A phase 3 trial studying how well lenvatinib works in treating patients withliver cancer who would not benefit from surgery compared againstsorafenib. The trial is taking place worldwide, patients and their physicianwill know if they are receiving lenvatinib or sorafenib

Phase 1

• Conditions: nresectable Hepatocellular Carcinoma; MedDRA version: 16.0Level: LLTClassification code 10019828Term: Hepatocellular carcinoma non-resectableSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-002992-33-IT
• Lead Sponsor: Eisai Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2013-05-10
• Last Update Posted: 23 November 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 954

Inclusion Criteria

- Confirmed diagnosis of unresectable HCC with any of the following
criteria: histologically or cytologically confirmed diagnosis of HCC,
diagnosis of HCC according to the AASLD criteria, including cirrhosis of
any etiology or with chronic hepatitis B or C infection criteria
- At least 1 measurable target lesion according to mRECIST meeting the
criteria set out in the protocol for the different lesions
-Subjects categorized to stage B or stage c based on BCLC staging
system
- Adequate bone marrow function defined as
o Absolute neutrophil count (ANC) = 1.5 × 10e9/L
o Hemoglobin (Hb) = 8.5 g/dL
o Platelet count = 75 × 10e9/L
- Adequate liver function
o Bilirubin = 3.0 mg/dL
o Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and
alanine aminotransferase (ALT) = 5 × the upper limit of normal (ULN)
- Adequate blood coagulation function, defined as international
normalized ratio (INR) = 2.3
- Adequate renal function, defined as creatinine clearance > 30 mL/min
calculated per the Cockcroft and Gault formula
- Adequate pancreatic function, defined as amylase and lipase = 1.5 ×
ULN
- Adequately controlled blood pressure with 0 or 1 antihypertensive
medications and no change in antihypertensive medications within 1
week prior to the cycle 1/ day 1
- 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 at time of informed consent
- Females must not be lactating or pregnant at Screening or Baseline. A
seperate baseline assessment is required if a negative pregnancy test
was obtained more then 72 hours before the first dose of study drug.
- All females will be considered to be of childbearing potential unless
they are postmenopausal or have been sterilized surgically.
- 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, 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. No sperm donation is allowed during the study period and for 30
days after study drug administration
- Provide written informed consent
- Willing and able to comply with all aspects of the protocol
o Albumin = 2.8 g/dL
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 610
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 330

Exclusion Criteria

- Imaging findings for HCC corresponding to any of the following: HCC
with greater or equal 50% liver occupation, clear invasion of the bile
duct, portal vein invasion at the main portal branch
- Subjects who have received any systemic chemotherapy, including
sorafenib, 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, e.g., 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 < 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 > 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 such as,
warfarin or similar agents requiring therapeutic INR monitoring.
(Treatment with low molecular weight heparin is allowed.)
- 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 treatment
- Active malignancy (except for HCC or definitively treated melanoma insitu,
basal or squamous cell carcinoma of the skin, or carcinoma in-situ
of the cervix) within the past 36 months
- Meningeal carcinomatosis
- Any history of, or current, brain or subdural metastases
- Subjects having > 1 + proteinuria on urine dipstick testing will undergo
24 h urine collection for quantitative assessment of proteinuria. Subjects
with urine protein = 1 g / 24 h 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 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 2
years
- 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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of the study is to compare overall survival (OS) in<br>subjects treated with lenvatinib versus sorafenib as a first-line<br>treatment in subjects with unresectable heptocellular carcinoma (HCC);Secondary Objective: sorafenib using mRECIST<br>- Compare safety and tolerability of subjects treated with lenvatinib<br>versus sorafenib<br>- Characterize the PK of lenvatinib using the population approach<br>- Assess the PK/PD relationship between exposure and efficacy/ safety<br>- Compare HCC-specific QoL of subjects treated with lenvatinib versus<br>sorafenib using the EORTC QLQ-HCC18 questionnaire;Primary end point(s): Overall survival (OS) measured from the date of randomization until<br>date of death from any cause. Subjects who are lost to follow-up will be<br>censored at the last date the subject was known to be alive, and subjects<br>who remain alive will be censored at the time of data cutoff;Timepoint(s) of evaluation of this end point: Database lock

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - PFS defined as the time from the date of randomization to the date of<br>first documentation of disease progression, or date of death, whichever<br>occurs first<br>- TTP, defined as the time from the date of randomization to the date of<br>first documentation of disease progression.<br>- ORR defined as the proportion of subjects who have best overall<br>XML File Identifier: pOP80URtPQLmFJoplrabsqwEJJ8=<br>Page 18/30<br>response of complete response (CR) or partial response (PR)<br>- Changes in HCC-specific QoL, measured using the EORTC QLQ-HCC18 instrument and defined as the percent change from baseline in the HCC<br>specific component<br>- Plasma PK lenvatinib exposure parameters;Timepoint(s) of evaluation of this end point: Database lock