Sorafenib and Nivolumab as First-Line Therapy in Treating Participants With Unresectable, Locally Advanced or Metastatic Liver Cancer

OUTLINE: This is a dose-escalation and expansion study of sorafenib in combination with
nivolumab.

DOSE-ESCALATION (Part 1): Between 3-12 patients will be enrolled in Part 1. Participants
receive sorafenib 400 mg orally (PO) once daily (QD) or twice daily (BID) on days 1-28, and
nivolumab 240 mg intravenously (IV) over 30 minutes on days 1 and 15. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

DOSE EXPANSION (Part 2): New participants are assigned to 1 of 2 arms.

LEAD-IN ARM I: Participants receive nivolumab IV over 30 minutes on days 1 and 15, and
sorafenib PO beginning on day 15 of course 1, then on days 1-28 of subsequent courses.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

LEAD-IN ARM II: Participants receive sorafenib PO on days 1-28, and 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.

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

Inclusion Criteria:

- Histologic or cytologic diagnosis of unresectable, locally advanced and/or metastatic
hepatocellular carcinoma (HCC) not amenable to curative surgery, transplantation, or
ablative therapies based upon assessment of treating investigator

- 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

- Untreated/pretreatment archival tumor tissue must be available for correlative
analyses

- Eastern Cooperative Oncology Group (ECOG) 0 or 1 at enrollment

- At least 4 weeks after any prior chemoembolization, radioembolization, local ablative
therapies, or hepatic radiation and recovery to =< grade 1 treatment-related toxicity

- At least 6 weeks after any major surgery including prior hepatic resection and
recovery to =< grade 1 treatment-related toxicity

- At least 7 days after minor surgery (such as central venous access) or biopsy and
recovery to =< grade 1 treatment-related toxicity

- 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

- Blood pressure less than 140/90 mm Hg with or without anti-hypertensive therapy

- Patients may be rescreened after initial ineligibility if due to elevated blood
pressure, if adequately medically managed within approximately 30 days

- Absolute neutrophil count at least 1,200/mcL

- Platelets at least 75,000/mcL

- Hemoglobin at least 9 g/dL

- Total bilirubin less than 2 mg/dL or 1.5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) less than
5 X ULN

- International normalized ratio (INR) less than 1. 5 X ULN

- Albumin at least 2.8 g/dL

- Creatinine less than 1. 5 X ULN and/or creatinine clearance >= 60 mL/min

- Child Pugh A score 5 or 6 liver function

- If HBV surface antigen (sAg) and/or core antibody (Ab) positive, must be treated with
appropriate antiviral therapy according to institutional practice with HBV
deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) less than 500 IU/mL

- If clinical or histologic diagnosis of cirrhosis and/or clinical or radiographic
evidence esophageal or gastric varices, must have had esophagogastroduodenoscopy (EGD)
surveillance and adequate endoscopic therapy according to institutional standards

- Able to swallow and retain oral medications

- Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 28
days before study enrollment

- 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

- Able to understand and willingness to provide informed consent, and the willingness to
comply with the requirements of the protocol

- Subjects must have signed and dated an Institutional Review Board
(IRB)/Independent Ethics Committees (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

Exclusion Criteria:

- Any prior systemic therapy for HCC

- Known fibrolamellar or mixed HCC-cholangiocarcinoma histology

- Requirement for diuretics, paracentesis, or other medications or procedures to control
ascites or hepatic encephalopathy within 6 months before enrollment

- Diuretics or medications such as lactulose used for other indications (e.g.
edema, constipation) are allowed

- History of upper gastrointestinal (GI) bleeding from esophageal and/or gastric varices
within 12 months before enrollment

- Requirement for systemic corticosteroids unless used for adrenal replacement, acute
therapy for asthma or bronchitis exacerbation (=< 2 weeks), or premedication for
contrast allergy

- Topical, intranasal, or inhaled steroids are not excluded

- Active autoimmune condition requiring systemic immunosuppressive medication

- Known human immunodeficiency virus (HIV) infection

- Active coinfection with HBV plus hepatitis delta (D) virus (HDV) or HCV:

- Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV DNA
and detectable HCV ribonucleic acid (RNA)

- Hepatitis D infection (HDV antibody positive) in subjects with detectable
hepatitis B surface antigen or HBV DNA

- Prior allogeneic transplant of any solid organ or bone marrow/stem cells

- Symptomatic hypothyroidism without replacement

- Patients may be rescreened after initiating adequate replacement therapy

- History of seizure disorder requiring antiepileptic medication or brain metastases
with seizures

- Non-healing wound, ulcer, non-healing traumatic bone fracture, or abscess within 30
days of enrollment

- 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

- Central or necrotic lung metastases

- Known brain or leptomeningeal metastases

- Uncontrolled hypertension (systolic pressure >140 mm Hg and/or diastolic pressure > 90
mm Hg [National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events
(CTCAE) v4.0] on repeated measurement) despite optimal medical management

- Active or clinically significant cardiac disease including:

- Congestive heart failure ? New York Heart Association (NYHA) > class II

- Active coronary artery disease including unstable or newly diagnosed angina or
myocardial infarction within 6 months prior to study entry

- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin

- Corrected QT interval (QTc) (Fridericia) > 450 msec on two consecutive
electrocardiograms (ECGs) (baseline ECG should be repeated if QTc is found to be
> 450 msec)

- 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

- Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular
accident (including transient ischemic attacks) or deep venous thrombosis (DVT) within
6 months of informed consent

- Tumor or bland thrombus in hepatic vasculature is not a contraindication provided
hepatic function criteria are met

- Subjects who have used strong CYP3A4 inducers (eg, 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

- Subjects who require therapeutic anticoagulation or anti-platelet therapy

- Low dose aspirin (=< 100 mg/day) is allowed

- Prophylactic doses of low molecular weight heparin (LMWH) are allowed if approved
by study chair or designee

- Subjects with any previously untreated and concurrent cancer that is distinct in
primary site or histology from HCC except cervical cancer in-situ, treated nonmelanoma
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)

- 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

- 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

- Women who are pregnant or breast-feeding at enrollment

- Inability to comply with the protocol and/or not willing or not available for followup
assessments

- Any condition which, in the investigator's opinion, makes the subject unsuitable for
trial participation