- A diagnosis of HCC based on histopathologic findings, or a diagnosis of cirrhosis and
a tumor with classical HCC imaging characteristics.
- Sorafenib was the only systemic therapy for HCC and was discontinued for disease
progression or intolerance (Main Global and ME2 Cohorts only).
- The participant received ≤2 prior systemic therapy regimen, excluding prior sorafenib
or chemotherapy, for the treatment of HCC (OLE Cohort only).
- ≥1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version
1.1 that has not been previously treated with locoregional therapy. A participant with
a lesion(s) that has previously been treated with locoregional therapy is also
eligible, if the lesion has documented progression after locoregional treatment and is
- 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
- If a woman of childbearing potential, a negative serum pregnancy test prior to
- Willing to provide blood for research. The participant has provided signed informed
consent prior to any study specific procedures and is amenable to compliance with
protocol schedules and testing.
- 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
- Previous brain metastases, leptomeningeal disease, or uncontrolled spinal cord
- History of or current hepatic encephalopathy or clinically meaningful ascites.
- Ongoing or recent hepatorenal syndrome.
- Liver transplant (Main Global and ME2 cohorts only; Participants with prior liver
transplant may be eligible for OLE cohort).
- Hepatic locoregional therapy following prior systemic therapy or within 28 days prior
- Major surgical procedure, traumatic injury, non-healing wound, or peptic ulcer ≤28
days prior to randomization.
- Received radiation to any nonhepatic (for example, bone) site within 14 days prior to
- 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 unapproved 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
- 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
- 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
- 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
- Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or
- Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet
agents. Aspirin at doses up to 100 milligrams/day is permitted.
- The participant received prior immunotherapy and is experiencing or has experienced
any of the following (OLE cohort only):
- Any clinically significant Grade ≥3 immune-related adverse event (irAE)
- Any grade neurologic or ocular irAE
- Any grade immune-related pneumonitis, cardiomyopathy, or hepatitis
- The participant received prior immunotherapy and at the time of study enrollment,
requires steroids or other immunosuppressive agents (OLE cohort only).