A Randomized Controlled Phase 2 Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy

Inclusion Criteria:

- Written informed consent granted prior to initiation of any study-specific screening
procedures

- 18 year of age or older

- Histologically or cytologically confirmed HCC

- Archival, fresh core needle biopsy or fine needle aspiration (FNA) tumor samples

- Received at least one cycle of prior systemic therapy (at least 3 weeks for
continuously administered drugs) and experienced radiographic disease progression or
was unable to tolerate therapy. If intolerance was manifested by a Grade 3 or 4
event of such nature that re-challenge is not acceptable, less than 3 weeks of
continuous administration will be allowed

- Discontinued prior treatment for at least 4 weeks, or at least 2 weeks (14 days) if
drug was administered continuously and orally (e.g. sorafenib or sunitinib), prior to
the study randomization

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1

- Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial
embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol
injection, or cryoablation) must have been completed ≥4 weeks prior to randomization

- Measurable disease as defined by a modified version of the revised Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (see section 9). Tumor
lesions previously treated with local therapy should demonstrate clear dimensional
increase by radiographic assessment in order to be selected as target lesion(s) at
baseline. (Radiological assessment needs to be redone within 7 days prior to
randomization if the pre-study AFP level has increased by more than 30% since the
last AFP level taken one to four months prior to randomization)

- Adequate bone marrow, liver, and renal functions at Pre-Study Visit, defined as:

- Platelet count ≥ 60 × 10^9/L

- Hemoglobin ≥ 9.0 g/dL

- Absolute neutrophil count (ANC) ≥1.5 × 10^9/L

- Total bilirubin ≤ 2 mg/dL

- Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 × upper limit of
normal (ULN)

- Serum creatinine ≤1.5 × ULN

- International normalized ratio (INR) 0.8 to 1.4 or ≤3 for patients receiving
anticoagulant such as coumadin or heparin. Patients who are therapeutically
anticoagulated are allowed to participate provided that no prior evidence of
underlying abnormality exists in these parameters

- Albumin ≥ 2.8 g/dL

- Women of childbearing potential must have a negative pregnancy test performed within
ten days prior to the start of study drug

- Male and female subjects of child-bearing potential must agree to use double-barrier
contraceptive measures, oral contraception, or avoidance of intercourse during the
study and for 90 days after last investigational drug dose received

Exclusion Criteria:

- More than 1 prior systemic regimen

- Child-Pugh B-C cirrhotic status

- Previous or concurrent cancer that is distinct from HCC in primary site or histology,
EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder
tumors (Ta, Tis & T1). Any cancer curatively treated >3 years prior to enrollment is
permitted

- History of congestive heart failure defined as Class II to IV per New York Heart
Association (NYHA) classification within 6 months prior to study entry; active
coronary artery disease (CAD); clinically significant bradycardia or other
uncontrolled, cardiac arrhythmia defined as ≥Grade 3 according to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0,
or uncontrolled hypertension; myocardial infarction occurring within 6 months prior
to study entry (myocardial infarction occurring >6 months prior to study entry is
permitted)

- Active clinically serious infections defined as ≥ Grade 3 according to NCI CTCAE,
version 4.0.

- Substance abuse, medical, psychological or social conditions that may, in the opinion
of the Investigator, interfere with the patient's participation in the study or
evaluation of the study results

- Any condition that is unstable or which could jeopardize the safety of the patient
and his/her protocol compliance

- Known human immunodeficiency virus (HIV) infection

- Pregnancy or breast-feeding

- History of liver transplant

- Inability to swallow oral medications

- Clinically significant gastrointestinal bleeding occurring ≤4 weeks prior to
randomization