A Study of Lenvatinib Plus Nivolumab in Participants With Hepatocellular Carcinoma

A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects With Hepatocellular Carcinoma

The primary objective of this study is to evaluate the tolerability and safety of a combination of lenvatinib plus nivolumab in participants with hepatocellular carcinoma (HCC).

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan
    • EISAI Trial Site 5
  • Chiba
    • Kashiwa, Chiba, Japan
      • EISAI Trial Site 1
  • Fukuoka
    • Iizuka, Fukuoka, Japan
      • EISAI Trial Site 6
  • Kanagawa
    • Kawasaki, Kanagawa, Japan
      • EISAI Trial Site 3
  • Osaka
    • Osakasayama, Osaka, Japan
      • EISAI Trial Site 4
  • Tokyo
    • Chuo-ku, Tokyo, Japan
      • EISAI Trial Site 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants must have confirmed diagnosis of hepatocellular carcinoma (HCC) with any of the following criteria:

  • Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors
  • Clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases criteria, including cirrhosis of any etiology and/or chronic hepatitis B or C infection
• Part 1: HCC for which no other appropriate therapy is available; Part 2: No prior systemic therapy for advanced/unresectable HCC
• Participants categorized to stage B (not applicable for transarterial chemoembolization), or stage C based on Barcelona Clinic Liver Cancer staging system
• Child-Pugh score A
• Participants must have an Eastern Cooperative Oncology Group Performance Status of 0 to 1
• Age greater than or equal to (>=) 20 years at the time of informed consent

Exclusion Criteria:

• Active co-infection with hepatitis B and hepatitis C
• Participants with any active, known, or suspected autoimmune disease
• Participants being treated with drugs that strongly inhibit or induce CYP3A4 and that may be possibly used during this study
• Females who are breastfeeding or pregnant

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Lenvatinib Plus Nivolumab; Participants will receive specified doses of lenvatinib (oral) and nivolumab (intravenous) on specified days.	Drug: Lenvatinib; Specified doses will be administered orally on specified days.; Drug: Nivolumab; Specified doses will be administered intravenously on specified days.
Experimental: Part 2: Lenvatinib Plus Nivolumab; If tolerable in Part 1, participants will receive specified doses of lenvatinib and nivolumab on specified days until criteria for discontinuation are met.	Drug: Lenvatinib; Specified doses will be administered orally on specified days.; Drug: Nivolumab; Specified doses will be administered intravenously on specified days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs)	DLT was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). DLT was defined as any of the following hematological or non-hematological toxicities considered to be at least possibly related to lenvatinib and/or nivolumab occurring during Cycle 1: 1) Febrile neutropenia or Grade 4 neutropenia for >7 days; 2) Grade 4 thrombocytopenia and Grade 3 thrombocytopenia with bleeding; 3) Grade 4 anemia; 4) Clinical deterioration manifested by drug-related hepatic decompensation; 5) >=Grade 3 non-hematological laboratory abnormalities with clinical symptoms that persisted; 6) Other Grade 3 toxicity lasting >3 days or Grade 4 non-hematological toxicity of any duration; 7) Grade 2 uveitis, eye pain, or blurred vision that did not respond to topical therapy; 8) Failure to administer 8 or more dose of the planned administration number of study drug in Cycle 1 as a result of treatment-related toxicity.	Cycle 1 (Cycle length = 28 days)
Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	A TEAE was defined as an adverse event (AE) that emerged during treatment and until the 30 days after the last dose or until the participants initiated new anticancer therapy, whichever was earlier, was absent at pretreatment (Baseline) or reemerged during treatment, was present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening (that is, participant was at immediate risk of death from AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).	From the first dose of study drug until 30 days after the last dose (up to 53 months)
Mean Change From Baseline in Vital Sign: Weight	Mean change from baseline in weight were evaluated.	Baseline, up to Month 53
Mean Change From Baseline in Vital Sign: Body Mass Index	Mean change from baseline in body mass index were evaluated.	Baseline, up to Month 53
Mean Change From Baseline in Vital Sign: SpO2 (Oxygen Saturation)	Mean change from baseline in SpO2 were evaluated.	Baseline, up to Month 53
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs)	Treatment-emergent markedly abnormal laboratory value was defined as a postbaseline laboratory value with grade 3 or higher, and with a grade increase from baseline, (that is [i.e.] increasing grade 0 to 3 or higher, grade 1 to 3 or higher, grade 2 to 3 or higher, grade 3 to 4 or 5, grade 4 to 5). Test abnormalities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 =mild; Grade 2 =moderate; Grade 3/Grade 4 =severe/life-threatening, Grade 5 =death.	From the first dose of study drug until 30 days after the last dose (up to 53 months)
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale	Performance status assessments were based on 5-grade ECOG scale (from 0 to 4), where 0=fully active, able to carry on all pre-disease performance without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work); 2=ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5=dead.	Baseline, up to Month 53
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	Change from baseline in left ventricular ejection fraction (LVEF) were evaluated by multigated acquisition scan (MUGA) or echocardiogram.	Baseline, up to Month 53

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 and Part 2: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Assessed by Investigator Review	ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) based on mRECIST assessed by investigator review. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is less than 10 millimeters [mm] if it exists in a lymph node). PR defined as at least 30% decrease in the sum of diameter of all target lesions without unequivocal progression of all non-target lesions, as compared with Baseline.	From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 52 months)
Part 1, Cmax: Maximum Observed Plasma Concentration for Lenvatinib	Cmax was defined as the maximum plasma concentration for lenvatinib. Cmax was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Tmax: Time to Reach the Cmax for Lenvatinib	Tmax was defined as the time to reach maximum observed plasma concentration (Cmax) for lenvatinib. Tmax was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)
Part 1, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib	AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for lenvatinib. AUC(0-t) was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 1 and Day 15: 0-24 hours post-dose (Cycle length=28 days)
Part 1, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib	AUC(0-Inf) was defined as the area under the plasma concentration-time curve from 0 to infinity for lenvatinib. AUC(0-Inf) was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)
Part 1, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib	t1/2 was defined as the terminal elimination phase half-life for lenvatinib. t1/2 was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)
Part 1, CL/F: Apparent Total Clearance for Lenvatinib	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as (Dose/AUC(0-inf))/F. Where AUC(0-inf) is the area under the plasma concentration-time curve from zero to infinity and F is the bioavailability of the drug.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was calculated as (CL/F)/Lambda Z. Where, CL/F is the apparent total clearance and lambda Z is the apparent terminal elimination rate constant.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib	Css,max was defined as the maximum plasma concentration at steady state for lenvatinib. Css,max was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib	Css,min is the minimum plasma concentration at steady state for lenvatinib. Css,min was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib	Tss,Max was defined as the time to reach maximum observed plasma concentration of lenvatinib at steady state. Tss,Max was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib	Rac(Cmax) was calculated as Css,max at Cycle 1 Day 15/Cmax at Cycle 1 Day 1.	Cycle 1 Day 1 and Day 15: 0-24 hours post-dose (Cycle length=28 days)
Part 1, Rac (AUC0-t): Accumulation Ratio of AUC(0-t) for Lenvatinib	Rac(AUC) was calculated as AUC(0-t) at Cycle 1 Day 15/AUC(0-t) at Cycle 1 Day 1.	Cycle 1 Day 1 and Day 15: 0-24 hours post-dose (Cycle length=28 days)
Part 1, MRT: Mean Residence Time for Lenvatinib	MRT was derived by non-compartmental analysis using lenvatinib plasma concentrations.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

Collaborators and Investigators

• Sponsor: Eisai Co., Ltd.
• Collaborators: Ono Pharmaceutical Co. Ltd

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2018
• Primary Completion (Actual): December 28, 2022
• Study Completion (Actual): December 28, 2022

Study Registration Dates

• First Submitted: January 26, 2018
• First Submitted That Met QC Criteria: January 26, 2018
• First Posted (Actual): February 1, 2018

Study Record Updates

• Last Update Posted (Actual): June 20, 2024
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: May 1, 2022

More Information

Terms related to this study

• 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; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Nivolumab; Lenvatinib
• Other Study ID Numbers: E7080-J081-117

Drug and device information, study documents

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