Inclusion Criteria:

• A diagnosis of HCC based on histopathologic findings, or a diagnosis of cirrhosis and a tumor with classical HCC imaging characteristics.
• Prior sorafenib treatment for at least 14 days and discontinuation of sorafenib ≥14 days prior to randomization.
• Radiographic disease progression during or after sorafenib therapy or discontinuation of sorafenib because of intolerance.
• Sorafenib was the only systemic therapy for HCC.
• ≥1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 that has not been previously treated with locoregional therapy.
• Child-Pugh score <7 (Child-Pugh Class A).
• Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.
• Baseline AFP ≥400 nanograms/milliliter.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Resolution of all clinically significant toxic effects of prior therapy.
• Total bilirubin ≤1.5 times upper limit of normal value (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤5 × ULN.
• Creatinine clearance ≥60 milliliters/minute.
• Urinary protein is ≤1+ on dipstick or routine urinalysis or 24-hour urine demonstrating <1 gram of protein.
• Absolute neutrophil count ≥1.0 × 10^9/Liter, hemoglobin ≥9 grams/deciliter, and platelets ≥75 × 10^9/Liter.
• International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤5 seconds above the ULN.
• Surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method.
• If a woman of childbearing potential, a negative serum pregnancy test prior to randomization.
• Willing to provide blood for research.

Exclusion Criteria:

• Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
• Concurrent malignancy. Participants with carcinoma in situ of any origin and participants with prior malignancies in remission may be eligible with sponsor approval.
• Previous brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
• History of or current hepatic encephalopathy or clinically meaningful ascites.
• Ongoing or recent hepatorenal syndrome.
• Liver transplant.
• Previous systemic therapy with vascular endothelial growth factor (VEGF) pathway inhibitors other than sorafenib for treatment of HCC.
• Hepatic locoregional therapy following sorafenib or within 28 days prior to randomization.
• Major surgical procedure, traumatic injury, non-healing wound, or peptic ulcer ≤28 days prior to randomization.
• Placement of a subcutaneous venous access device within 7 days prior to the first dose of study treatment unless the procedure is judged of low risk of bleeding.
• Enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or in medical research judged not to be scientifically or medically compatible with this study.
• Discontinued from study treatment from another clinical trial within 28 days prior to randomization.
• Known allergy to any of the treatment components.
• Uncontrolled hypertension.
• Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, <6 months prior to randomization.
• Any bleeding episode considered life-threatening, or any Grade 3 or 4 gastrointestinal bleeding episode in the 3 months prior to randomization requiring intervention.
• Esophageal or gastric varices that require intervention or represent high bleeding risk. Participants with evidence of portal hypertension or prior bleeding must have had endoscopic evaluation within 3 months prior to randomization.
• Gastrointestinal perforation or fistulae within 6 months prior to randomization.
• Symptomatic congestive heart failure (New York Heart Association II-IV), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
• Pregnant or breast-feeding.
• Any medical or psychiatric condition that may increase the risk associated with study participation or may interfere with the interpretation of study results. Conditions include but are not limited to:
  • Human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
  • Active or uncontrolled clinically serious infection. (Participants with chronic viral hepatitis are eligible.)
  • Ongoing or recent history of drug abuse.
  • Uncontrolled hereditary or acquired thrombotic or bleeding disorder.
• Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection.
• Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or similar agents.
• Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted.