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)

A Single-Arm, Multicenter, Phase 2 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)

The primary objective of this study is to assess the safety and tolerability of subsequent systemic treatment of physician's choice (TPC) following the first-line lenvatinib treatment in unresectable hepatocellular carcinoma (uHCC) participants.

Study Overview

• Status: Terminated
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Drug: Lenvatinib

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Pasadena, California, United States, 91105
      • California Liver Research Institute
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Lenvatinib; Participants will receive lenvatinib 12 or 8 milligrams (mg) once daily in continuous 28-day cycles until disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, or study termination by the sponsor. Upon completion of lenvatinib treatment, eligible participants will receive commercially available systemic TPC for hepatocellular carcinoma in the subsequent treatment period.

Drug: Lenvatinib; Lenvatinib capsules will be administered orally, once daily in continuous 28-day cycles. Body weight (BW) ≥60 kilograms (kg) - Lenvatinib 12 mg (taken as three 4-mg capsules); BW <60 kg - Lenvatinib 8 mg (taken as two 4-mg capsules); Other Names: E7080; LENVIMA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	From the first dose of study drug up to 28 days after the last dose of study drug (approximately 3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time from the date of first dose of study treatment to the date of death from any cause. Participants who are lost to follow-up are censored at the last date the participant was known to be alive, and participants who remain alive are censored at the time of data cutoff. OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.	From first dose date until date of death from any cause (approximately 3 months)
Progression-free Survival (PFS)	PFS based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) (and including the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 conventions for non-hepatic lesions) is defined as the time from the date of the first dose of first-line lenvatinib treatment to the date of the first documentation of PD, or the date of death during the subsequent systemic TPC, whichever occurs first. PD is defined at least 20% increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameters of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.	From first dose date until PD or date of death from any cause (approximately 3 months)
Time to Progression (TTP)	TTP based on mRECIST (and including the RECIST 1.1 conventions for non-hepatic lesions) is defined as the time from the date of the first dose of first-line lenvatinib treatment to the date of the first documentation of disease progression during subsequent systemic TPC. PD is defined at least 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. TTP was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.	From first dose date until PD (approximately 3 months)

Collaborators and Investigators

• Sponsor: Eisai Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2018
• Primary Completion (Actual): January 7, 2019
• Study Completion (Actual): January 7, 2019

Study Registration Dates

• First Submitted: February 9, 2018
• First Submitted That Met QC Criteria: February 9, 2018
• First Posted (Actual): February 14, 2018

Study Record Updates

• Last Update Posted (Actual): December 6, 2019
• Last Update Submitted That Met QC Criteria: November 19, 2019
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Lenvatinib; Unresectable hepatocellular carcinoma; E7080
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Lenvatinib
• Other Study ID Numbers: E7080-M001-222

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No