A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma
This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Limited )
First received: January 2, 2013
Last updated: September 3, 2015
Last verified: September 2015
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 subjects with unresectable Hepatocellular Carcinoma (HCC).
Hepatocellular Carcinoma (HCC)
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Multicenter, Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma
Primary Outcome Measures:
Secondary Outcome Measures:
- Progression-free survival (PFS) [ Time Frame: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurs first ] [ Designated as safety issue: No ]
- Time to progression (TTP) [ Time Frame: The time from the date of randomization to the date of first documentation of disease progression ] [ Designated as safety issue: No ]
- Objective Response Rate (ORR) [ Time Frame: Date of randomization to the date of disease progression (measured every 8 weeks) or death (whichever occurs first). ] [ Designated as safety issue: No ]
The proportion of subjects who have best overall response of complete response (CR) or partial response (PR).
- Health Related Quality of Life (HRQoL) [ Time Frame: Baseline Visit, Day 1 of each subsequent cycle, and at the Off-Treatment Visit ] [ Designated as safety issue: No ]
HRQoL will be assessed using EORTC QLQ-C30, the HCC-specific questionnaire (HC-18), and a generic instrument EQ-5D-3L.
- Plasma PK lenvatinib exposure parameters [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1 ] [ Designated as safety issue: No ]
Other Outcome Measures:
- Disease control rate [ Time Frame: Best overall response of SD must be at least 7 weeks after randomization ] [ Designated as safety issue: No ]
The proportion of subjects who have best overall response of CR or PR, or stable disease (SD).
- Clinical benefit rate [ Time Frame: Duration of SD ≥ 23 weeks after randomization ] [ Designated as safety issue: No ]
The proportion of subjects who have best overall response of CR or PR or durable SD.
- Exploratory biomarker analysis [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1 ] [ Designated as safety issue: No ]
The baseline and/or change from baseline of exploratory soluble, tissue, and/or genetic biomarkers and their correlations with clinical outcomes.
| Estimated Enrollment:
| Study Start Date:
| Estimated Primary Completion Date:
||April 2016 (Final data collection date for primary outcome measure)
Active Comparator: Lenvatinib
Lenvatinib: 12 mg (or 8 mg) once daily (QD) oral dosing
Other Name: E7080, Lenvima
Active Comparator: Sorafenib
Sorafenib: 400 mg twice daily (BID) oral dosing
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
Subjects 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
At least one measurable target lesion according to mRECIST meeting the following criteria:
- The lesion can be accurately measured in at least one dimension as greater than or equal to 1.0 cm (viable tumor for typical; and longest diameter for atypical), and
- The lesion is suitable for repeat measurement
- Nonhepatic lesion c. Lymph node (LN) lesion that measures at least one dimension as greater than or equal to 1.5 cm in the short axis, except for porta hepatis LN that measures greater than or equal to 2.0 cm in the short axis d. Non-nodal lesion that measures greater than or equal to 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.
- Subjects categorized to stage B (not applicable for transarterial chemoembolization [TACE]) or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system
Adequate bone marrow function, defined as:
- Absolute neutrophil count (ANC) greater than or equal to 1.5 X 109/L
- Hemoglobin (Hb) greater than or equal to 8.5 g/dL
- Platelet count greater than or equal to 75 X 109/L
Adequate liver function, defined as:
- Albumin greater than or equal to 2.8 g/dL
- Bilirubin less than or equal to 3.0 mg/dL
- Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) less than or equal to 5 X the upper limit of normal (ULN)
- Adequate blood coagulation function, defined as international normalized ratio (INR) less than or equal to 2.3
- Adequate renal function defined as creatinine clearance greater than 40 mL/min calculated per the Cockcroft and Gault formula
- Adequate pancreatic function, defined as amylase and lipase less than or equal to 1.5 X ULN
- Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents, defined as BP less than or equal to 150/90 mm Hg at Screening and no change in antihypertensive therapy within 1 week prior to the Cycle1/Day1
- Child-Pugh score A
- ECOG-PS 0 or 1
- Survival expectation of 12 weeks or longer after starting study drug
- Males or females aged at least 18 years (or any age greater than 18 years as determined by country legislation) at the time of informed consent
- 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 IU/L or equivalent units of B-hCG). 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.
- 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)
- 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 subject 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.
- Male subjects 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.
- Provide written informed consent
- Willing and able to comply with all aspects of the protocol
Imaging findings for HCC corresponding to any of the following:
- HCC with greater than or equal to 50 percent liver occupation
- Clear invasion into the bile duct
- Portal vein invasion at the main portal branch (Vp4)
- Subjects who have received any systemic chemotherapy, including anti-VEGF therapy, or any systemic investigational anticancer agents, including lenvatinib, for advanced/unresectable HCC. Note: Subjects who have received local hepatic injection chemotherapy are eligible.
- Subjects 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
- Subjects who have not recovered from toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as less than Grade 2 severity per Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
- Significant cardiovascular impairment: history of congestive heart failure greater than 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
- Prolongation of QTc interval to greater than 480 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 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.
- Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 28 days prior to randomization
- Gastric or esophageal varices that require interventional treatment within 28 days prior to randomization. Prophylaxis with pharmacologic therapy (eg, nonselective beta-blocker) is permitted.
- 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
- Subjects whose only target lesion(s) is in bone will be excluded
- Meningeal carcinomatosis
- Any history of or current brain or subdural metastases
- Subjects having greater than 1+ proteinuria on urine dipstick testing will undergo a 24-hour urine collection for quantitative assessment of proteinuria. Subjects with a urine protein greater than or equal to 1 g/24 hours will be ineligible.
- Surgical arterial-portal venous shunt or arterial-venous shunt
- Any medical or other condition that in the opinion of the investigator would preclude the subject's participation in a clinical study
- Known intolerance to lenvatinib or sorafenib (or any of the excipients)
- Human immunodeficiency virus (HIV) positive or active infection requiring treatment (except for hepatitis virus)
- Any history of drug or alcohol dependency or abuse within the prior 6 months
- Any subject who cannot be evaluated by either triphasic liver CT or triphasic liver MRI because of allergy or other contraindication to both CT and MRI contrast agents
- Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study
- Subject has had a liver transplant
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01761266
No publications provided
||Eisai Inc. ( Eisai Limited )
History of Changes
|Other Study ID Numbers:
|Study First Received:
||January 2, 2013
||September 3, 2015
||United States: Food and Drug Administration
Keywords provided by Eisai Inc.:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on October 07, 2015
Digestive System Diseases
Digestive System Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors