Inclusion Criteria

Inclusion criteria:

- Eastern Cooperative Oncology Group Performance Status of 0 or 1

- Child-Pugh score of < 7 (Child-Pugh Class A only)

- Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B not amenable to
locoregional therapy or refractory to locoregional therapy

- Diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or
cytologic confirmation

- There are either clinical, laboratory, or radiographic findings consistent with a
diagnosis of liver cirrhosis

- Has a liver mass measuring at least 2 cm with characteristic vascularization seen on
either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI)
with gadolinium

- At least 1 measurable or evaluable lesion that is viable (ie, is vascularized), and
has not been previously treated with locoregional therapy. A lesion that has been
previously treated will qualify as a measurable or evaluable lesion if there was
demonstrable progression following locoregional therapy

- Previously treated with sorafenib and has discontinued sorafenib treatment at least
14 days prior to randomization. patients may have experienced:

- Radiographically documented disease progression during sorafenib therapy or
after discontinuation of sorafenib therapy, or

- Discontinuation of sorafenib due to an adverse drug reaction, despite dose
reduction by 1 level and BSC

- The patient has received sorafenib as the only systemic therapeutic intervention.
Any hepatic locoregional therapy that has been administered prior to sorafenib is
allowed, but not following sorafenib. Radiation to metastatic sites (eg, bone)
following sorafenib therapy is permitted.

- Resolution of clinically significant toxicity of any anti cancer therapy to grade ≤ 1
by the NCI-CTCAE v. 4.0

Adequate Organ Function defined as:

- Total bilirubin < 3.0 mg/dL (51.3 µmol/L), aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) ≤ 5 × ULN

- Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute

- Absolute neutrophil count (ANC) ≥ 1.0 × 10^3/μL (1.0 × 10^9/L), hemoglobin ≥ 9 g/dL
(5.58 mmol/L), and platelets ≥ 75 × 10^3/µL (75 × 10^9/L)

- International Normalized Ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 5
seconds above ULN. Patients receiving prophylactic low-dose anticoagulant therapy are
eligible provided that INR ≤ 1.5 and PTT ≤ 5 seconds above the upper limit of normal
(ULN)

- The patient's urinary protein is ≤ 1+ on dipstick or routine urinalysis. If urine
dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be
collected and must demonstrate < 1000 mg of protein in 24 hours to allow
participation in the study

Exclusion criteria:

- Major surgery within 28 days prior to randomization, or central venous access device
placement within 7 days prior to randomization

- Hepatic locoregional therapy within 28 days prior to randomization

- Radiation to any nonhepatic (eg, bone) site within 14 days prior to randomization

- Sorafenib within 14 days prior to randomization

- Received any investigational therapy or non-approved drug within 28 days prior to
randomization

- Received any previous systemic therapy with vascular endothelial growth factor (VEGF)
inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors
(including investigational agents) other than sorafenib for treatment of HCC

- Fibrolamellar carcinoma

- Received any transfusion, blood component preparation, erythropoietin, albumin
preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior
to randomization

- Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar
agents. Patients receiving prophylactic, low-dose anticoagulation therapy are
eligible provided that the coagulation parameters defined in the inclusion
criteria(INR ≤ 1.5 and PTT ≤ 5 seconds above the upper limit of normal [ULN]) are met

- Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg,
indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar
agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel,
dipyridamole, picotamide, indobufen, anagrelide, triflusal).Aspirin (ASA) at doses up
to 100 mg/day is permitted

- Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or
poorly controlled cardiac arrhythmia

- Any arterial thrombotic event, including myocardial infarction, unstable angina,
cerebrovascular accident, or transient ischemic attack, within 6 months prior to
randomization

- Uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard medical
management

- Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months
prior to randomization requiring transfusion, endoscopic or operative intervention
(patients with any bleeding episode considered life-threatening during the 3 months
prior to randomization are excluded, regardless of transfusion or intervention
status)

- Esophageal or gastric varices that require immediate intervention (eg, banding,
sclerotherapy) or represent a high bleeding risk. Patients with evidence of portal
hypertension (including splenomegaly) or any prior history of variceal bleeding must
have had endoscopic evaluation within the 3 months immediately prior to
randomization. Patients with evidence of portal hypertension are eligible for study
participation if endoscopic evaluation does not indicate esophageal or gastric
varices that require immediate intervention or represent a high bleeding risk;
however, these eligible patients must receive supportive therapy (eg, beta blocker
therapy) according to institutional standards and clinical guidelines during study
participation

- Central nervous system (CNS) metastases or carcinomatous meningitis

- History of or current hepatic encephalopathy or current clinically meaningful ascites