• Willing and able to provide written informed consent prior to performance of any study- specific procedures.

• Age ≥ 18 years.

• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants:

‣ For cirrhotic participants with no histological confirmation of diagnosis, clinical confirmation is required per AASLD criteria.

⁃ Pathological diagnoses of HCC will be made according to the International Working Party criteria.

• HCC with a component that measures at least 3 cm and that is located 1 cm or greater away from sensitive structures, including large blood vessels, large bile ducts, pericardium, diaphragm, gallbladder, stomach, and bowel.

• Is not a candidate for local therapies alone, including liver transplantation, tumor ablation, transarterial embolization, radiation therapy, or resection.

• No prior systemic therapy for advanced or metastatic HCC.

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1

• Evaluable target lesions as per Response Evaluation Criteria in Solid Tumors RECIST v1.1 or mRECIST.

• Child-Pugh A or Child-Pugh B7 liver function.

• Life expectancy of ≥ 12 weeks.

• Adequate bone marrow function defined as:

‣ Peripheral absolute neutrophil count ≥ 1000/mm\^3

⁃ Platelet count ≥ 50,000/ mm\^3

⁃ Hemoglobin ≥ 8.0 g/dL

• Adequate renal function defined as creatinine clearance ≥ 50 ml/min

• Adequate liver and pancreatic function defined as:

‣ Total bilirubin ≤ 2.0 x institution's upper limit of normal, and

⁃ Alanine transaminase (ALT) or Aspartate transaminase (AST) ≤ 5 x institution's upper limit of normal, and

⁃ Albumin ≥ 2 g/dL

• Adequate central nervous system function defined as:

• a. patients with seizure disorder may be enrolled if on anticonvulsants and seizures are well controlled.

• Systolic blood pressure \<160 mm Hg.

• Patients with partners of childbearing potential must agree to use adequate contraception during participation in the study.

• Patients able to become pregnant are eligible to enter the study if they are either:

‣ Of non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including: i. Has had a hysterectomy; or ii. Has had a bilateral oophorectomy, or iii. Has had a bilateral tubal ligation, or iv. Is post-menopausal (demonstrates total cessation of menses for greater than or equal to 1 year); OR

⁃ Of childbearing potential, has a negative serum pregnancy test at screening, and agrees to one of the following contraceptives: i. An intrauterine device with a documented failure rate of less than 1% per year; ii. Vasectomized partner who is sterile prior to the subject's entry and is the sole sexual partner for that woman; iii. Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, during the clinical trial, and for at least 14 days after the last dose of investigational product; iv. Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm.