertinent to the safety of the study treatment will be 
recorded and included in the final report.
Safety variables include the following: AEs, laboratory changes (complete blood counts, 
electrolytes, chemistry, and coagulation) if determined clinically significant by treating 
investigator and/or Study Chair, changes in vital signs (blood pressure, heart rate, 
respiratory rate, and temperature), and in some instances, changes in imaging findings 
if indicative of a safety event. 
All AEs whether considered drug-related or not, will be recorded in case report forms in 
the OnCore® CTMS including Grade, attribution to one or both study drugs, other 
attribution(s), start/stop dates, and whether serious and/or unexpected.  For all events, 
the relationship to treatment and the intensity of the event will be determined by the 
investigator. This trial will use the NCI CTCAE v.4.03 (https://ctep.cancer.gov/) for 
assessment of toxicity and SAE reporting with regard to toxicity grade. Investigators 
should refer to the Safety Information section of the current IB for sorafenib and 
nivolumab, including the DCSI (development core safety information), for the expected 
side effects of the study drugs.  


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7.4.1 AE and SAE definitions
7.4.1.1 Definition of adverse event (AE)
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation participant 
administered study drug and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (such as 
an abnormal laboratory finding determined to be of clinical significance by the treating 
investigator or Study Chair), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used 
to assess all adverse events (AE). The casual relationship can be one of the following:

Related: There is a reasonable causal relationship between study drug 
administration and the AE.

Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints). Conditions that started before 
signing of informed consent and for which symptoms or treatment are present after 
signing of informed consent, at unchanged intensity, are recorded as medical history 
(e.g. allergic rhinitis). Conditions that started or deteriorated after signing of informed 
consent will be documented as AEs.
7.4.1.2 Definition of serious adverse event (SAE)
An SAE is classified as any AE that, at any dose, meets any of the following criteria:
1. Results in death.
2. Is life-threatening.
a. The term ‘life-threatening’ in the definition refers to an event in which the 
patient was at risk of death at the time of the event, it does not refer to an 
event which hypothetically might have caused death if it were more 
severe.
3. Requires inpatient hospitalization or prolongation of existing hospitalization.
a. A hospitalization or prolongation of hospitalization will not be regarded as 
an SAE if at least one of the following exceptions is met:
b. The admission results in a hospital stay of less than 12 hours.
c. The admission is pre-planned. (i.e., elective or scheduled surgery 


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arranged prior to the start of the study)
d. The admission is not associated with an AE. (e.g., social hospitalization 
for purposes of respite care).
e. However, it should be noted that invasive treatment during any 
hospitalization may fulfill the criterion of ‘medically important’ and as such 
may be reportable as an SAE dependent on clinical judgment.  In addition, 
where local regulatory authorities specifically require a more stringent 
definition, the local regulation takes precedence.
4. Results in persistent or significant disability or incapacity.
a. Disability means a substantial disruption of a person’s ability to conduct 
normal life’s functions.
5. Is a congenital anomaly or birth defect.
6. Grade 3 or 4 hypersensitivity or infusion reaction to nivolumab.
7. Is another medically important serious event as judged by the investigator 
(defined as a medical event(s) that may not be immediately life-threatening or 
result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the 
definition above.) Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization.) 
8. Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE. 
9. Although pregnancy, overdose, potential drug-induced liver injury (DILI), and 
cancer are not always serious by regulatory definition, these events must be 
handled as SAEs.
10.Any component of a study endpoint that is considered related to study therapy 
should be reported as an SAE (e.g., death is an endpoint, if death occurred due 
to anaphylaxis, anaphylaxis must be reported).
7.4.2 Reporting of SAE to Bayer
All SAEs occurring from date of informed consent until 100 days after last dose of 
protocol therapy regardless of attribution should be reported to Bayer within 24 business 
hours/1 business day using a MedWatch Form 3500A (which can be accessed at 
http://www.accessdata.fda.gov/scripts/medwatch/ and in Appendix 14.9), using one of 
the mechanisms below.  Any serious adverse events (SAE) occurring later than 100 


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days after the last dose of protocol therapy also should be recorded and reported if 
assessed as at least possibly related to study drug or a protocol-specified procedure.
Bayer SAE Electronic Mailbox: 
@bayer.com 
Bayer SAE Facsimile:  
 
Bayer USPS Address:
Global Pharmacovigilance - USA 
Bayer Corporation
Reports for all Bayer products can also be phoned in via the Clinical 
Communications Dept.: 
Bayer SAE Phone:
 
 (Medical Communications)
7.4.3 Reporting of SAE to BMS for protocol versions 1.0-3.0
For patients enrolled to Part 1 and Part 2 under protocol versions 1.0-3.0, all SAEs 
occurring from date of informed consent until 100 days after last dose of protocol 
therapy regardless of attribution should be reported to BMS within 24 business hours/1 
business day using a MedWatch Form 3500A (which can be accessed at 
http://www.accessdata.fda.gov/scripts/medwatch/ and in Appendix 14.9), using one of 
the mechanisms below.  Any serious adverse events (SAE) occurring later than 100 
days after the last dose of protocol therapy also should be recorded and reported if 
assessed as at least possibly related to study drug or a protocol-specified procedure.
BMS SAE Email Address:  
@BMS.com
BMS SAE Facsimile Number:  
Starting with protocol version 4.0 for patients enrolled to Part 2, nivolumab will be 
sourced as a standard of care therapy for advanced HCC in setting of Child Pugh B liver 
dysfunction and will not be provided by BMS. SAE reporting to BMS is not required for 
patients receiving treatment under protocol version 4.0 or later versions.
7.4.3.1 SAE Reconciliation Reports
The Study Chair or designee at UCSF will reconcile the clinical database SAE cases at 
all study sites (case level only) transmitted to BMS Global Pharmacovigilance 
) using the reporting form in Appendix 14.10. Frequency of 
reconciliation should be every 3 months and prior to the database lock or final data 
summary, or until activation of protocol version 4.0. BMS GPV&E will email, upon 
request from the Investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to 
 The data elements 
listed on the GPV&E reconciliation report will be used for case identification purposes. If 
the Investigator determines a case was not transmitted to BMS GPV&E, the case 
should be sent immediately to BMS.


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7.4.4 SAE follow up reports
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
business hours/1 business day to both Bayer (for patients enrolled to both Part 1 and 2) 
and BMS (for patients enrolled prior to protocol version 4.0 and not required after 
activation of protocol version 4.0) using the same procedures used for transmitting the 
initial SAE report.  All SAEs should be followed to resolution or stabilization. 
7.4.5 IND safety reporting
UCSF will report to the FDA all IND reportable events occurring in patients enrolled on 
this study (at UCSF or sub-site) using FDA Medwatch Form 3500A (which can be 
accessed at http://www.accessdata.fda.gov/scripts/medwatch/ and in Appendix 14.9).  
Reportable events must meet the definition in Federal Regulations (21 CFR §312.32): 
1. Suspected adverse reaction (defined as a reasonable possibility that the 
investigational agent caused the adverse event)  
2. Unexpected (not listed in the investigator brochure or package insert(s), or is not 
listed at the specificity or severity that has been observed)
3. Serious (as defined in Section 7.4.1.2)
If the adverse event does not meet all three of the definitions, it should not be submitted 
as an expedited IND safety report.  The timeline for submitting an IND safety report to 
FDA is no later than 15 calendar days after the Investigator determines that the 
suspected adverse reaction qualifies for reporting (21 CFR 312.32(c)(1)).  Any 
unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA 
no later than 7 calendar days after the Investigator’s initial receipt of the information (21 
CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety 
report will be submitted to FDA as a Follow-up IND Safety Report without delay, as 
soon as the information is available (21 CFR 312.32(d)(2)). 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as 
required by FDA. 
The Study Chair or designee will cross reference this submission according to local 
regulations to the Bayer and/or BMS Investigational Compound Number (IND) at the 
time of submission, based upon investigator attribution of causality.  Additionally, Study 
Chair or designee will submit a copy of these reports to Bayer and BMS at the time of 
submission to FDA.
7.4.6 Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) for each drug. Overview listings of frequent events that have 
occurred so far in the clinical development are shown in the current IBs.  If relevant new 


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safety information is identified, the information will be integrated into an update of the 
corresponding IB and distributed to any participating site(s).
The expectedness of AEs and SAEs will be determined locally by the treating 
investigator and Study Chair or designee.  For reportable SAE, expectedness will also 
be assessed by Bayer and BMS according to the applicable reference document and 
according to all local regulations.
7.4.7
Pregnancies
The investigator must report to Bayer and BMS any pregnancy occurring in a study 
subject, or in his partner, during the subject’s participation in this study.  The report 
should be submitted within the same timelines as an SAE, although a pregnancy per se 
is not considered an SAE.  
For a study subject, the outcome of the pregnancy should be followed up carefully, and 
any abnormal outcome of the mother or the child should be reported.
For the pregnancy of a study subject’s partner, all efforts should be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For any reports of pregnancy occurring in study subject or WOCBP partner, a 
Medwatch form (Appendix 14.9) should be used for reporting as an SAE.
8. Statistical methods and determination of sample size
8.1
Analysis sets
8.1.1 DLT population (Part 1)
Subjects must receive 2 doses of nivolumab and at least 75% of sorafenib doses within 
28 days (1 cycle), or experience a qualifying DLT event (Section 6.2.3), to be evaluable 
for DLT.  Patients enrolled to Part 1 who are determined ineligible after enrollment 
and/or who are not evaluable for the endpoint of DLT will be replaced (see Section 
5.2.2). 
8.1.2 Safety population (Parts 1 and 2)
The safety population will include all enrolled patients who receive at least one dose 
each of sorafenib and nivolumab and have the potential to complete 1 cycle (28 days) of 
safety assessments.  All patients will be evaluable for toxicity and safety assessment 
from the time of their first treatment with the investigational combination.  Patients who 
are determined ineligible after enrollment or who are not evaluable for safety (e.g. due 
to withdrawal of consent or discontinuation due to complications of HCC or underlying 
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toxicity before completing 1 cycle) will not be included in safety analyses (see Section 
5.2.2).
8.1.3 Efficacy population (Parts 1 and 2) 
The evaluable population for the secondary efficacy endpoint of ORR  will include all 
patients have received at least one complete cycle of therapy (4 weeks) and have had 
restaging imaging for response assessment (Section 7.3.5) or been removed for clinical 
progression.  Imaging to confirm progression should be obtained if possible. Patients 
who are determined ineligible after enrollment or who do not complete at least 1 cycle of 
therapy (4 weeks) and who do not have a qualifying progression event (radiographic or 
clinical) (e.g. due to withdrawal of consent or discontinuation due to complications of 
HCC or underlying liver disease assessed as not related to tumor progression and not 
treatment-related toxicity) will not be included in efficacy analyses (see Section 5.2.2).
8.2 Statistical and analytical plans
8.2.1 Primary endpoints
Primary and secondary endpoints will be measured in evaluable patients as defined in 
Section 8.1.  
8.2.1.1 Part 1: Dose Escalation Cohort primary endpoint
For Part 1, the primary endpoint of MTD will be determined according to Section 6.2.3.
8.2.1.2 Part 2: Child Pugh B Expansion Cohort primary endpoint
For Part 2: Child Pugh B Expansion Cohort, the primary endpoint is safety of the 
combination in patients with Child Pugh B liver function as measured by rate of grade 
≥3 AE (CTCAE v. 4.03) assessed as at least possibly related to sorafenib, nivolumab, or 
the combination of therapies. Adverse events will be graded using NCI CTCAE v.4.03 
(https://ctep.cancer.gov/). Relationship to sorafenib, nivolumab, or combination will be 
adjudicated by the treating investigator and/or Study Chair. 
This is a pilot study. For Part 2, an acceptable rate of grade ≥3 treatment-related AE 
would be ≤ 50% based upon rate of treatment-related grade ≥3 AE of 24.5% of Child 
Pugh B7-8 HCC patients treated with nivolumab in the CheckMate 040 Child Pugh B 
cohort,38 and 28% of Child Pugh B7-9 HCC patients treated with nivolumab in a 
retrospective institutional cohort,39  along with rates of grade 3-4 treatment-related AE of 
30-36% in Child Pugh B7-9 HCC in the GIDEON registry.40 
With an expected sample size of 12 patients with Child Pugh B7-9 HCC treated in Part 
2, the 95% confidence interval (CI) for determining the rate of grade ≥3 treatment-
related AE if the actual rate is 50% will be (0.22, 0.78).  If the actual rates are 30%, 40% 
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If the Child Pugh B Expansion Cohort end of enrollment date of 30 April 2022 is reached 
before completion of enrollment of n=12, rates of grade ≥3 treatment-related AE will be 
described along with 95% CI according to the sample size accrued at time of 
discontinuation (Table 8.2.1-1).
Table 8.2.1-1. Sample Size of Child Pugh B Expansion Cohort for Estimating Rate of Grade ≥3 TRAE. 
Sample size in Child Pugh B 
Expansion Cohort
Actual rate of Grade ≥3 TRAE
95% CI
30%
0.0, 0.71
40%
0.0, 0.71
50%
0.10, 0.90
6
60%
0.30, 1.0
30%
0.0, 0.55
40%
0.0, 0.71
50%
0.15, 0.85
8
60%
0.29, 0.96
30%
0.02, 0.58
40%
0.10, 0.71
50%
0.19, 0.81
10
60%
0.30, 0.90
30%
0.07, 0.60
40%
0.14, 0.70
50%
0.22, 0.78
12
60%
0.30, 0.86
8.2.2 Secondary endpoints 
For secondary endpoints, due to the small sample size in this pilot study, descriptive 
statistics with mean and 95% confidence intervals will be used.  For continuous 
variables, descriptive statistics will include the number of non-missing values, mean, 
standard deviation, median, min and maximum. For categorical variables, descriptive 
statistics will include counts and percentages per category. For comparison between 
subgroups, ANOVA and t-tests will be used when appropriate to determine the 
association of the efficacy endpoints and specific biomarkers.  


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8.2.2.1 Safety and tolerability
Safety events will be classified using NCI CTCAE v.4.03 (https://ctep.cancer.gov/).
Overall rates of AE and SAE will be summarized based on frequency and proportion of 
total subjects, by system organ class, preferred term, Grade, and investigator-assessed 
relationship to sorafenib, nivolumab, or the combination.  Dose reductions, dose delays, 
and discontinuations for toxicity will be summarized. 
8.2.2.2 Rate of irAE for combination overall and in Child Pugh B patients 
Safety events assessed by treating investigator and/or Study Chair as being at least 
possibly Immune-related on nivolumab (irAE) will be summarized based on frequency 
and proportion of total subjects, by system organ class and preferred term as for overall 
safety.  Rate of irAE in Child Pugh B patients in Part 2 will also be summarized.
8.2.2.3 ORR by RECIST 1.1 for overall study and in Parts 1 and 2 
individually
ORR is a key secondary endpoint and will be based on RECIST 1.15 as assessed by 
local radiographic review.  ORR will be analyzed for all efficacy-evaluable patients 
(Parts 1 and 2 combined) as well as for Part 1 and Part 2 individually. ORR defined as 
the proportion of subjects with RECIST 1.1-measurable disease at study entry (which is 
required for eligibility) who have a CR or partial response (PR) using RECIST 1.1 at any 
time during the main study.  Subjects with measurable disease at study entry who have 
unknown or missing response information will be treated as non-responders.  
The ORR of sorafenib was approximately 2% in SHARP trial,2 and the ORR of 
nivolumab as monotherapy was 10.2% in Child Pugh B7-8 patients treated with 
nivolumab in the Child Pugh B cohort of CheckMate 040.38 The ORR of nivolumab in 
Child Pugh A patients treated with nivolumab as 1st line therapy in CheckMate 459 was 
15%.45  Thus, an ORR of at least 15% for the combination of sorafenib plus nivolumab 
in this study would be an encouraging signal of efficacy, if accompanied by acceptable 
safety in Child Pugh B patients in Part 2 as defined above, and would warrant 
consideration of a larger study. 
For the overall study population, a sample size of 24 evaluable patients from Parts 1 
and 2 combined T will have 83% power with 1-sided alpha of 5% to determine true ORR 
>15%, using Chi-square tests with 1-sided alpha of 5%. 
8.2.2.4 Duration of response (DOR), PFS, and OS for Child Pugh B 
Expansion Cohort and overall study population
In subjects who achieve PR or CR, DOR is defined as the time from first documented 
evidence of CR or PR until the first documented sign of disease progression or death.   
For all patients, PFS will be calculated in months from date of first dose of protocol 
therapy to date of first documented radiographic and/or clinical disease progression or 


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death from any cause.  For patients discontinued from study for other reasons than 
progression or death (see Section 5.2), PFS will be censored at the date last known to 
be progression-free.  OS is defined as the time from the date of first dose of protocol 
therapy to the date of death due to any cause. Censoring will be performed using the 
date of last known contact for those who are alive at the time of analysis.
Median DOR, median PFS and OS will be summarized overall and according to 
treatment group. Kaplan-Meier medians and quartiles may be provided if data warrant.  
If data warrant, Kaplan-Meier quartile estimates along with the 95% CI will be 
calculated.  Descriptive summaries including swim lane plots may also be generated 
depending on results.
8.2.3 Exploratory endpoints
For exploratory endpoints, due to the small sample size in the study, descriptive 
statistics with mean and 95% confidence intervals will be used.  Depending on funding 
availability, we plan to explore immunologic and genomic biomarkers (including PBMC 
T cell subsets and TCR frequency and diversity, tumor immune subset composition and 
immune infiltrates) for relationships to clinical features including etiology of liver disease, 
baseline liver function, and to the primary and secondary efficacy endpoints. No type I 
error will be adjusted for multiple endpoints. For continuous variables, descriptive 
statistics will include the number of non-missing values, mean, standard deviation, 
median, min and maximum. For categorical variables, descriptive statistics will include 
counts and percentages per category. For comparison between subgroups, ANOVA 
and t-tests will be used when appropriate to determine the association of the efficacy 
endpoints and the specific biomarkers. For association between biomarkers, Spearman 
correlations will be calculated to determine the significance of the association between 
the biomarkers of interest.  A selection of planned analyses is described further below.
8.2.3.1 PBMC immune cell subset frequencies and relationship to treatment 
and clinical outcomes
Serial blood samples for PBMC analyses will be collected at time points in Section 7.1, 
Schedule of procedures.  Immune cell subsets will be measured using flow cytometry as 
has been previously described, or similar updated methods.29,30  PBMC analyses for all 
patients will be performed in the UCSF CIL.
Baseline levels of individual PBMC T cell and other immune cell subset components as 
well as change in levels on combination treatment will be explored for relationship with 
ORR, baseline liver function, as well as secondary efficacy endpoints (including PFS, 
DOR, OS) to determine if there is an association using Fisher’s Exact tests.  


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8.2.3.2 PBMC T cell receptor (TCR) clonotype frequency and diversity and 
relationship to treatment and clinical outcomes 
If funds are available, the frequency of individual TCR clonotypes and the diversity of 
overall TCR clonotype repertoire from PBMC samples will be measured by next-
generation sequencing as has been previously described or by a similar, updated 
methodology.31  PBMC analyses for patients enrolled at UCSF will be performed in 
UCSF CIL.
The frequency of TCR clonotypes with identical sequences31 will be calculated by 
dividing the number of identical sequence reads by the total number of sequencing 
reads for that sample.  TCR repertoire diversity will be calculated as the number of 
unique clonotypes comprising the top 25% of cumulative reads sorted by abundance.31  
Baseline frequency and diversity as well as changes on combination treatment will be 
explored for relationship with ORR, baseline liver function, as well as secondary efficacy 
endpoints using Fisher’s Exact tests. 
PBMC TCR clonotype diversity/frequency will also be described at baseline and after 
starting combination therapy in Part 2 to characterize the time course of these effects 
and to better understand the relative impact of each study drug.
8.2.3.3 Tumor immune infiltrates, T cell subsets, and TCR profiling
The presence and composition of tumor immune infiltrates including T cell subsets in 
pretreatment archival tumor sample will be explored for relationship with ORR, baseline 
liver function, as well as secondary efficacy endpoints (including PFS, DOR, OS, AFP 
response) and with tumor PD-L1 status by IHC to determine if there is a relationship 
using Fisher’s Exact tests.  Descriptive comparisons between primary and metastatic 
site samples and according to tumor location (e.g. liver vs. non-liver) or etiology (e.g. 
viral vs. nonviral), will be performed between subsets in the overall study depending on 
sample availability.  TCR frequency and diversity may be analyzed depending on 
sample adequacy.
 
Any leftover archival material from any other tumor samples obtained on treatment or 
post-treatment for diagnostic purposes (e.g. if patient is determined to require palliative 
resection or need a biopsy to confirm progression) may be accessioned and analyzed 
for immune infiltration, T cell subsets, and TCR profile depending on quantity of 
evaluable tumor tissue available.
Tumor tissue immune cell profiling and TCR analyses will be performed in UCSF CIL 
depending on funding adequacy.
8.2.3.4 Tumor and immune cell PD-L1 expression
Tumor and immune cell PD-L1 expression will be tested in batch after completion of 
enrollment. The proportion of subjects with archival tumor samples positive for PD-L1 or 


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PD-L1 and CD-45 expression by IHC will be reported along with 95% CI.  For subjects 
with more than one tumor sample available for testing, designation as positive for PD-L1 
expression will be based upon ≥1 positive sample.  Concordance and rates of positivity 
between primary and metastatic site, tumor location (e.g. liver vs. non-liver), etiology 
(e.g. viral vs. nonviral), and pre-treatment,  , and post-treatment samples (if available) 
will be described individually due to expectation of small subset/paired sample sizes.  
PD-L1 expression status in tumor and immune cells will be explored for association with 
ORR, PFS, and OS.
Tumor and IC PD-L1/CD45 analyses will be performed in UCSF CIL or other laboratory 
approved by Study Chair dependent upon funding and sample availability.
8.2.3.5 AFP response
Among patients with baseline AFP ≥ 20 ng/mL, baseline AFP levels (using various cut 
points from literature) will be explored for association with ORR, PFS, and OS using 
Fisher’s Exact tests or by Wilcoxon Rank-Sum test.  Changes in levels on therapy will 
be measured as an increase by ≥ 20% and ≥ 50% from baseline, stable value within 
20% and 50% of baseline, or decrease by ≥ 20% and ≥ 50% from baseline.  The 
changes in level will be used to evaluate the predictive value for ORR, PFS, or OS.  
8.3
Planned interim analyses
8.3.1 Part 1: Dose Escalation Cohort DLT analyses
In Part 1, a standard 3+3 design for dose escalation and expansion decisions will be 
used as described above. 
8.4
Determination of sample size
The total sample size will be 6-24 patients for Parts 1 and 2 combined. 
8.4.1 Part 1: Dose Escalation Cohort sample size
It is estimated that 6-12 patients will be enrolled to Part 1 following 3+3 dose escalation 
rules in Section 6.2.2.  
8.4.2 Part 2: Child Pugh B Expansion Cohort sample size
The Part 2 expected evaluable sample size is n=12 patients. 


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9. Data handling and quality assurance
9.1
Pre-study documentation
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with 
GCP and all applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects 
before any protocol related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study 
under the Investigational Drug Application (IND) is allowed to proceed or the 
Investigator has received a letter from FDA stating that the study is exempt from IND 
requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of 
Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all 
applicable regulatory requirements.  The IRB must comply with the regulations in 21 
CFR §56 and applicable regulatory requirements.
9.2
Institutional Review Board approval
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g. advertisements used to recruit participants) will be 
reviewed and approved by the UCSF IRB (UCSF Institutional Review Board).  Prior to 
obtaining IRB approval, the protocol must be approved by the Helen Diller Family 
Comprehensive Cancer Center Gastrointestinal Oncology Site Committee and by the 
Protocol Review Committee (PRC).  The initial protocol and all protocol amendments 
must be approved by the IRB prior to implementation.  
9.3
Informed consent
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their 
participation.  Participants must sign the IRB-approved informed consent form prior to 
participation in any study specific procedure.  The participant must receive a copy of the 
signed and dated consent document.  The original signed copy of the consent 
document must be retained in the medical record or research file. 
9.4
Changes in the protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol 
must be documented in the form of an amendment.  The amendment must be signed by 
the Investigator and approved by PRC and the IRB prior to implementation.  


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If it becomes necessary to alter the protocol to eliminate an immediate hazard to 
patients, an amendment may be implemented prior to IRB approval.  In this 
circumstance, however, the Investigator must then notify the IRB within writing within 
five (5) working days after implementation.  The Study Chair and the UCSF study team 
will be responsible for updating any participating sites.
9.5
Handling and documentation of clinical supplies
The UCSF Principal Investigator and each participating site will maintain complete 
records showing the receipt, dispensation, return, or other disposition of all 
investigational drugs.  The date, quantity and batch or code number of the drug, and the 
identification of patients to whom study drug has been dispensed by patient number and 
initials will be included.  The sponsor-investigator will maintain written records of any 
disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients.  Furthermore, the Principal Investigator 
will not allow the investigational drug to be used in any manner other than that specified 
in this protocol.
9.6
Case report forms (CRFs)
The Principal Investigator and/or his/her designee, will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the 
study.  Study specific Case Report Forms (CRFs) will document safety and treatment 
outcomes for safety monitoring and data analysis.  All study data will be entered into 
OnCore® via standardized CRFs in accordance with the study calendar, using single 
data entry with a secure access account.  The CRC will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs.
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records 
maintained by UCSF personnel.  All source documentation should be kept in separate 
research folders for each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs.  The PI will 
approve all completed CRFs to attest that the information contained on the CRFs is true 
and accurate. 
All source documentation and OnCore data will be available for review/monitoring by 
the UCSF DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study 
data.  At study completion, when the CRFs have been declared to be complete and 
accurate, the database will be locked.  Any changes to the data entered into the CRFs 
after that time can only be made by joint written agreement among the Study Chair, the 
Trial Statistician, and the treating investigator.


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9.7
Oversight and monitoring plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring entity for this study.  The UCSF DSMC will monitor the study in accordance 
with the NCI-approved Data and Safety Monitoring Plan (DSMP) for multi-center trials 
(Appendix 14.11).  The DSMC will routinely review all adverse events and suspected 
adverse reactions considered “serious”.  The DSMC will audit study-related activities to 
ensure that the study is conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate 
regulatory authorities at the time of continuing review, or in an expedited fashion, as 
applicable.  See Appendix 14.11, Data and Safety Monitoring Plan for additional 
information.
9.8
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at weekly conference calls with the participating sites 
for Phase I dose escalation studies prior to each cohort escalation and at the completion of 
each cohort or more frequently as needed to discuss risk assessment.  The following issues will 
be discussed as appropriate:

Enrollment information 

Cohort updates (i.e. DLTs) and enrollment status

Adverse events (i.e. new adverse events and updates on unresolved adverse 
events and new safety information)

Protocol violations

Other issues affecting the conduct of the study
9.9
Record keeping and record retention
The Principal Investigator is required to maintain adequate records of the disposition of 
the drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends.  The Principal Investigator is required to 
prepare and maintain adequate and accurate case histories that record all observations 
and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include 
the case report forms and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for 
each individual shall document that informed consent was obtained prior to participation 
in the study.
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 


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regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). Source documents include all recordings of 
observations or notations of clinical activities and all reports and records necessary for 
the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 
2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.
9.10
Coordinating Center documentation of distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the 
distribution of study documents as well as their receipt (when possible). The HDFCCC 
recommends that the Study Chair maintain a correspondence file and log for each 
segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, 
cover letters, amendment outlines (summary of changes), etc., along with distribution 
documentation and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the 
date sent, recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the 
protocol, its updates and safety information are distributed.
9.11
Regulatory documentation
Prior to implementing this protocol at UCSF or any participating site, the protocol, informed 
consent form, and any other information pertaining to participants must be approved by the 
UCSF IRB. Prior to implementing this protocol at the participating sites, approval of the UCSF 
IRB approved protocol must be obtained from the participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol,  informed consent form, and HIPAA 
authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 

Curriculum vitae and medical license for each investigator and consenting professional 

Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 

Participating site laboratory certifications and normals. 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.


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9.12
Audit and inspection
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) 
are possible.  The investigator should notify Bayer and BMS immediately of any such 
inspection.
10.
Protection of Human Subjects 
10.1 Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all participants involved in human 
experimentation. This is accomplished through the IRB mechanism and the process of 
informed consent. The IRB reviews all proposed studies involving human 
experimentation and ensures that the participant’s rights and welfare are protected and 
that the potential benefits and/or the importance of the knowledge to be gained 
outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
10.2 Protection of Privacy
Participants will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this 
discussion, they will be asked to sign the HIPAA form and informed consent documents. 
The original signed document will become part of the participant’s medical records, and 
each participant will receive a copy of the signed document. The use and disclosure of 
protected health information will be limited to the individuals described in the informed 
consent document.
11.
Premature termination of the study
The investigator has the right to close his/her center at any time for reasons such as 
listed below.

If risk-benefit ratio becomes unacceptable owing to, for example,
- Safety findings from this study (e.g. SAEs)
- Results of any interim analysis
- Results of parallel clinical studies


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- Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 5.3.
12.
Ethical and legal aspects
12.1
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the investigator abide by Good 
Clinical Practice (GCP) guidelines and under the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable 
local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the EC/IRB 
approval must be obtained and also forwarded to Bayer.
Strict adherence to all specifications laid down in this protocol is required for all aspects 
of study conduct; the investigator may not modify or alter the procedures described in 
this protocol.  
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Bayer.  However, the investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the 
trial subjects without prior IEC/IRB/Bayer approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution.  Any deviations from the protocol must be explained and documented by the 
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The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  The Principal Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected and properly documented.
12.2
Subject information and consent
Each subject or legal representative or proxy consenter will have ample time and 
opportunity to ask questions and will be informed about the right to withdraw from the 
study at any time without any disadvantage and without having to provide reasons for 
this decision.
Only if the subject or legal representative or proxy consenter voluntarily agrees to sign 
the informed consent form and has done so, may he/she enter the study.  Additionally, 
the investigator and other information provider (if any) will personally sign and date the 
form.  The subject or legal representative or proxy consenter will receive a copy of the 
signed and dated form. The signed informed consent statement is to remain in the 
investigator site file or, if locally required, in the patient’s note/file of the medical 
institution.
The informed consent form and any other written information provided to subjects or 
legal representatives or proxy consenters will be revised whenever important new 
information becomes available that may be relevant to the subject’s consent, or there is 
an amendment to the protocol that necessitates a change to the content of the subject 
information and / or the written informed consent form.  The investigator will inform the 
subject or legal representative or proxy consenter of changes in a timely manner and 
will ask the subject to confirm his/her participation in the study by signing the revised 
informed consent form.  Any revised written informed consent form and written 
information must receive the IRB’s approval in advance of use.
12.3
Publication policy
The Principal Investigator will ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov.
12.4
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual.


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13.
Reference list
1.
Cheng AL, Kang YK, Chen Z, et al: Efficacy and safety of sorafenib in 
patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III 
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Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced 
hepatocellular carcinoma. N Engl J Med 359:378-90, 2008
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Cheng AL, Kang YK, Lin DY, et al: Sunitinib Versus Sorafenib in Advanced 
Hepatocellular Cancer: Results of a Randomized Phase III Trial. J Clin Oncol, 2013
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El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with 
advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, 
phase 1/2 dose escalation and expansion trial. Lancet, 2017
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Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-
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Wilhelm S, Carter C, Lynch M, et al: Discovery and development of 
sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835-44, 
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Sharpe AH, Wherry EJ, Ahmed R, et al: The function of programmed cell 
death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8:239-45, 
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Bruix J, Qin S, Merle P, et al: Regorafenib for patients with hepatocellular 
carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-
blind, placebo-controlled, phase 3 trial. Lancet 389:56-66, 2017
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Ryerson AB, Eheman CR, Altekruse SF, et al: Annual Report to the Nation 
on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. 
Cancer 122:1312-37, 2016
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Crocenzi TSE-K, A. B.; Yau, T.; et al.: Nivolumab in Sorafenib-Naive and -
Experienced Patients With Advanced Hepatocellular Carcinoma: CheckMate 040 Study, 
American Society of Clinical Oncology Annual Meeting. Chicago, IL, J Clin Oncol, 2017
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Kelley RK: Brivanib and FOLFOX in hepatocellular carcinoma: finding the 
common themes among negative trials. J Clin Oncol 31:3483-6, 2013
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Abou-Alfa GK, Schwartz L, Ricci S, et al: Phase II study of sorafenib in 
patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293-300, 2006
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Abou-Alfa GK, Amadori D, Santoro A, et al: Safety and Efficacy of 
Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B 
Cirrhosis. Gastrointest Cancer Res 4:40-4, 2011
14.
Velu V, Titanji K, Zhu B, et al: Enhancing SIV-specific immunity in vivo by 
PD-1 blockade. Nature 458:206-10, 2009
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Wang C, Thudium KB, Han M, et al: In vitro characterization of the anti-
PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. 
Cancer Immunol Res 2:846-56, 2014
16.
Habicht A, Dada S, Jurewicz M, et al: A link between PDL1 and T 
regulatory cells in fetomaternal tolerance. J Immunol 179:5211-9, 2007
17.
El-Khoueiry ABS, B.; Yau, T.; Crocenzi, T.; et al.: Phase 1/2 Safety and 
Antitumor Activity of Nivolumab in Patients With Advanced Hepatocellular Carcinoma:


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Interim Analysis of the CheckMate 040 Dose-Escalation Study, American Society of 
Clinical Oncology Annual Meeting. Chicago, IL, J Clin Oncol, 2016
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Takeuchi Y, Nishikawa H: Roles of regulatory T cells in cancer immunity. 
Int Immunol, 2016
19.
Heine A, Schilling J, Grunwald B, et al: The induction of human myeloid 
derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by 
the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer 
Immunol Immunother 65:273-82, 2016
20.
Chuang HY, Chang YF, Liu RS, et al: Serial low doses of sorafenib 
enhance therapeutic efficacy of adoptive T cell therapy in a murine model by improving 
tumor microenvironment. PLoS One 9:e109992, 2014
21.
Chen ML, Yan BS, Lu WC, et al: Sorafenib relieves cell-intrinsic and cell-
extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor 
immunity. Int J Cancer 134:319-31, 2014
22.
Kato Y, al. e: Upregulation of memory T cell population and enhancement 
of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade, 
American Association for Cancer Research. Washington, D.C., 2017
23.
Cabrera R, Ararat M, Xu Y, et al: Immune modulation of effector CD4+ and 
regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer 
Immunol Immunother 62:737-46, 2013
24.
Kalathil SGL, A. A.; Miller, A.; Iyer, R.; Thanavala, Y.: PD-1+ and Foxp3+ 
T cell reduction correlates with survival of HCC patients after sorafenib therapy. JCI 
Insight 1(11):e86182, 2016
25.
Florcken A, Takvorian A, Van Lessen A, et al: Sorafenib, but not sunitinib, 
induces regulatory T cells in the peripheral blood of patients with metastatic renal cell 
carcinoma. Anticancer Drugs 23:298-302, 2012
26.
Busse A, Asemissen AM, Nonnenmacher A, et al: Immunomodulatory 
effects of sorafenib on peripheral immune effector cells in metastatic renal cell 
carcinoma. Eur J Cancer 47:690-6, 2011
27.
Lu LC, Lee Y-H, Chang C-J, et al: Increased expression of programmed 
death-ligand 1 (PD-L1) on infıltrating immune cells of hepatocellular carcinoma (HCC) 
tissues after sorafenib treatment, American Association for Cancer Research. 
Washington D.C., 2017
28.
Carbognin L, Pilotto S, Milella M, et al: Differential Activity of Nivolumab, 
Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed 
Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and 
Genitourinary Cancers. PLoS One 10:e0130142, 2015
29.
Fong L, Kwek SS, O'Brien S, et al: Potentiating endogenous antitumor 
immunity to prostate cancer through combination immunotherapy with CTLA4 blockade 
and GM-CSF. Cancer Res 69:609-15, 2009
30.
Kavanagh B, O'Brien S, Lee D, et al: CTLA4 blockade expands FoxP3+ 
regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 
112:1175-83, 2008
31.
Cha E, Klinger M, Hou Y, et al: Improved survival with T cell clonotype 
stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med 6:238ra70, 2014


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32.
Ji RR, Chasalow SD, Wang L, et al: An immune-active tumor 
microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 
61:1019-31, 2012
33.
Hamid O, Schmidt H, Nissan A, et al: A prospective phase II trial exploring 
the association between tumor microenvironment biomarkers and clinical activity of 
ipilimumab in advanced melanoma. J Transl Med 9:204, 2011
34.
Kwek SS, Lewis J, Zhang L, et al: Preexisting Levels of CD4 T Cells 
Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated 
with Ipilimumab. Cancer Immunol Res, 2015
35.
Chan SL, Mo FK, Johnson PJ, et al: New utility of an old marker: serial 
alpha-fetoprotein measurement in predicting radiologic response and survival of 
patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol 
27:446-52, 2009
36.
Kuzuya T, Asahina Y, Tsuchiya K, et al: Early decrease in alpha-
fetoprotein, but not des-gamma-carboxy prothrombin, predicts sorafenib efficacy in 
patients with advanced hepatocellular carcinoma. Oncology 81:251-8, 2011
37.
Personeni N, Bozzarelli S, Pressiani T, et al: Usefulness of alpha-
fetoprotein response in patients treated with sorafenib for advanced hepatocellular 
carcinoma. J Hepatol 57:101-7, 2012
38.
Kudo MM, A.; Santoro, A.; et al.: Checkmate-040: Nivolumab (NIVO) in 
patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) 
status, Gastrointestinal Cancers Symposium. San Francisco, J Clin Oncol, 2019
39.
Kambhampati S, Bauer KE, Bracci PM, et al: Nivolumab in patients with 
advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: Safety and 
clinical outcomes in a retrospective case series. Cancer 125:3234-3241, 2019
40.
Marrero JA, Kudo M, Venook AP, et al: Observational registry of sorafenib 
use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 
65:1140-1147, 2016
41.
Miller AA, Murry DJ, Owzar K, et al: Phase I and pharmacokinetic study of 
sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 
27:1800-5, 2009
42.
Finn RS, Cheng AL: Atezolizumab and Bevacizumab in Hepatocellular 
Carcinoma. Reply. N Engl J Med 383:695, 2020
43.
Kudo M, Finn RS, Qin S, et al: Lenvatinib versus sorafenib in first-line 
treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 
3 non-inferiority trial. Lancet 391:1163-1173, 2018
44.       Marrero JA, Kulik LM, Sirlin CB, et al: Diagnosis, Staging, and Management of 
Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the 
Study of Liver Diseases. Hepatology 68:723-750, 2018
45.
Bi Y, Liu J, Furmanski B, et al: Model-informed Drug Development 
Approach Supporting Approval of the 4-week (Q4W) Dosing Schedule for Nivolumab 
(Opdivo) across Multiple Indications: A Regulatory Perspective. Ann Oncol, 2019
46.
Yau TP, J.W.; Finn, R.S.; et al. : CHECKMATE 459: A RANDOMIZED, 
MULTI-CENTER PHASE 3 STUDY OF NIVOLUMAB (NIVO) VS SORAFENIB (SOR) 
AS FIRST-LINE (1L) TREATMENT IN PATIENTS (PTS) WITH ADVANCED 


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HEPATOCELLULAR CARCINOMA (AHCC), European Society of Medical Oncology. 
Barcelona, Spain, 2019
47.
Garcia-Tsao G, Sanyal AJ, Grace ND, et al: Prevention and management 
of gastroesophageal varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol 
102:2086-102, 2007


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APPENDIX 1: RECIST 1.1
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor 
response.  While either CT or MRI may be utilized, as per RECIST 1.1, CT is the 
preferred imaging technique in this study.
* As published in the European Journal of Cancer:
E.A.  Eisenhauer, P.  Therasse, J.  Bogaerts, L.H.  Schwartz, D.  Sargent, R.  Ford, 
J.  Dancey, S.  Arbuck, S.  Gwyther, M.  Mooney, L.  Rubinstein, L.  Shankar, L.  Dodd, 
R.  Kaplan, D.  Lacombe, J.  Verweij.  New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1).  Eur J Cancer.  2009 Jan;45(2):228-47. 


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APPENDIX 2: ECOG performance status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.


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APPENDIX 3: Child Pugh score
The Child Pugh score will be calculated using the modified Child Pugh scoring system46 
at time points specified in Section 7.1, Schedule of procedures.  Ascites should be 
assessed by clinical examination (rather than radiographic findings).  Encephalopathy 
and ascites are considered as present (i.e. at least 2 points) in any patient taking 
medications for these conditions (e.g., lactulose, diuretics) even if well-controlled at the 
time of Child Pugh score assessment.


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APPENDIX 4: AJCC staging for HCC
AJCC stage (8th Ed.) will be determined based upon review of imaging and other clinical 
data from date of radiographic (by diagnostic imaging) or histologic diagnosis, 
whichever is earliest.  AJCC stage will also be determined at date of enrollment.  AJCC 
stage will be recorded in CRFs on OnCore. 
AJCC Staging for HCC, adapted from www.nccn.org


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APPENDIX 5: BCLC staging for HCC
BCLC stage will be determined based upon review of imaging and other clinical data 
from date of radiographic (by diagnostic imaging) or histologic diagnosis, whichever is 
earliest.  BCLC stage will also be determined at date of enrollment. BCLC stage will be 
recorded in CRFs on OnCore. 
Bruix and Sherman Hepatology 53(3) 2011


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APPENDIX 6: irAE management
The following algorithms from Nivolumab IB (v.15.0) represent clinical guidance to the 
treating investigator for management of selected irAE which have been associated with 
nivolumab.  Additional management including optimal supportive care should be 
employed in all cases as clinically appropriate, according to clinical judgment of treating 
investigator. Subspecialty consultation for additional management recommendations 
should be obtained whenever needed, e.g. for severe or refractory cases, at discretion 
of treating investigator.
Endocrine irAE*
*For cases with new onset diabetes mellitus, the role for steroid therapy is unknown and 
consultation with Endocrinologist is strongly recommended.  For symptomatic diabetes, 
nivolumab should be withheld, and insulin replacement should be initiated as needed. 
Monitoring of blood sugar should continue to ensure appropriate insulin replacement is 
utilised. Nivolumab must be permanently discontinued for life-threatening diabetes.


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GI irAE


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Hepatic irAE
Subjects with advanced HCC generally have underlying cirrhosis with decreased 
hepatic function, thus this protocol allows inclusion of patients with AST or ALT 
elevations within the CTCAE Grade 2 range. The protocol-specific approach for the 
management of hepatic events in this population with baseline hepatic dysfunction is as 
follows:
1. 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.
2. Check for alternate causes of elevated AST or ALT including test HBV or HCV 
viral load as applicable, discontinue any new medications or supplements, and 
consider imaging for tumor progression and/or vascular involvement.
3. For ALT or AST levels > 8x ULN, initiate steroid therapy promptly at 1-2 
mg/kg/day methylprednisolone or oral equivalent.
4. For all subjects initiating steroids, Hepatology/Gastroenterology consult is 
recommended if any evidence associated hepatic decompensation (e.g. new 
ascites, encephalopathy, or elevated INR).
5. If AST or ALT levels do not improve within 3-5 days or the levels worsen after the 
start of steroid therapy, it is recommended to contact Study Chair and consider 
adding mycophenolate mofetil at 1 g BID.
6. Tapering of steroids can start once AST or ALT levels have declined by 1 
CTCAE grade.
7. Taper steroids slowly over no less than 1 month.
As outlined in Section 6.7.2.1, nivolumab therapy may resume when AST or ALT have 
returned to near baseline unless the criteria for permanent discontinuation are reached.


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Neurologic irAE


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Pulmonary irAE


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Renal irAE


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Skin irAE


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APPENDIX 7: Sorafenib drug diary
PATIENT ID #:_______________       CYCLE #: _________    
INSTRUCTIONS:  PLEASE FILL OUT AND BRING THIS SHEET TO YOUR NEXT VISIT.
DOSE LEVEL: 
 400 mg (2 x 200 mg tablets) orally twice a day 
 400 mg (2 x 200 mg tablets) orally once a day
 400 mg (2 x 200 mg tablets) orally every other day
SORAFENIB 200 MG TABLETS: TAKE ORALLY WITHOUT FOOD WITH A GLASS OF WATER.
Day
Date
Morning time of dose
 # of caps taken
Evening time of dose
# of tablets taken
Missed Dose 
Time/date missed
EXAMPLE
1/1/2017
___:___AM    # ___ tabs 
___:___PM  # ____ tabs
# ____tabs:
Day 1
 
 
 
Day 2
 
 
 
Day 3
 
 
 
Day 4
 
 
 
Day 5
 
 
 
Day 6
 
 
 
Day 7
 
 
 
Day 8
 
 
 
Day 9
 
 
 
Day 10
 
 
 
Day 11
 
 
 
Day 12
 
 
 
Day 13
 
 
 
Day 14
 
 
 
Day  15
 
 
 
Day 16
 
 
 
Day 17
 
 
 
Day 18
 
 
 
Day 19
 
 
 
Day 20
 
 
 
Day 21
 
 
 
Day 22
 
 
 
Day 23
 
 
 
Day 24
 
 
 
Day 25
 
 
 
Day 26
 
 
 


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Day 27
 
 
 
Day 28
 
 
 
Day 29
 
 
 
Day 30
Day 31
 
 
 
Please complete this section at the end of cycle when returning any leftover pills 
and pill bottle:
Number of pills returned: _________________
Date:
Patient Signature: 
                     Date:
Health Care Provider Signature:  
          
Date:


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APPENDIX 8: Biospecimen acquisition and handling
Archival FFPE tumor blocks and/or sections
Samples of all available archival specimens (preferentially at least 1 representative 
FFPE block(s) plus H&E slide(s) from prior diagnostic core biopsy or biopsies and/or 
resection specimen(s), or if block not available, at least 10*5 µm and 10*10 µm 
unstained slides plus H&E slide will be requested, or maximum available in cases of 
limited sample) will be accessioned from UCSF and/or outside institution clinical 
laboratories as soon as possible after consent is obtained for study participation.  Any 
leftover material (after all planned tissue extraction for study correlative analyses has 
been completed) will be returned to outside institution Pathology department (for non-
UCSF patients) or logged and stored according to UCSF Biorepository SOP or 
returned at end of study for UCSF subjects if consented for banking in companion 
banking and registry study, CC#124512 (see below).   If multiple tumors and/or satellite 
nodules are present, at least 1 block and/or corresponding unstained slides plus 
matching H&E slide should be requested for each discrete lesion whenever available.
Block/slides should be delivered or shipped to: 
Attn: CC#174523
UCSF-Biospecimen Repository and Tissue Biomarker Technology Lab
UCSF Helen Diller Family Comprehensive Cancer Center 
For patients who consent to the companion study CC#124512, left-over specimens will 
be collected, processed, and banked and clinical data will be collected according to 
separate CC#124512 protocol.


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Whole blood for PBMC isolation (UCSF site only)
In all patients enrolled at UCSF, approximately 60 mL of whole blood will be collected 
into green top (sodium heparin) tubes (e.g. six 10 cc tubes filled approximately to 10 
mL) at the time points listed in the study Schedule of procedures (Section 7.1) and 
according to instructions below.  The tubes will be delivered by study coordinator or 
approved courier directly to the UCSF Immune Monitoring Core for PBMC isolation then 
freezing for future analysis in batch after study completion.
Whole blood for PBMC Sample Collection and Delivery Instructions:

Draw 60 mL into the appropriate number of green top tubes (e.g. six 10cc tubes) 
by phlebotomist or other trained health care provider.

Invert the tube gently several times to avoid clotting.

Label samples with study ID (CC#174523), subject ID, cycle/day, date, time of 
blood draw.

For each delivery, an inventory of the samples should accompany the delivery. 
This inventory should include the study ID (CC#174523) subject ID, cycle/day, 
date, and time of blood draw.

All samples should be delivered on a Monday through Thursday between 
approximately 9am-5pm PST or on a Friday between approximately 9am-1pm 
PST by a coordinator or approved courier service:

Samples should not be sent after approximately 1pm Friday through Sunday or 
on University holidays, to prevent arrival over the weekend or on holidays, unless 
by special arrangement with the UCSF CIL staff.

Samples have to be packed according to the ICAO/IATA-Packing-Instructions in 
a room temperature shipper or specimen bag.
Deliver samples at room temperature within approximately 12 hours or less after time of 
blood collection to:
Attn: CC#174523
UCSF Cancer Immunotherapy Laboratory (CIL)


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APPENDIX 9: MedWatch 3500A form
This form will be used for submission of SAE events to Bayer, BMS, and FDA as 
appropriate.  

For SAE occurring at UCSF: Reports will be sent to Bayer, BMS, and FDA as 
applicable depending upon criteria in Section 7.4.

For SAE occurring at sub-site: Reports will be sent to Bayer, BMS, and UCSF.  
IND safety reporting will be submitted by study team at UCSF.
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm


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APPENDIX 10: BMS SAE Reconciliation Reports
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 11: UCSF Data and Safety Monitoring Plan (DSMP) for 
Multicenter Institutional Study 
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and participant safety 
for all HDFCCC institutional clinical trials and cancer-specific trials at UCSF.  A summary of 
DSMC activities for this trial includes:  
 

Participant monitoring prior to dose escalation. 

Review of participant data in each cohort 

Approval of dose escalation by DSMC Chair or Vice Chair 

Review of serious adverse events 

Minimum of biennial regulatory auditing 
 
2. 
Monitoring and Reporting Guidelines 
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the trial and for monitoring its safety 
and progress at all participating sites.  The Study Chair will conduct continuous review of data 
and participant safety at weekly UCSF Site Committee meetings.  The discussions are 
documented in the UCSF Site Committee meeting minutes.  
The UCSF HDFCCC Data and Safety Monitoring Committee (DSMC) is responsible for 
participant safety for all domestic sites for HDFCCC Multicenter and Consortium institutional 
clinical trials.  The International sites must be monitored by a Clinical Research Organization 
(CRO) that is formally approved by the HDFCCC Cancer Center Clinical Research Oncology 
Committee (CCCROC) and the HDFCCC DSMC via the HDFCCC Policy of Minimum Standards 
for Partnership with International CROs. 
All multicenter phase I dose escalation trials are monitored prior to the requested dose 
escalation of the dosing cohort. All participants are monitored through the Dose Limiting Cohort 
until the Maximum Tolerated Dose (MTD) is determined.  Once the MTD is determined, then the 
trial is audited on an annual basis with twenty percent of the participants enrolled in this 
expansion cohort that are audited through their first five cycles of treatment. Scheduled auditing 
of participant source documents is complete after all files have been reviewed for five cycles of 
treatment (20% of participants). For Phase I high risk therapeutic trials that are not dose finding, 
all participants are monitored on a quarterly basis (depending on accrual) through the first cycle 
of therapy.    
DSMC Monitor/Auditors will send a follow-up report to the study team within 20 business days 
after the monitoring visit is complete for the PI and the study team to resolve all action items 
from this report within 20 business days.  An abbreviated regulatory review (i.e., reviewing 
protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each 
participant monitoring review; however, a full regulatory review will occur on a biennially basis 
by the DSMC for regulatory compliance. 


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Monitoring of enrolled participants in the dose expansion portion of the trial will be complete 
after 20% of enrolled participants have been monitored through two cycles of treatment.  
However, regulatory reviews of the trial, safety reviews (i.e., Serious Adverse Event (SAE) 
reviews and Protocol Violation (PV) reviews), as well as audit/inspection preparation (as 
applicable) will continue until the trial is closed by the IRB.  
Multicenter communication 
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center and provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical trial.  The 
UCSF Coordinating Center will also coordinate monthly conference calls with the participating 
sites.  The following issues will be discussed as appropriate: 

Enrollment information. 

Cohort updates (i.e., DLTs). 

Adverse events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information). 

Protocol violations. 

Other issues affecting the conduct of the study. 
 
Dose Level Considerations 
The PI/Study Chair, participating investigators, and research coordinators from each site will 
review enrollment for each dose level cohort during the regularly scheduled conference calls.  
The dose level for ongoing enrollment will be confirmed for each participant scheduled to be 
enrolled at a site.  Dose level assignments for any participant scheduled to begin treatment 
must be confirmed by the UCSF Coordinating Center via email. 
If a participant experiences a Dose Limiting Toxicity (DLT), the UCSF Coordinating Center will 
notify all sites within one business day of awareness.  If the DLT occurs at a participating site, 
the local investigator must report the DLT to the UCSF Coordinating Center within one business 
day.  The Study Chair has one business day (after first becoming aware of the event at either 
the UCSF Coordinating Center or the participating site) in which to report the DLT information to 
all participating sites.   
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites as per the 
study-specific guidelines.  The data (i.e., redacted copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to the monitoring 
visits or the DSMC will be provided with access to the participating site’s electronic medical 
record (EMR) access in order for the DSMC to perform remote monitoring of the participating 
site’s compliance with the protocol and applicable FDA regulations 
 


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Dose Escalations 
At the time of dose escalation, a written and signed Dose Escalation Report will be submitted to 
the DSMC Chair (or Vice Chair) and DSMC Director describing the cohorts, dose levels, 
adverse events, safety reports, and any Dose Limiting Toxicities (DLTs) observed, in 
accordance with the protocol.  The report will be reviewed by the DSMC Chair or Vice Chair and 
written authorization to proceed or a request for more information will be issued within two 
business days of the request.  The report is then reviewed at the subsequent DSMC Committee 
meeting.  In the event that the committee does not concur with the DSMC Chair’s (or Vice 
Chair’s decision, study accrual is held while further investigation takes place.   
 
3. 
Review and Oversight Requirements 
 
3.1 
Adverse Event Monitoring  
All clinically significant adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of study drug, will be 
entered into OnCore, UCSF’s Clinical Trial Management System.   
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to investigational agent or study procedure.  Attribution categories are: 

Definite – clearly related to the investigational agent(s) or study procedure. 

Probable – likely related to the investigational agent(s) or study procedure. 

Possible – may be related to the investigational agent(s) or study procedure. 

Unrelated – clearly not related to the investigational agent(s) or study procedure. 
 
All adverse events entered into OnCore will be reviewed on a weekly basis at the UCSF 
Coordinating Center’s Site Committee meetings.  The UCSF Site Committee will review and 
discuss the selected toxicity, grade, and the attribution assignment for the adverse events that 
occurred at both the UCSF Coordinating Center and the participating sites. 
3.2 
Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according  to the 
following criteria: 
 
 
•
Death, 
•
Life-threatening adverse experience*, 
•
Inpatient hospitalization or prolongation of existing hospitalization, 
•
Persistent or significant disability/incapacity, 
Congenital anomaly/birth defect, or cancer, or 


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•
Any other experience that suggests a significant hazard, contraindication, side 
effect or precaution that may require medical or surgical intervention to prevent one 
of the outcomes listed above, 
•
Event that changes the risk/benefit ratio of the study.  
* A life-threatening adverse experience is any AE that places the patient or subject, in the view 
of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form. 
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information:  
www.fda.gov/medwatch/getforms.htm 
All serious adverse events are entered into OnCore, as well as submitted to the IRB (per IRB 
guidelines).  All SAEs, whether expected or unexpected, must be reported to the UCSF 
Coordinating Center within 10 business days of becoming aware of the event or during the next 
scheduled conference all, whichever is sooner.  The SAEs are reviewed and monitored by the 
Data and Safety Monitoring Committee on an ongoing basis and discussed at DSMC meetings, 
which take place every six weeks.  The date the SAE was sent to all required reporting agencies 
will be documented in OnCore.  
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or definitely 
related either to the investigational drug or any research related procedure, the Study Chair at 
the UCSF Coordinating Center or the assigned designee must be notified within 1 business day 
from the participating site(s) and the Study Chair must then notify the DSMC Chair (or Vice 
Chair) and the DSMC Director within one business day of this notification.   
3.3 
Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC at the time the increased rate is 
identified via a report.  The report will indicate if the incidence of adverse events observed in the 
study is above the range stated in the Investigator’s Brochure or package insert. 
If at any time the Study Chair voluntarily holds enrollment or stops the study due to safety 
issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one 
business day via e-mail and the IRB must be notified their reporting requirements. 
3.4   
Data and Safety Monitoring Board (DSMB) Reports 


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Data and Safety Monitoring Board (DSMB) Reports which provide information on trial accrual, 
participant safety, and data integrity will be provided to all sites, including the domestic and 
international sites, on an annual basis.  The DSMB Report will be signed by the DSMC Chair (or 
Vice Chair) and provided to the DSMC Committee for formal review at the next scheduled 
DSMC Committee meeting. 
Data and Safety Monitoring Committee Contacts: 
  Katie Kelley, MD (DSMC Chair) 
  
 
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158 
John McAdams (DSMC Director)  
 
 
 
UCSF HDFCCC 
               San Francisco, CA 94158 

ICF_001.pdf: 
CC# 174523
ICF 04-06-2021
PAGE 1 OF 29
R. KATE KELLEY, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO CONSENT TO 
PARTICIPATE IN A RESEARCH STUDY
Study Title: CC# 174523 - Multicenter Pilot Study of the Safety, Efficacy, 
and Immune Cell Profiling in Advanced Hepatocellular Carcinoma (HCC) 
Patients Treated with the Combination of Sorafenib plus Nivolumab as 
First-Line of Systemic Therapy
Principal Investigator:
R. Kate Kelley MD
Associate Professor of Clinical Medicine
University of California San Francisco
San Francisco, CA 94143-
This is a clinical research study. Your study doctor, R. Kate Kelley MD, or one of her 
associates at the University of California San Francisco (UCSF) Helen Diller Family 
Comprehensive Cancer Center, will explain the study to you.
Research studies include only people who choose to take part. It is your choice whether 
or not you want to take part in this study. Please take your time to make your decision 
about participating. You may discuss your decision with your family, friends, and health 
care team. If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have a type of liver cancer 
called hepatocellular carcinoma (HCC) that cannot be removed by surgery (including 
liver transplant) that may or may not have spread to other parts of your body or you 
have Child Pugh B liver function.
Why is this study being done?
The purpose of this study is to test the safety of sorafenib at different dose levels and 
dose frequencies when combined with nivolumab and see if adding nivolumab makes 
sorafenib more effective against HCC or Child Pugh B liver function. The investigators 
hope to learn more about the side effects and how the body handles this drug 
combination, as well as about how it works against HCC or Child Pugh B liver function.
Sorafenib, a standard treatment for HCC, works by turning off some of the chemicals in 
the tumor cells that let the tumor grow new blood vessels. Sorafenib is approved by the 
United States Food and Drug Administration (FDA) for treating certain types of HCC, 
renal cell carcinoma, and thyroid cancers.
Nivolumab is an antibody (a type of human protein) that may allow the body’s immune 
system to work against tumor cells. Nivolumab is approved by the FDA for treating 
certain types of melanoma and lung cancers. 
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023
NCT03439891


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R. KATE KELLEY, MD
The FDA has not approved the combination of sorafenib and nivolumab for treating 
HCC or Child Pugh B liver function. Therefore, sorafenib and nivolumab are being used 
in this study as investigational drugs.
There will be two parts to this study: 

Part 1 – Dose Escalation – This part of the study will be to determine the best 
dose and frequency for sorafenib when combined with nivolumab in patients with 
advanced or metastatic HCC. 
Once the best dose and frequency for sorafenib has been found, Part 2 of the study 
will begin.

Part 2 – Safety Cohort – This part of the study will be to determine the safety and 
how well side effects of the combination of these study drugs are tolerated in 
patients with Child Pugh B liver function and patients with advanced HCC.
Bayer is providing the study drug (sorafenib) and funding to UCSF to conduct this study.
How many people will take part in this study?
About 24 people will take part in this study.

In Part 1 (Dose Escalation), about 6-12 people (at UCSF) will take part in this 
study. Once the study team has determined the best dose and frequency for 
sorafenib, Part 2 of the study will begin.

In Part 2 (Safety Cohort), about 12 people (at UCSF and UC Davis) will take part 
in this study.
What will happen if I take part in this research study?
Part 1
Part 1 of the study is the dose escalation phase. If you are enrolled in Part 1 (dose 
escalation), you will take sorafenib (a pill) at the dose and frequency indicated by your 
study doctor starting on Day 1 of Cycle 1. The first 6 patients will be treated with 
sorafenib at a dose of 2 tablets (400 mg) once a day, which is lower than the full starting 
dose of sorafenib but is a dose with acceptable safety and tolerability when given by 
itself. If this lower dose does not cause any unacceptable side effects, up to 6 more 
patients may participate in Part 1, with a higher starting dose of sorafenib of 2 tablets 
(400 mg) twice a day. The side effects and tolerability of these doses will be evaluated 
carefully for all patients.
Each cycle is 28 days. You will also come into the clinic every two weeks (Days 1 and 
Days 15 of every cycle) to receive nivolumab. Nivolumab is given as an infusion into a 
vein in your arm. One infusion takes about 30 minutes.
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
Part 2
Part 2 of the study is the safety cohort phase. The safety cohort phase is for patients 
with Child Pugh B liver function and patients with advanced HCC. This phase of the 
study starts when the dose escalation phase (Part 1) is complete, and the best dose 
level and dose frequency for sorafenib is determined.
Patients enrolled in Part 1 will continue to receive study drugs after Part 2 opens, until 
their disease gets worse, if there are too many bad side effects from the study drugs, if 
they decide to stop participating in the study, or if the study closes. 
All patients in Part 2 will take the same dose level and dose frequency of sorafenib 
(which was determined in Part 1). If you are enrolled in Part 2 (safety cohort), you will 
take sorafenib (a pill) at a dose of 2 tablets (400 mg) once a day starting on Cycle 1 Day 
1. Each cycle is 28 days.
You will also come into the clinic every two weeks (Days 1 and Days 15 of every cycle) 
to receive nivolumab. Nivolumab is given as an infusion into a vein in your arm. One 
infusion takes about 30 minutes. Nivolumab may be switched to a monthly infusion on 
or after Cycle 4, Day 1 if you do not have any unfavorable side effects. The doses and 
frequency of drugs may be adjusted by your study doctor if you have any side effects.
Before you begin the main part of the study...
You will need to have the following exams, tests or procedures to find out if you can be 
in the main part of the study. These exams, tests or procedures are part of regular 
cancer care and may be done even if you do not join the study. If you have had some of 
them recently, they may not need to be repeated. This will be up to your study doctor.
All procedures must be done within 28 days prior to receiving the study drug (Cycle 1 
Day 1), unless otherwise noted.
Screening
These tests and procedures may take up to about 6-9 hours but can be done over 
several different days.

You will be asked about the medications you are currently taking and have taken
in the past including herbal medications

You will be asked about personal information (age, gender, ethnic origin, etc.)

Your medical and disease history will be reviewed from your medical records

You will be asked about any side effects you’re having

You will have a 12 lead Electrocardiogram (ECG) to assess your heart function
o
An ECG records the electrical activity of your heart. Wires or “leads” will
be attached to your chest with an adhesive and you will be asked to lie still
while the machine prints out an electrical “record” of your heart activity.
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
This takes about 15-30 minutes.

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

You will have a computed tomography (CT) scan and/or magnetic resonance 
imaging (MRI) of the chest, abdomen, and pelvis depending on which scans your 
doctor believes would be best for your tumors. These are special procedures 
which use X-rays (CT) or magnetic fields (MRI) to create pictures of the inside of 
your body. These pictures will allow your doctor to monitor your disease before, 
during, and after you receive nivolumab and sorafenib and to see if the tumors 
change in size.
o
A CT scan uses special x-ray equipment to make detailed pictures of body 
tissues and organs. For the CT scan, you may be given a "contrast 
material" (a special dye that makes it easier for doctors to see different 
tissues in your body). The contrast material may be given orally, 
intravenously, or rectally (less likely). Oral contrast material is given to you 
to drink and is used to help outline the stomach and intestines. 
Intravenous (IV) contrast material is given to you by injecting the contrast 
material into a line which is attached to a needle in your arm and is used 
to get clearer pictures of your body cavity. A rectal contrast fills up the 
loops of your lower bowel so the doctors can see your tumor better. After 
you have been given the contrast material (either by mouth, by vein, or 
rectum), you will lie flat on a table that will move you into the CT scan 
machine. You will be asked to lie still and may be asked to hold your 
breath for a few seconds. The CT scan is done in the radiology 
department and takes about half an hour.
o
An MRI scan takes an image of your head or body to observe the location 
and size of your tumor. For the MRI scan, you may be given a "contrast 
material" (a special dye that makes it easier for doctors to see different 
tissues in your body). Gadolinium is contrast material that causes some 
tumors to appear much brighter than normal tissue on MRI scans (these 
tumors may not be visible without gadolinium). The contrast material may 
be given to you in your arm through an intravenous catheter (a tiny tube 
inserted into a vein). You will then lie down on a narrow bed which will be 
placed in a tunnel that is 6 feet long by 22 inches wide and open at each 
end. You will lie there quietly for about one hour, during which time you 
will hear a loud machine-like noise. The MRI scan is done in the radiology 
department and takes approximately an hour and a half to complete.

Your blood will be collected (about 7-8 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry tests
o
Complete blood count (looking at your red and white blood cells and 
platelets)
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
o
Thyroid function testing
o
Checking for hepatitis B (HBV), C (HCV), or D (HDV) infection
o
Blood clotting testing
o
Tumor marker testing
o
Pregnancy test- if you are a woman of childbearing potential and if your 
urine results could not be confirmed as negative
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood
o
If you are positive for hepatitis (a viral infection), the study doctor will 
confirm that you are on an antiviral therapy to treat it

Your urine will be collected for the following tests:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study.
o
Kidney and bladder function tests

Your archival tumor tissue will be collected
o
If available, archival (leftover) tumor tissue samples will be collected from 
a previous surgery or biopsy.
During the main part of the study...
If the exams, tests and procedures show that you can be in the main part of the study, 
and you choose to take part, then you will need the following tests and procedures. 
Some of them are part of routine cancer care and may not need to be repeated if you 
have had them done recently. This will be up to your study doctor.
If you’re participating in Part 1, you will take sorafenib starting on Cycle 1 Day 1. 
Depending on when you join the study, how frequently you take sorafenib and the dose 
at which you take sorafenib may be different. You can ask your study doctor how often 
you should take your dose and how much of the drug you will be taking. You will also 
receive nivolumab at the standard dose through an infusion to a vein in your arm or port 
if you have previously had one placed starting on Cycle 1 Day 1. The infusion will take 
about 30 minutes.
If you’re participating in Part 2, you will take sorafenib starting on Cycle 1 Day 1. 
Everyone in Part 2 will take sorafenib at the same frequency and dose. You will also 
receive nivolumab at the standard dose through an infusion to a vein in your arm 
starting on Cycle 1 Day 1. The infusion will take about 30 minutes. Nivolumab may be 
switched to a monthly infusion on or after Cycle 4 Day 1 if you do not have any 
unfavorable side effects. The doses and frequency of drugs may be adjusted by your 
study doctor if you have any side effects.
Cycle 1 Day 1
The following tests and procedures will take about 3-4 hours.

You will be asked about the medications you are currently taking and have 
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IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
taken in the past including herbal medications

Part 1 (Dose Escalation):
o
You will begin taking sorafenib

Ask your study doctor how often you’ll be taking sorafenib
o
Nivolumab will be infused into a vein in your arm or port if you have 
previously had one placed

Part 2 (Safety Cohort):
o
You will begin taking sorafenib
o
Nivolumab will be infused into a vein in your arm or port if you have 
previously had one placed 

You will be asked about any side effects you’re having

Your drug diary will be checked
o
The study team will check your drug diary to make sure you’re taking 
sorafenib at the right schedule

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

Your urine will be collected for the following tests:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study (must 
be done 24 hours prior to your first dose of nivolumab).
o
Kidney and bladder function tests

Your blood will be collected (about 6-7 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry tests
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Thyroid function testing
o
Blood clotting testing
o
Tumor marker testing
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood
Cycle 1 Day 15
The following tests and procedures will take about 3-4 hours.

You will be asked about the medications you are currently taking and have 
taken in the past including herbal medications

Part 1 (Dose Escalation) only:
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IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
o
You will take your dose of sorafenib (at home or in the clinic)
o
Nivolumab will be infused into a vein in your arm or port if you have 
previously had one placed

Part 2 (Safety Cohort) only:
o
You will take your dose of sorafenib (at home or in the clinic)
o
Nivolumab will be infused into a vein in your arm or port if you have 
previously had one placed

You will be asked about any side effects you’re having

Your drug diary will be checked
o
The study team will check your drug diary to make sure you’re taking 
Sorafenib at the right schedule

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

Your urine will be collected for the following test:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study (must 
be done 24 hours prior to receiving your dose of nivolumab).

Your blood will be collected (about 6 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry tests
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Blood clotting testing
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
Cycle 2 Day 1
The following tests and procedures will take about 3-4 hours.

You will be asked about the medications you are currently taking and have taken 
in the past including herbal medications

You will take your dose of sorafenib (at home or in the clinic)

Nivolumab will be infused into a vein in your arm or port if you have previously 
had one placed

You will be asked about any side effects you’re having

Your drug diary will be checked
o
The study team will check your drug diary to make sure you’re taking 
Sorafenib at the right schedule
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

Your urine will be collected for the following tests:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study (must 
be done 24 hours prior to receiving your dose of nivolumab).
o
Kidney and bladder function test

Your blood will be collected (about 5-6 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry testing
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Thyroid function testing
o
Blood clotting ability
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood
Cycle 2 Day 15
The following tests and procedures will take about 3-4 hours.

You will be asked about the medications you are currently taking and have 
taken in the past including herbal medications

You will take your dose of sorafenib (at home or in the clinic)

Nivolumab will be infused into a vein in your arm or port if you have previously 
had one placed

You will be asked about any side effects you’re having

Your drug diary will be checked
o
The study team will check your drug diary to make sure you’re taking 
Sorafenib at the right schedule

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

Your urine will be collected for the following tests:
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study (must 
be done 24 hours prior to receiving your dose of nivolumab).

Your blood will be collected (about 4-5 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry tests
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Blood clotting testing
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood

Your drug diary will be checked
o
The study team will check your drug diary to make sure you’re taking 
Sorafenib at the right schedule
Cycle 3 Day 1 and beyond
You will be asked to come into the clinic on day 1 of each Cycle. The following tests and 
procedures will take about 5-7 hours when including scans, or 3-4 hours without scans.

You will be asked about the medications you are currently taking and have 
taken in the past including herbal medications

You will take your dose of sorafenib (at home or in the clinic)

Nivolumab will be infused into a vein in your arm or port if you have previously 
had one placed.
o
Part 2 (Safety Cohort) only: Depending on how you respond to 
nivolumab, your study doctor may change your dosing schedule for 
nivolumab to a monthly infusion (Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 
Day 1, etc.).

You will be asked about any side effects you’re having

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

Approximately every 8 weeks (or 2 complete cycles), you will have a computed 
tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, 
abdomen, and pelvis.

Your urine will be collected for the following tests:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study (must 
be done 24 hours prior to receiving your dose of nivolumab).
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IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
o
Kidney and bladder function tests

Your blood will be collected (about 5-7 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry tests
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Blood clotting testing
o
Thyroid function testing
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
o
Tumor marker testing
o
On C3D1 and C7D1 Only: Additional blood samples to study the 
immune cells and other molecular markers in your blood
Cycle 3 Day 15 and beyond
You will be asked to come into the clinic on day 15 of each Cycle. The following tests 
and procedures will take about 1-2 hours.

You will be asked about the medications you are currently taking and have 
taken in the past including herbal medications

You will take your dose of sorafenib (at home or in the clinic)

Nivolumab will be infused into a vein in your arm or port if you have previously 
had one placed

You will be asked about any side effects you’re having

Your vital signs will be taken (temperature, blood pressure, respirations, and 
heart rate)

Your urine will be collected for the following test:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study (must 
be done 24 hours prior to receiving your dose of nivolumab).

Your blood will be collected (about 3-4 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Blood chemistry tests
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Blood clotting testing
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
When you are finished receiving Sorafenib and Nivolumab...
After you are finished taking Sorafenib and Nivolumab, the following tests and 
procedures will be performed.
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
Safety Follow Up
These visits will occur once you finish taking your study drugs.
Safety Follow Up Visit 1 (30 days after last dose)
This visit will take about 1-2 hours.

You will be asked about the medications you are currently taking and have 
taken in the past including herbal medications

You will be asked about any side effects you’re having

Your drug diary will be checked
o
The study team will check your drug diary to make sure you’re taking 
sorafenib at the right schedule

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

You will have a computed tomography (CT) scan or magnetic resonance 
imaging (MRI) of the chest, abdomen, and pelvis. It may not be performed if it 
was done within 28 days prior to this visit.

Your urine will be collected for the following tests:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study.
o
Kidney and bladder function tests

Your blood will be collected (about 6-7 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Blood chemistry tests
o
Blood clotting testing
o
Thyroid function testing
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
o
Tumor marker testing
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood
Safety Follow Up Visit 2 (100 days after last dose)
This visit will take about 1-2 hours.
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD

You will be asked about the medications you are currently taking and have 
taken in the past including herbal medications

You will be asked about any side effects you’re having

You will have a physical examination including measurement of your height, 
weight, and vital signs (temperature, blood pressure, respirations, and heart 
rate)

You will be asked about your ability to perform daily activities (performance 
status)

Your liver function will be assessed by physical exam and the results of serum 
liver tests

You will have a computed tomography (CT) scan or magnetic resonance 
imaging (MRI) of the chest, abdomen, and pelvis. Having these scans may not 
be required if the most recent scans were performed within 28 days prior to this 
visit.

Your urine will be collected for the following tests:
o
Pregnancy test for women of childbearing potential. Results of the 
pregnancy test must be negative for you to participate in this study.
o
Kidney and bladder function tests

Your blood will be collected (about 5-6 teaspoons) by inserting a needle into a 
vein in your arm. The blood sample will be used for the following:
o
Complete blood count (looking at your red and white blood cells and 
platelets)
o
Blood chemistry tests
o
Blood clotting testing
o
Thyroid function testing
o
Pregnancy test: if you are a woman of childbearing potential and your 
urine results could not be confirmed as negative
o
Additional blood samples to study the immune cells and other molecular 
markers in your blood
Long term Follow up
After your last dose of nivolumab and sorafenib, the study team will check on your 
health and disease status every 3 months for up to two years. This may be during your 
routine visits with your doctor, or by telephone.
How long will I be in the study?
You will be asked to take sorafenib and nivolumab until your disease gets worse, if 
there are too many bad side effects from the study drugs, if you decide you don’t want 
to participate in the study, or if the study closes. After you are finished taking nivolumab 
and sorafenib, the study team will check on your health and disease status for up to two 
years after your last dose of the study drugs.
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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Can I continue study drugs if my disease gets worse?
With most anti-cancer drugs, an increase in the size or number of tumors detected with 
imaging scans (such as CT/MRI scans) or a physical examination indicates that your 
disease has gotten worse (progressed). This usually means that you should consider 
switching to another therapy. However, with cancer immunotherapy drugs, that is not 
always the case. An early increase in the size or number of tumors may not always be a 
sign of disease progression. The study drugs are thought to work by stimulating your 
immune system to attack your tumors. When cells from your immune system fight your 
tumors, one result can be an apparent increase in the size or number of those tumors. 
In some patients, an early increase can be followed by a reduction in tumor size later.
Because of this possibility, you will have the option of continuing to receive the study 
drugs even after a scan early in the course of the study shows an increase in your 
tumors. A later scan will help to see if the increase was caused by real worsening of 
your disease or if it was caused by immune cells entering your tumors. This 
confirmatory scan may be performed sooner than 8 weeks after the original scan that 
showed your tumor had gotten larger, depending on any symptoms you may be having 
or other test results. Your study doctor will let you know.
You should carefully discuss with your study doctor the option to continue in spite of an 
apparent increase in tumor size. There are risks of continuing to receive the study 
drugs. This is because of the possibility that an increase in your tumor represents true 
worsening of your disease. In that case, you may be exposed to the potential risk of 
side effects due to the study drugs or from cancer progression. Also, there may be risk 
in delaying the start of other treatment options that may stop your cancer from growing. 
In addition, your cancer may progress to the point that you are no longer able to receive 
other potentially effective therapies.
After you talk with your study doctor, you will need to decide if you want to continue with 
study drug infusions in spite of apparent disease progression.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about 
stopping or decide to stop. He or she will tell you how to stop your participation safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the study drugs can be evaluated by your doctor. Another reason to tell your doctor that 
you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you.
The study doctor may stop you from taking part in this study at any time if he/she 
believes it is in your best interest, if you do not follow the study rules, or if the study is 
stopped.
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be 
watched carefully for any side effects. However, doctors don't know all the side effects 
that may happen. Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after 
you stop taking the study drugs. In some cases, side effects can be serious, long 
lasting, or may never go away. There also is a risk of death.
You should talk to your study doctor about any side effects you experience while taking 
part in the study.
Side Effects Associated with Nivolumab
Nivolumab may cause one or more of the side effects listed below. This information is 
based on data from cancer subjects in other clinical trials with nivolumab. In addition, 
there may be side effects that are not yet known that may occur. You should tell your 
doctor or nurse right away about any possible side effects you experience.
Very common side effects of nivolumab include [more than 10% of subjects]:

Diarrhea

Fatigue

Itching

Rash
Common side effects of nivolumab include [1% to less than 10% of subjects]:

Abdominal pain

Allergic reaction/hypersensitivity

Abnormal liver function tests (such as alkaline phosphatase, ALT, AST, or 
bilirubin) which can be a sign of liver inflammation or injury and can be 
associated with abnormal liver function

Chills

Constipation

Cough

Creatinine increased: lab test result associated with decreased kidney function

Decreased appetite

Dizziness

Dry mouth

Dry skin

Fever

Headache

Increased blood sugar

Lipase and/or amylase blood tests increased which are lab tests which can be 
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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R. KATE KELLEY, MD
associated with pancreas inflammation or pancreatitis

Inflammation of the colon

Inflammation of the mouth

Infusion related reaction

Loss of color (pigment) from areas of skin

Lung inflammation (pneumonitis - see details below)

Musculoskeletal pain

Nausea

Redness

Shortness of breath

Sodium levels in the blood low

Swelling, including face, arms, and legs

Thyroid gland function decreased

Thyroid gland function increased

Thyroid stimulating hormone increased: lab test result associated with abnormal 
thyroid function

Tingling, burning, numbness or weakness, possibly in arms, legs, hands and 
feet

Vomiting
Uncommon side effects of nivolumab include [0.1% to less than 1% of subjects]:

Adrenal gland function decreased

Bilirubin (liver function blood test) increased

Bronchitis

Dehydration

Diabetes which may require treatment with insulin

Double vision

Dry eye

Erythema multiforme: skin inflammatory reaction

Hair loss

Heart rate increased

Heart rhythm abnormal

High blood pressure

Hives

Inflammation of the eye

Inflammation of the kidney

Inflammation of the pancreas

Inflammation of the pituitary gland

Inflammation of the stomach

Inflammation of the thyroid gland

Joint pain or stiffness

Liver inflammation

Low blood pressure
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


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
Muscle inflammation

Pemphigoid: blistering of the skin or mouth caused by the immune system 
attacking healthy tissue

Pituitary gland function decreased

Psoriasis: characterized by patches of abnormal, scaly skin

Renal (kidney) failure or kidney injury

Respiratory failure

Upper respiratory tract infection

Vision blurred
Rare side effects of nivolumab include [ 0.01% to less than 0.1% of subjects]:

Anaphylactic reaction (severe allergic reaction)

Cranial nerve disorder

Damage to the protective covering of the nerves in the brain and spinal cord

Diabetes complications resulting in excess blood acid

Disease caused by body’s immune system attacking healthy organs

Drug induced liver injury

Guillain-Barre syndrome, an autoimmune disorder associated with progressive 
muscle weakness or paralysis

Inflammation of blood vessels

Inflammation of the lining of the brain and spinal cord

Inflammation of the brain, potentially life-threatening or fatal

Lung infiltrates, associated with infection or inflammation

Muscle inflammation

Myasthenic syndrome (neurologic syndrome characterized by muscle 
weakness) including myasthenia gravis, a nerve disease that may cause 
weakness of eye, face, breathing, and swallowing muscles.

Polymyalgia rheumatica, an inflammatory disorder causing muscle pain and 
stiffness

Rhabdomyolysis: muscle fiber released into the blood stream which could 
damage your kidneys

Rosacea: acne-like skin condition resulting in redness of face

Rupture of the intestine/hole in the intestine

Sarcoidosis, a disease involving abnormal collections of inflammatory cells 
(granulomas) in organs such as lungs, skin, and lymph nodes

Stevens Johnson syndrome: inflammatory disorder of skin and mucous 
membranes, resulting in blistering and shedding of skin

Syndrome associated with fever, white blood cell activation and abnormal 
function (including destruction of other blood cells by certain white blood cells), 
low blood cell counts, rash, and enlargement of the spleen

Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering 
and peeling of the top layer of skin resembling a severe burn

Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of the 
lymph nodes which causes the lymph nodes to become enlarged, inflamed and 
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painful, commonly affecting lymph nodes of the neck and possibly associated 
with fever or muscle and joint pains

Vogt Koyanagi Harada syndrome; a disease that affects the pigmented tissue; 
this may affect the eye leading to swelling, pain and/or blurred vision; the ear 
leading to hearing loss, ringing in the ears and /or the skin leading to loss of skin 
color

Inflammation of heart muscle or lining (such as myocarditis, pericarditis) which 
can cause altered heart rhythm or in rare cases heart failure
Lung Inflammation (pneumonitis): In rare cases, nivolumab can cause inflammation 
of the tissues of the lung. This adverse effect has been reported infrequently in patients 
treated with nivolumab. While many patients with x-ray or CT abnormalities have not 
developed any symptoms, some patients have developed mild to severe symptoms and 
in rare cases, death has occurred as a result of their lung inflammation. Signs and 
symptoms of lung inflammation may include difficulty breathing, pain or discomfort while 
breathing, chest pain, cough, shortness of breath, increased rate of breathing, fever, 
low blood oxygen levels, or fatigue.
Your study doctor and nurse will watch you closely for changes in your ability to breathe 
and for other signs or symptoms that might show you are developing this type of lung 
inflammation and will perform regular tests including physical exams, measurement of 
oxygen levels through non- invasive testing (i.e., pulse oximeter), blood tests, chest x-
rays and/or CT scans.
People who had prior organ, bone marrow, or stem cell transplant are not eligible to 
participate in this study. If you have a solid organ transplant after participating in this 
study, you would be at risk of organ rejection, which can be serious or life threatening, If 
you have a bone marrow or stem cell transplant after participating in this study, you 
would be at risk for graft versus host disease or other complications which can be 
serious or life threatening.
Please inform your study doctor or nurse AT ONCE if you experience any of the 
following:

Any new or increased shortness of breath;

Any new or increased chest pain;

Any new or increased pain/difficulty while breathing;

Any new or increased cough or any significant change in your type of cough; for 
example, any new or increased mucous or blood in your cough;

Any change in the amount of oxygen you require;

Any fever, fatigue, or other symptoms that occur at the same time as any 
changes to your breathing or other lung symptoms.
If you start to develop symptoms, your study doctor will ask you to return to the clinic for 
additional tests, which could include a physical exam, measurement of oxygen levels, 
blood tests, chest x-rays, and/or CT scans. You will be monitored very closely for 
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changes in your overall lung symptoms, monitoring may require hospitalization. You 
may require specific treatment in order to control pneumonitis. You may also be seen by 
a special doctor called a pulmonologist, who has special training to be an expert in how 
your lungs work.
Prolonged treatment with medicines that suppress inflammation, sometimes needed to 
manage the side effects of nivolumab, may lower your body’s ability to fight off certain 
infections (i.e., opportunistic infections). These infections may require treatment with 
antibiotic or antifungal medications and may be fatal.
Side Effects Associated with Sorafenib
You might experience some or all of these side effects. It is also possible that you might 
experience side effects that are unknown at this time. As is true for any experimental 
drug, there may be unknown and potentially serious or life-threatening side effects that 
could occur with sorafenib.
Very common side effects of sorafenib are [more than 10% of subjects]:

Diarrhea

Feeling sick (nausea)

Feeling weak or tired (fatigue)

Pain (including mouth pain, abdominal pain, headache, bone pain, tumor pain)

Hair loss (alopecia)

Flushed or painful palms or soles (hand foot skin reaction)

Itching or rash

Throwing up (vomiting)

Bleeding)

High blood pressure, or increases in blood pressure (hypertension)

Infections

Loss of appetite (anorexia)

Constipation

Joint pain (arthralgia)

Fever

Weight loss

Dry skin

Low phosphate levels in the blood (hypophosphatemia)

Increased levels of pancreatic enzymes (amylase or lipase) in the blood

Decreased levels of lymphocytes in your blood stream (lymphopenia)

Reddening of the skin in patches (erythema)
Common side effects of sorafenib include [up to 10% of subjects]:

Flu-like illness

Indigestion (dyspepsia)
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
Difficulty swallowing (dysphagia)

Inflamed or dry mouth, tongue pain (stomatitis and mucosal inflammation)

Low calcium levels in the blood (hypocalcemia)

Low potassium levels in the blood (hypokalemia)

Low glucose levels in the blood (hypoglycemia)

Muscle pain (myalgia)

Disturbed sensations in fingers and toes, including tingling or numbness 
(peripheral sensory neuropathy)

Depression

Erection problems (impotence)

Altered voice (dysphonia)

Acne

Inflamed, dry, or scaly skin that sheds (dermatitis, skin desquamation)

Heart failure

Heart attack (myocardial infarction) or chest pain

Tinnitus (ringing sound in the ear)

Kidney failure

Abnormally high levels of protein in the urine (proteinuria)

General weakness or loss of strength (asthenia)

Decrease in the number of white blood cells (leukopenia and neutropenia)

Decrease in number of red blood cells (anemia)

Low number of platelets in the blood (thrombocytopenia)

Inflammation of hair follicles (folliculitis)

Underactive thyroid gland (hypothyroidism)

Low sodium levels in the blood (hyponatremia)

Distortion of the sense of taste (dysgeusia)

Red in the face and often in other areas of the skin (flushing)

Runny nose (rhinorrhea)

Heartburn (gastroesophageal reflux disease)

Skin cancer (keratoacanthomas/squamous cell cancer of the skin)

A thickening of the outer layer of the skin (hyperkeratosis)

A sudden, involuntary contraction of a muscle (muscle spasms)

Increases in liver enzymes (transaminases)
Uncommon side effects of sorafenib include [up to 1% of subjects]:

Inflamed stomach lining (gastritis)

Pain in the tummy (abdomen) caused by pancreatitis, inflammation of the gall 
bladder and/or bile ducts

Yellow skin or eyes (jaundice) caused by high levels of bile pigments 
(hyperbilirubinemia)

Allergic like reactions (including skin reactions and hives)

Dehydration

Enlarged breasts (gynecomastia)
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
Breathing difficulty (lung disease)

Eczema

Overactive thyroid gland (hyperthyroidism)

Multiple skin eruptions (erythema multiform)

Abnormally high blood pressure

Holes in the gut wall (gastrointestinal perforation)

Reversible swelling in the rear part of the brain that can be associated with 
headache, altered consciousness, fits, and visual symptoms including visual 
loss (reversible posterior leukoencephalopathy)

A sudden, severe allergic reaction (anaphylactic reaction)

Transient increase in blood enzymes (alkaline phosphatase)

Abnormal lab test results reflecting blood clotting (INR, abnormal prothrombin 
level)

Serious bleeding (including bleeding in the brain, gut wall, and respiratory tract; 
hemorrhage) 
Rare side effects of sorafenib include: [up to 0.1% of subjects]

Allergic reaction when swelling of the skin (e.g. face, tongue) that may cause 
difficulty in breathing or swallowing (angioedema)

Abnormal heart rhythm (QT prolongation)

Inflammation of the liver, which may lead to nausea, vomiting, abdominal pain, 
and jaundice (drug induced hepatitis)

A sunburn-like rash that may occur on skin that has previously been exposed to 
radiotherapy and can be severe (radiation recall dermatitis)

Serious reactions of the skin and/or mucous membranes which may include 
painful blisters and fever, including extensive detachment of the skin (Stevens-
Johnson syndrome and toxic epidermal necrolysis)

Abnormal muscle breakdown which can lead to kidney problems 
(rhabdomyolysis)

Damage of the kidney causing them to leak large amounts of protein (nephrotic 
syndrome)

Inflammation of the vessels in the skin which may result in rash (leucocytoclastic 
vasculitis)
Frequency cannot be estimated from data for the following side effect:

Impaired brain function that can be associated with drowsiness, behavioral 
changes, or confusion (encephalopathy)

Aneurysm and artery dissections
Risks from Study Drug Combination
There may be additional side effects related to the combination of nivolumab and 
sorafenib that are not yet known. It is possible that this combination of drugs will cause 
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new or more serious side effects than taking these drugs separately. You will be 
monitored closely for side effects and your doctor may change your medications if it 
appears that this combination is causing serious side effects. You should tell your 
doctor about any side effects you experience while on this study. When additional 
information about side effects is known, you will be notified of any further study drug 
related effects.
Risks related to study procedures

Blood drawing (venipuncture) risks: Drawing blood may cause temporary 
discomfort from the needle stick, bruising, infection, and fainting.

Dose Escalation risks: Since patients will be assigned to different doses of study 
drug, some patients may receive a dose of the drug that is too small to be effective 
while others may receive a higher dose that may cause increased side effects. You 
can ask your study doctor what dose you will be given.

Infusion risks: As with most intravenous products, you may experience pain, 
irritation, swelling or bruising, or a slight chance of infection at the site where the 
intravenous catheter (small tube) is inserted into your vein. These side effects may 
also be observed at the site where blood is drawn for laboratory tests.

Intravenous line risks: The temporary placement of an intravenous line may 
cause discomfort when inserting the needle, as well as bruising; bleeding; and 
rarely, infection.

Radiation risks: This research study involves exposure to radiation. Not all this 
radiation exposure is necessary for your medical care and is for research purposes 
only. This amount of radiation may involve a low, lifetime risk of cancer. However, 
we believe that this risk, given your overall medical condition is not clinically 
relevant. If you have any questions regarding the use of radiation or the risks 
involved, please consult your study doctor.

CT scan risks: CT scans involve the risks of radiation (see above). In addition, if 
contrast material (iodine dye) is used, there is a slight risk of developing an allergic 
reaction, from mild (itching, rash) to severe (difficulty breathing, shock, or rarely, 
death). The contrast material may also cause kidney problems, especially if you are 
dehydrated or have poor kidney function. The study doctors will ask you about any 
allergies or related conditions before the procedure. If you have any of these 
problems, you may not be allowed to have a CT scan.
Having a CT scan may mean some added discomfort for you. In particular, you may 
be bothered by feelings of claustrophobia when placed inside the CT scanner, or by 
lying in one position for a long time. If contrast material is used, you may feel 
discomfort when it is injected. You may feel warm and flushed and get a metallic 
taste in your mouth. Rarely, the contrast material may cause nausea, vomiting or a 
headache.

MRI risks: Because the MRI machine acts like a large magnet, it could move iron- 
containing objects in the MRI room during your examination, which in the process 
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could possibly harm you. Precautions have been taken to prevent such an event 
from happening; loose metal objects, like pocket knives or key chains, are not 
allowed in the MRI room. If you have a piece of metal in your body, such as a 
fragment in your eye, aneurysm clips, ear implants, spinal nerve stimulators, or a 
pacemaker, you will not be allowed into the MRI room and cannot have an MRI.
Having an MRI may mean some added discomfort for you. In particular, you may 
be bothered by feelings of claustrophobia and by the loud banging noise during the 
study. Temporary hearing loss has been reported from this loud noise. This is why 
you will be asked to wear earplugs. At times during the test, you may be asked to 
not swallow for a while, which can be uncomfortable.
Because the risks to a fetus from MRI are unknown, pregnant women must not 
participate in this study.
Contrast agent (gadolinium) risks: A few side effects of gadolinium injection 
such as mild headache, nausea, and local pain may occur. Rarely (less than 
1% of the time) low blood pressure and lightheadedness occurs. This can be 
treated immediately with intravenous fluids. Very rarely (less than on in one 
thousand), patients are allergic to gadolinium. These effects are most 
commonly hives and itchy eyes, but more severe reactions have been seen 
which result in shortness of breath.
Patients with severe kidney disease sometimes have a bad reaction to 
gadolinium contrast. The condition is called nephrogenic systemic fibrosis 
(NSF). It can cause skin to tighten or scar and can damage internal organs. 
Sometimes it can be life-threatening. There are no reports of NSF in patients 
with normal kidney function. Before you have a MRI scan requiring an injection 
of gadolinium contrast, you will have a blood test in order to check the function 
of your kidneys. Based on your medical history and the results of the test, a 
doctor will decide whether it is safe for you to undergo the MRI scans.

Reproductive risks: You should not become pregnant or father a baby while on 
this study because the drugs in this study can affect an unborn baby. Women 
should not breastfeed a baby while on this study. It is important to understand that 
you need to use two methods of birth control while on this study. If you are a 
woman of child bearing potential, you need to continue using birth control for 5 
months after your last dose of each study drug, and if you are a male partner of a 
woman of child bearing potential, 7 months after your last dose of each study drug. 
Check with your study doctor about what kind of birth control methods to use and 
how long to use them. Some methods might not be approved for use in this study.

Hepatitis test risks: Being tested for Hepatitis may cause anxiety regardless of the 
test results. A positive test result means that you have been infected with a virus. 
Receiving positive results may make you very upset. If other people learn about 
your positive test results, you may have trouble obtaining insurance or employment. 
If you receive positive results, the study doctor will discuss your care and treatment 
options with you. If your test is negative, there is still the possibility that you could 
be infected with the Hepatitis virus and test positive at some time in the future. 
There is always the possibility that the test results could be wrong.
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
Electrocardiogram risks: The ECG involves placing electrodes on the skin. You 
may experience an allergic reaction to the adhesive used to attach the electrodes to 
the skin. These symptoms are generally mild and clear up on their own. Please let 
your doctor know if you are aware of any allergies.

Unknown Risks: The experimental drugs may have side effects that no one knows 
about yet. The researchers will let you know if they learn anything that might make 
you change your mind about participating in the study.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better. While doctors hope 
that sorafenib in combination with nivolumab will be more useful against cancer 
compared to the usual treatment, there is no proof of this. We do know that the 
information from this study will help doctors learn more about sorafenib and nivolumab 
as a treatment for cancer. This information could help future cancer patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study.

Taking part in another study.

Getting no treatment.

Getting comfort care, also called palliative care. This type of care helps reduce 
pain, tiredness, appetite problems and other problems caused by the cancer. It 
does not treat the cancer directly, but instead tries to improve how you feel. 
Comfort care tries to keep you as active and comfortable as possible.
Please talk to your doctor about your choices before deciding if you will take part in this 
study.
How will information about me be kept confidential?
Participation in research involves some loss of privacy. We will do our best to make 
sure that information about you is kept confidential, but we cannot guarantee total 
privacy. Some information from your medical records will be collected and used for this 
study. If you do not have a UCSF medical record, one will be created for you. Your 
signed consent form and some of your research tests will be added to your UCSF 
medical record. Therefore, people involved with your future care and insurance may 
become aware of your participation and of any information added to your medical 
record as a result of your participation. Study tests that are performed by research labs, 
and information gathered directly from you by the researchers will be part of your 
research records and may be added to your medical record. Your personal information 
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may be given out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be 
used.
California regulations require laboratories to report new cases of hepatitis B and 
hepatitis C infection to the county public health department. The reports include the 
patient’s name, social security number, and other identifying information. Information 
about these new infections is used to track these diseases statewide and nationwide. 
Other than this required reporting, your results will be treated confidentially by the study 
staff. Personally identifying information will not be reported to other departments or 
agencies. For a full list of reportable conditions, go to the following link:  
https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Document%20Library/Report
ableDiseases.pdf
Authorized representatives from the following organizations may review your research 
data for the purpose of monitoring or managing the conduct of this study:

Representatives of Bayer

Representatives of the University of California

Representatives of the Food and Drug Administration (FDA)

Representatives of the National Cancer Institute (NCI)
Are there any costs to me for taking part in this study?
Two types of procedures will be done during this study. Some are part of your standard 
medical care and others are only for research. You or your insurer will be billed for the 
standard medical care. You will be responsible for your co-pays, deductibles, and any 
other charges that your insurer will not pay. There is a possibility that your insurer may 
not cover all standard medical care costs if you are receiving medical services out of 
network. Any procedures done only for research will not be charged to you or your 
insurer.
If you have questions about what costs you will be responsible for, please talk with the 
study investigator before deciding to enroll in the study. Depending on the type of study, 
some of your costs could be substantial.
Bayer will provide sorafenib at no cost to you. Nivolumab will be billed to you or your 
insurance.
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
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It is important that you tell your study doctor, R. Kate Kelley MD, if you feel that you 
have been injured because of taking part in this study. You can tell the doctor in person 
or call him/her 
.
Treatment and Compensation for Injury: If you are injured as a result of being 
in this study, the University of California will provide necessary medical 
treatment. The costs of the treatment may be billed to you or your insurer just like 
any other medical costs or covered by the University of California depending on 
a number of factors. The University does not normally provide any other form of 
compensation for injury. For further information about this, you may call the office 
of the Institutional Review Board at 415- 476-1814.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to 
take part in the study. If you decide to take part in this study, you may leave the study at 
any time. No matter what decision you make, there will be no penalty to you and you 
will not lose any of your regular benefits. Leaving the study will not affect your medical 
care. You can still get your medical care from our institution.
We will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you 
have about this study. Contact your study doctor R. Kate Kelley at the UCSF GI 
Oncology clinic, 
.
If you wish to ask questions about the study or your rights as a research participant to 
someone other than the researchers or if you wish to voice any problems or concerns 
you may have about the study, please call the office of the Institutional Review Board at 
415-476-1814.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time.
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OPTIONAL RESEARCH PARTICIPATION
This section of the informed consent form is about additional research that is being 
done using tumor samples after the main research has been completed. You can still be 
in the main study even if you say "no" to taking part in this additional research.
Optional Research on Leftover Samples (All Subjects)
If you give permission, biomarker studies will also be performed on archival (leftover) 
tissue collected at any time when you have tumor tissue available from a previous 
surgery or biopsy.
If you agree, specimens collected during this study would also be saved (“banked”) for 
future research to learn more about cancer and other diseases.
The research that may be done with tissue is not designed specifically to help you. It 
might help people who have liver cancer and other diseases in the future.
Reports about research done with your tissue will not be given to you or your doctor. 
These reports will not be put in your health record. The research will not have an effect 
on your care. Results from the future research may be published but your data will not 
be reported individually.
Things to Think About
The choice to let us keep specimens for future research is optional and is up to you. No 
matter what you decide to do, it will not affect your care.
Your tissue will be stored in a repository at UCSF. If you decide now that your 
specimens can be kept for future research, you can change your mind at any time. Just 
contact the study doctor, R. Kate Kelley, MD, in writing at the address below, and let us 
know that you do not want us to keep your specimens.
R. Kate Kelley, MD
UCSF GI Medical Oncology Dept.
Any identifiable specimen that remains will no longer be used for research and 
destroyed. However, if any research has already been done using portions of your 
specimens, the data will be kept and analyzed as part of those research studies.
In the future, people who do research may need to know more about your health. While 
the study doctor may give them reports about your health, it will not give them your 
name, address, phone number, or any other information that will let the researchers 
know who you are.
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Your specimen will be used only for research and will not be sold. The research done 
with your tissue may help to develop new products in the future. You will not be paid for 
allowing your tumor samples to be used in research even though the research done 
with your samples may help to develop new products in the future. You will not receive 
any payment or financial benefit from any products, tests, or discoveries derived from 
these samples.
Benefits
The benefits of research using tissue and blood include learning more about what 
causes cancer and other diseases, how to prevent them, and how to treat them.
Risks
Confidentiality: Donating specimens may involve a loss of privacy, but information about 
you will be handled as confidentially as possible. The manager of the tissue bank and 
select tissue bank staff members will have access to information about you but they will 
not release any identifying information about you to researchers using your specimen. 
The UCSF IRB and other University of California personnel also may see information 
about you to check on the tissue bank such as for auditing purposes.
All records will be coded and permanently kept in password protected electronic files or 
locked files with access limited to the study investigators. All collected specimens will be 
assigned a corresponding code number by the study investigators and will then be 
processed without knowledge of your identity. Only the UCSF investigator has access 
to the records that link this coded ID number to you. In addition, specimens shared with 
other researchers, and the coded ID number will be used to identify your specimens.
Genetic information about your blood or tumor samples that results from this study does 
not have medical or treatment importance at this time, so you will not receive the results 
of this testing. However, there is a risk that information about taking part in a genetic 
study may influence insurance companies and/or employers regarding your health. 
Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to employers, health providers, 
insurance companies, and others. Patterns of genetic variation also can be used by law 
enforcement agencies to identify a person or his/her relatives. Therefore, your genetic 
information potentially could be used in ways that could cause you or your family 
distress, such as by revealing that you (or a relative) carry a genetic disease or by 
leading to the denial of employment or insurance for you (or a relative). To further 
safeguard your privacy, genetic information obtained in this study will not be placed in 
your medical record.
It is also possible that your or your family’s privacy could be invaded in ways that are 
currently not possible but made possible in the future by advances in technology. For 
instance, some scientists performing research with tissue bank materials may try to 
determine the code of part or all of your chromosomes. This coding could be a way to 
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accurately identify the sample as coming from you. If a scientist publishes your coding, 
the source of that coding could be identified as you if someone else has your code 
through other means to compare to the published coding. The likelihood of this 
happening is very small, but future technology developments may increase the 
possibility of this occurring.
Additionally, due to the rarity of the cancer and the likelihood that the research done 
with the tissue samples will be published in the future, it may be possible to identify you 
from publications even though your name will not be used in any published reports.
Making Your Choice
Please read the sentence below and think about your choice. After reading put your 
initials in the "Yes", or "No" box. If you have any questions, please talk to your doctor or 
nurse, or call our Institutional Review Board at 415-476-1814.
No matter what you decide to do, it will not affect your care.
1. Any leftover tissue samples collected for this clinical trial or any leftover samples 
from other biopsies or surgeries I have had for regular medical care may be used 
for future research.
YES
NO
************************************************************
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023


CC# 174523
ICF 04-06-2021
PAGE 29 OF 29
R. KATE KELLEY, MD
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of 
Rights to keep.
You will be asked to sign a separate form authorizing access, use, creation, or 
disclosure of health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to 
which you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
Date
Witness (only required if the participant is a non-English speaker)
IRB NUMBER: 17-23590
IRB APPROVAL DATE: 08/23/2022
IRB EXPIRATION DATE: 08/22/2023