Trial to Evaluate Safety and Efficacy of Treatment of Physician Choice (TPC) Following First-Line Treatment of Lenvatinib in Subjects With Unresectable Hepatocellular Carcinoma (uHCC)

Key Inclusion Criteria:

* Participants must have confirmed diagnosis of unresectable Hepatocellular Carcinoma (uHCC) with any of the following criteria:

  1. Histologically or cytologically confirmed diagnosis of uHCC
  2. Clinically confirmed diagnosis of uHCC according to American Association for the Study of Liver Diseases criteria, including cirrhosis of any etiology or with chronic hepatitis B or C infection criteria
* At least one measurable target lesion regardless if hepatic or non-hepatic according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) meeting the following criteria:

  1. Hepatic lesion

     * The lesion can be accurately measured in at least one dimension as ≥1.0 centimeters (cm) (viable tumor for typical; and longest diameter for atypical), and
     * The lesion is suitable for repeat measurement,
  2. Nonhepatic lesion

     * Lymph node lesion that measures at least one dimension as ≥1.5 cm in the short axis
     * Non-nodal lesion that measures ≥1.0 cm in the longest diameter Lesions previously treated with radiotherapy or locoregional therapy must show radiographic evidence of disease progression to be deemed a target lesion.
* Participants categorized on the Barcelona Clinic Liver Cancer staging system to Stage B (not applicable for transarterial chemoembolization) or Stage C
* Adequate bone marrow function, liver function, blood coagulation function, renal function, and pancreatic function as assessed by laboratory tests.
* Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents, defined as BP ≤150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive therapy within 1 week prior to Cycle 1/Day 1
* Child-Pugh A
* Eastern Cooperative Oncology Group Performance Status of 0 or 1
* Survival expectation of 12 weeks or longer before starting study drug

Key Exclusion Criteria:

* Imaging findings for HCC corresponding to any of the following:

  1. HCC with ≥50% liver occupation
  2. Clear invasion into the bile duct
  3. Portal vein invasion at the main portal branch (Vp4)
* Participants who have received any systemic chemotherapy, including sorafenib, regorafenib or other anti-vascular endothelial growth factor therapy, nivolumab, or any systemic investigational anticancer agents, including lenvatinib, for advanced/uHCC.
* Participants who have received any anticancer therapy (including surgery, percutaneous ethanol injection, radio frequency ablation, transarterial \[chemo\] embolization, hepatic intra-arterial chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or any blood enhancing treatment (including blood transfusion, blood products, or agents that stimulate blood cell production, e.g., granulocyte colony-stimulating factor) within 28 days prior to the first dose of lenvatinib study treatment.
* Participants who have not recovered from toxicities as a result of prior anticancer therapy such as the local hepatic injection chemotherapy or any prior therapy for other cancer types.
* Significant cardiovascular impairment within 6 months of the first dose of study drug
* Prolongation of QT interval corrected for heart rate using Fridericia's correction (QTcF) to \>480 milliseconds (ms)
* Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib in the opinion of the investigator
* Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic international normalized ratio monitoring
* Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least half teaspoon) within 28 days prior to the first dose of lenvatinib study treatment
* Gastric or esophageal varices that require treatment
* Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 36 months
* Any history of or current brain or subdural metastases
* Participants having \>1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 grams/24 hour will be ineligible
* Arterial-portal venous shunt or arterial-venous shunt preventing proper diagnosis of tumor
* Any medical or other condition that in the opinion of the investigator would preclude the participant's participation in a clinical study
* Known intolerance to lenvatinib or any of the excipients
* Human immunodeficiency virus positive or active infection requiring treatment (except for hepatitis virus)
* Any history of drug or alcohol dependency or abuse within the prior 2 years
* Major surgery within 3 weeks prior to the first dose of lenvatinib study treatment or scheduled for surgery during the study
* Participant has had a liver transplant
* Females who are breastfeeding or pregnant at Screening or Baseline
* Females of childbearing potential who within 28 days before study entry did not use a highly effective method of contraception or do not agree to use a highly effective method of contraception throughout the entire study period