A Study of Lenvatinib Plus Nivolumab in Participants With Hepatocellular Carcinoma

Eisai Co., Ltd.30 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Carcinoma, Hepatocellular

Interventions

LenvatinibDRUG

Specified doses will be administered orally on specified days.

NivolumabDRUG

Specified doses will be administered intravenously on specified days.

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

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

Locations (6)

Eisai Trial Site 1

Kashiwa, Chiba, Japan

Eisai Trial Site 6

Iizuka, Fukuoka, Japan

Eisai Trial Site 3

Kawasaki, Kanagawa, Japan

Eisai Trial Site 4

Sayama, Osaka, Japan

Eisai Trial Site 2

Outcomes

Primary Outcomes

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.

Time frame: 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).

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)