Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC)

Phase I/II Study of E7080 in Patients With Advanced Hepatocellular Carcinoma (HCC)

The purpose of this study is to determine maximum tolerated dose (MTD), efficacy, safety and tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor effect of E7080 when is administered continually once daily in participants with advanced hepatocellular carcinoma.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Lenvatinib

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba
    • Kashiwa-shi, Chiba, Japan
  • Fukuoka
    • Kurume-shi, Fukuoka, Japan
  • Hokkaido
    • Sapporo-shi, Hokkaido, Japan
  • Kanagawa
    • Kawasaki-shi, Kanagawa, Japan
  • Osaka
    • Osaka-shi, Osaka, Japan
    • Osakasayama-shi, Osaka, Japan
  • Saga
    • Saga-shi, Saga, Japan
  • Tokyo
    • Chuo-ku, Tokyo, Japan
    • Minato-ku, Tokyo, Japan
    • Musashino-shi, Tokyo, Japan
• Korea, Republic of
  • Seoul
    • Gangnam-gu, Seoul, Korea, Republic of
    • Songpa-gu, Seoul, Korea, Republic of

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Histologically or clinically confirmed diagnosis of advanced HCC.
2. Eastern Cooperative Oncology Group-Performance Status (ECOG-PS): 0-1.
3. Adequate laboratory values/organ function tests.

Exclusion criteria:

1. Simultaneous or metachronous cancers.
2. Pericardial, ascites, or pleural effusion requiring drainage.
3. Brain metastasis/meningeal carcinomatosis presenting clinical symptoms or requiring treatment.
4. Malabsorption syndrome.
5. Artery-portal vein shunt or artery-vein shunt preventing proper diagnosis of tumor.
6. Use of drugs known to inhibit cytochrome P3A4.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lenvatinib	Drug: Lenvatinib; In the Dose-Escalation Component of the study, lenvatinib will be administered as continuous once-daily oral dosing. Dose-escalation will occur based on safety information obtained during Cycle 1. The recommended dose for the Expansion Component of the study will use the MTD in Cycle 1.; Other Names: E7080

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib	The MTD was defined as the highest dose level at which no more than 1 of 6 participants had a dose limiting toxicities (DLT). DLT was defined as any of the following events: grade 4 or higher hematologic toxicity or grade 3 thrombocytopenia that required blood transfusion, grade 3 or higher nonhematologic toxicity, grade 4 hypertension uncontrolled by antihypertensive drug(s), aspartate aminotransferase/alanine aminotransferase (AST/ALT) greater than (>) 10.0*upper limit of normal (ULN), proteinuria 4+ by urine dipstick, proteinuria 3+ by urine dipstick was to be monitored by 24-hour urine collection, proteinuria >3.5 gram (g) for 24 hours, diarrhea/vomiting/nausea of grade 3 or higher that was uncontrollable despite maximal supportive therapies and abnormal clinical laboratory values that required no treatment, grade 3 proteinuria by dipstick, diarrhea/vomiting/nausea that was managed with supportive therapies were not considered as DLT.	Up to 28 days (Cycle1)
Phase 2: Time to Progression (TTP) by Independent Review Assessment	TTP was defined as the time from the date of registration to the date when progressive disease (PD) was first confirmed. PD was evaluated according to modified response evaluation criteria in solid tumors (mRECIST) by an independent imaging review. PD was defined as at least a 20 percent (%) increase in the sum of long diameter (LD) of target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 millimeter (mm) (including new lesions).	From day of registration to the day when PD was first confirmed (approximately up to 6.1 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Best Overall Response (BOR) of Lenvatinib by Investigator Assessment	BOR was performed using RECIST1.1 and was measured as complete response (CR) defined as when an overall response of CR was obtained 2 or more consecutive times at intervals of at least 28 days (the date when the second overall response of CR was confirmed and the BOR established as CR was regarded as the "CR confirmed date), partial response (PR) defined as when the overall response of PR or better (CR or PR) was obtained 2 or more consecutive times at intervals of at least 28 days (the date when the second overall response of PR was confirmed and the BOR established as PR will be regarded as the "PR confirmed date), PD defined as when the BOR was neither CR, PR, or stable disease (SD), and the overall response was PD, SD defined as when the BOR obtained was neither CR nor PR, but no PD from the initial administration to the end of Cycle 2 and the overall response of SD or better occurred at least once and not evaluable (NE) was when the overall response was NE in all cases.	Every 8 weeks (approximately up to 18.4 months)
Phase 1: Objective Response Rate (ORR) by Investigator Assessment	ORR was defined as the percentage of participants who achieved a tumor response measured by RECIST 1.1 of CR defined as disappearance of all target lesions (a short diameter is less than (<)10 mm if it exists in a lymph node) plus PR defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.	From day of registration to the day when PD was first confirmed or death (approximately 6.1 years)
Phase 1: Disease Control Rate (DCR) by Investigator Assessment	DCR was measured by RECIST 1.1 and defined as CR which was defined as disappearance of all target lesions (a short diameter was <10 mm if it exists in a lymph node) plus PR which was defined as at least 30% decrease in the sum of the long diameter (hereafter referred to as sum of LD) of all target lesions, as compared with baseline summed LD plus SD which was reduction in tumor volume of less than 50% or an increase in the volume of 1 or more measurable lesions of less than 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to PD.	Up to Week 16
Phase 2: Progression-free Survival (PFS) by Independent Review Assessment	PFS was defined as the time from the date of registration until the date when PD was first confirmed or death (whichever occurred first) as determined by mRECIST and PD was defined as at least a 20% increase in the sum of long diameters of target lesions, taking as reference the baseline sum of diameters of target lesions.	From day of registration to the day when PD was first confirmed or death (approximately 6.1 years)
Phase 2: Objective Response Rate (ORR) by Independent Review Assessment	ORR was defined as the percentage of participants who achieved a tumor response measured by mRECIST of CR defined as disappearance of all target lesions (a short diameter is <10 mm if it exists in a lymph node) plus PR defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.	From day of registration to the day when PD was first confirmed or death (approximately 6.1 years)
Phase 2: Disease Control Rate (DCR) by Independent Review Assessment	DCR was measured by mRECIST and defined as CR which was defined as disappearance of all target lesions (a short diameter is <10 mm if it exists in a lymph node) plus PR which was defined as at least 30% decrease in the sum of the long diameter (hereafter referred to as sum of LD) of all target lesions, as compared with baseline summed LD plus SD which was reduction in tumor volume of less than 50% or an increase in the volume of 1 or more measurable lesions of less than 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to PD.	Weeks 8 and 16
Phase 2: Overall Survival (OS)	OS was defined as the time from the date of registration until the date of death.	From day of registration to the day of death (approximately 6.1 years)

Collaborators and Investigators

• Sponsor: Eisai Co., Ltd.

Publications and helpful links

General Publications

• Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, Tamai T, Suzuki T, Hisai T, Hayato S, Okita K, Kumada H. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017 Apr;52(4):512-519. doi: 10.1007/s00535-016-1263-4. Epub 2016 Oct 4.

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2009
• Primary Completion (Actual): June 15, 2014
• Study Completion (Actual): August 13, 2015

Study Registration Dates

• First Submitted: July 23, 2009
• First Submitted That Met QC Criteria: July 23, 2009
• First Posted (Estimate): July 24, 2009

Study Record Updates

• Last Update Posted (Actual): February 1, 2019
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Carcinoma; Hepatocellular
• 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-J081-202