A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-line Treatment of Participants With Unresectable Hepatocellular Carcinoma
Condition: Hepatocellular Carcinoma (HCC)
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Lenvatinib; Sorafenib
Intervention description: 12 mg (or 8 mg) once daily (QD) oral dosing.; 400 mg twice daily (BID) oral dosing.
Intervention MeSH terms: Sorafenib; Lenvatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 954.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatocellular Carcinoma; Neoplasms; Cancer

Summary:

      E7080-G000-304 is a multicenter, randomized, open-label, noninferiority Phase 3 study to
      compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic
      treatment in participants with unresectable Hepatocellular Carcinoma (HCC).
    

Eligibility criteria:

        1. Participants must have confirmed diagnosis of unresectable HCC with any of the
             following criteria:

               -  Histologically or cytologically confirmed diagnosis of HCC.

               -  Clinically confirmed diagnosis of HCC according to American Association for the
                  Study of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology or
                  with chronic hepatitis B or C infection criteria

          2. At least one measurable target lesion according to modified Response Evaluation
             Criteria in Solid Tumors (mRECIST) meeting the following criteria:

             • Hepatic lesion

               1. The lesion can be accurately measured in at least one dimension as >=1.0
                  centimeter (cm) (viable tumor for typical; and longest diameter for atypical),
                  and

               2. The lesion is suitable for repeat measurement.

                  • Nonhepatic lesion

               3. Lymph node (LN) lesion that measures at least one dimension as >=1.5 cm in the
                  short axis, except for porta hepatis LN that measures >=2.0 cm in the short axis.

               4. 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.

          3. Participants categorized to stage B (not applicable for transarterial
             chemoembolization [TACE]) or stage C based on Barcelona Clinic Liver Cancer (BCLC)
             staging system.

          4. Adequate bone marrow function, defined as:

               -  Absolute neutrophil count (ANC) >=1.5 X 10^9 per liter (/L)

               -  Hemoglobin (Hb) >=8.5 gram per deciliter (g/dL)

               -  Platelet count >=75 X 10^9/L.

          5. Adequate liver function, defined as:

               -  Albumin >=2.8 g/dL

               -  Bilirubin less than or equal to (<=) 3.0 mg/dL

               -  Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine
                  aminotransferase (ALT) <=5 X the upper limit of normal (ULN).

          6. Adequate blood coagulation function, defined as international normalized ratio (INR)
             <=2.3.

          7. Adequate renal function defined as creatinine clearance greater than (>) 40 milliliter
             per minute (mL/min) calculated per the Cockcroft and Gault formula.

          8. Adequate pancreatic function, defined as amylase and lipase <=1.5 X ULN.

          9. 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 the Cycle1/Day1.

         10. Child-Pugh score A.

         11. Eastern Cooperative Oncology Group (ECOG)- performance status (PS) 0 or 1.

         12. Males or females aged at least 18 years (or any age >18 years as determined by country
             legislation) at the time of informed consent.

         13. Females must not be lactating or pregnant at Screening or Baseline (as documented by a
             negative beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of
             25 International Units Per Liter (IU/L) or equivalent units of BhCG).

             A separate baseline assessment is required if a negative screening pregnancy test was
             obtained more than 72 hours before the first dose of study drug.

         14. All females will be considered to be of childbearing potential unless they are
             postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age
             group and without other known or suspected cause) or have been sterilized surgically
             (ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with
             surgery at least 1 month before dosing).

         15. Females of childbearing potential must not have had unprotected sexual intercourse
             within 30 days before study entry and must agree to use a highly effective method of
             contraception (e.g., total abstinence, an intrauterine device, a double barrier method
             [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral
             contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout
             the entire study period and for 30 days after study drug discontinuation. If currently
             abstinent, the participant must agree to use a double barrier method as described
             above if she becomes sexually active during the study period or for 30 days after
             study drug discontinuation. Females who are using hormonal contraceptives must have
             been on a stable dose of the same hormonal contraceptive product for at least 4 weeks
             before dosing and must continue to use the same contraceptive during the study and for
             30 days after study drug discontinuation.

         16. Male participants must have had a successful vasectomy (confirmed azoospermia) or they
             and their female partners must meet the criteria above (i.e., not of childbearing
             potential or practicing highly effective contraception throughout the study period and
             for 30 days after study drug discontinuation). No sperm donation is allowed during the
             study period and for 30 days after study drug discontinuation.

         17. Provide written informed consent.

         18. Willing and able to comply with all aspects of the protocol.

        Exclusion Criteria

          1. Imaging findings for HCC corresponding to any of the following:

               -  HCC with >=50 percent liver occupation

               -  Clear invasion into the bile duct

               -  Portal vein invasion at the main portal branch (Vp4).

          2. Participants who have received any systemic chemotherapy, including anti-vascular
             endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer
             agents, including lenvatinib, for advanced/unresectable HCC. Note: Participants who
             have received local hepatic injection chemotherapy are eligible.

          3. 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, eg, granulocyte
             colony-stimulating factor [G-CSF]) within 28 days prior to randomization.

          4. Participants who have not recovered from toxicities as a result of prior anticancer
             therapy, except alopecia and infertility. Recovery is defined as < Grade 2 severity
             per Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).

          5. Significant cardiovascular impairment: history of congestive heart failure > New York
             Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke
             within 6 months of the first dose of study drug, or cardiac arrhythmia requiring
             medical treatment at Screening.

          6. Prolongation of corrected QT interval (QTc) interval to >480 millisecond (ms)

          7. Gastrointestinal malabsorption or any other condition that might affect the absorption
             of lenvatinib in the opinion of the investigator.

          8. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR
             monitoring, eg, warfarin or similar agents. Treatment with low molecular weight
             heparin and factor X inhibitors which do not require INR monitoring is permitted.
             Antiplatelet agents are prohibited throughout the study.

          9. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5
             teaspoon) within 28 days prior to randomization.

         10. Gastric or esophageal varices that require interventional treatment within 28 days
             prior to randomization. Prophylaxis with pharmacologic therapy (eg, nonselective
             beta-blocker) is permitted.

         11. 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.

         12. Participants whose only target lesion(s) is in bone will be excluded.

         13. Meningeal carcinomatosis.

         14. Any history of or current brain or subdural metastases.

         15. Participants having >1+ proteinuria on urine dipstick testing will undergo a 24-hour
             urine collection for quantitative assessment of proteinuria. Participants with a urine
             protein >=1g/24 hours will be ineligible.

         16. Surgical arterial-portal venous shunt or arterial-venous shunt.

         17. Any medical or other condition that in the opinion of the investigator would preclude
             the participant's participation in a clinical study.

         18. Known intolerance to lenvatinib or sorafenib (or any of the excipients).

         19. Human immunodeficiency virus (HIV) positive or active infection requiring treatment
             (except for hepatitis virus).

         20. Any history of drug or alcohol dependency or abuse within the prior 6 months.

         21. Any participant who cannot be evaluated by either triphasic liver computed tomography
             (CT) or triphasic liver Magnetic resonance imaging (MRI) because of allergy or other
             contraindication to both CT and MRI contrast agents.

         22. Major surgery within 3 weeks prior to randomization or scheduled for surgery during
             the study.

         23. Participants has had a liver transplant.