A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma

An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma

This is an open-label Phase 1b study designed to evaluate the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with hepatocellular carcinoma (HCC). The study will evaluate objective response rate and duration of response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: lenvatinib; Drug: pembrolizumab (200 mg)

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux
    • Pessac, Bordeaux, France, 33604
      • Hôpital Haut-Levêque Centre médico-chirurgical Magellan
  • Brittany
    • Rennes, Brittany, France, 35042
      • Centre Eugène Marquis de Rennes
  • Occitanie
    • Toulouse, Occitanie, France, 31059
      • CHU Toulouse
  • Provence-Alpes-Côte d'Azur
    • Marseille, Provence-Alpes-Côte d'Azur, France, 13005
      • Hôpital Timone
• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20089
      • IRCCS Istituto Clinico Humanitas
  • Province Of Bologna
    • Bologna, Province Of Bologna, Italy, 15-40138
      • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan
      • EISAI Trial Site 2
  • Kanagawa
    • Kawasaki, Kanagawa, Japan
      • EISAI Trial Site 4
  • Osaka
    • Sayama, Osaka, Japan
      • EISAI Trial Site 3
  • Tokyo
    • Chuo-ku, Tokyo, Japan
      • EISAI Trial Site 1
• Russian Federation
  • Barnaul, Russian Federation
    • Altay Regional Oncology Dispensary
  • Bashkortostan
    • Ufa, Bashkortostan, Russian Federation
      • Republican Clinical Oncology Dispensary
  • Leningrad Oblast
    • Saint Petersburg, Leningrad Oblast, Russian Federation
      • St. Petersburg City Clinical Oncology Dispansery
  • Moscow Oblast
    • Moscow, Moscow Oblast, Russian Federation
      • S.I. Russian Oncological Research Center n.a. N. N. Blokhin RAMS
• Spain
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marques de Valdecilla
  • Community Of Madrid
    • Madrid, Community Of Madrid, Spain, 28007
      • Hospital General Universitario Gregorio Marañon
    • Madrid, Community Of Madrid, Spain, 28041
      • Hospital Universitario 12 de Octubre
  • Province Of Badajoz
    • Badajoz, Province Of Badajoz, Spain, 06080
      • Hospital Infanta Cristina de Badajoz
  • Province Of Salamanca
    • Salamanca, Province Of Salamanca, Spain, 37007
      • Hospital Universitario de Salamanca
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, NW3 2QG
      • Royal Free Hospital
• United States
  • California
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center (CPMC)
    • Santa Monica, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine Mount Sinai
  • Texas
    • Edinburg, Texas, United States, 78539
      • BRCR Global Texas

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Confirmed diagnosis of hepatocellular carcinoma (HCC)
• HCC for which no other appropriate therapy is available. Note: Expansion Part: No prior systemic therapy for advanced/unresectable HCC
• Stage B (not applicable for transarterial chemoembolization [TACE]), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system
• At least 1 measurable target lesion according to modified Response Evaluation Criteria in Solid Tumors (mRECIST)
• Child-Pugh score A
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1
• Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within normal limits. (control by thyroid replacement therapy is acceptable.) Participants with T3, free T3 or free T4 abnormalities at screening who are asymptomatic can be eligible
• Adequately controlled blood pressure
• Adequate renal function
• Adequate bone marrow function
• Adequate blood coagulation function
• Adequate liver function
• Males or females age ≥ 18 years at the time of informed consent
• Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol

Exclusion Criteria:

• Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• 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 medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial
• Active infection (any infection requiring systemic treatment). Hepatitis B or C [HBV/HCV] is allowed
• Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment

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 8 or 12 mg plus pembrolizumab 200 mg; Participants will receive oral lenvatinib at a starting dose of 8 or 12 milligrams (mg) once a day (QD) in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle. The starting dose of lenvatinib will be based on Baseline body weight. Participants weighing greater than or equal to 60 kilograms (kg) will receive 12 mg QD; participants weighing less than 60 kg will receive 8 mg QD.

Drug: lenvatinib; 4 mg capsules; Drug: pembrolizumab (200 mg); 30-minute intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT Part: 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 the time from the first dose of study drug to 120 days (if participant initiated new anticancer therapy) following last dose of study drug, was absent at pretreatment (Baseline) or reemerged during treatment, was at pretreatment (Baseline) but stopped before treatment or worsened in severity during treatment relative to the pretreatment state, when 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 first dose until 120 days after the last dose (up to 50.2 months)
Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	A TEAE was defined as an AE that emerged during the time from the first dose of study drug to 120 days (if participant initiated new anticancer therapy) following last dose of study drug, was absent at pretreatment (Baseline) or reemerged during treatment, was at pretreatment (Baseline) but stopped before treatment or worsened in severity during treatment relative to the pretreatment state, when 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 first dose until 120 days after the last dose (up to 50.2 months)
DLT Part: 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: (1) any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; (2) failure to administer >=75 percent (%) of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; (3) participants who discontinued treatment due to treatment-related toxicity in Cycle 1; (4) greater than (>) 2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity did not meet DLT criteria.	From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days)
DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR)	ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed by IIR analysis. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 millimeter [mm] if it exists in a lymph node). 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 the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 46.2 months)
DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR	DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on mRECIST assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).	From date of first documented confirmed CR or PR until date of first documentation of PD or death, whichever occurred first (up to 46.2 months)
DLT+Expansion Part: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR	DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on RECIST v1.1 assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).	From date of first documented confirmed CR or PR until date of first documentation of PD or death, whichever occurred first (up to 46.2 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review	ORR was defined as the percentage of participants who had BOR of CR or PR based on mRECIST assessed by investigator review. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.	From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 46.2 months)
DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review	DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) based on mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).	From date of first documented confirmed CR or PR until date of first documentation of PD or death, whichever occurred first (up to 46.2 months)
DLT+Expansion Part: Progression-free Survival (PFS) Based on mRECIST and RECIST v1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review	PFS was defined as the time from the first study dose date to the date of first documentation of PD or death (whichever occurred first) based on mRECIST and RECIST v1.1 assessed by IIR, and mRECIST assessed by investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).	From the first study dose date to the date of first documentation of PD or death, whichever occurred first (up to 46.2 months)
DLT+Expansion Part: Time-to-Progression (TTP) Based on mRECIST and RECIST v1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review	TTP was defined as the time from the first study dose date to the date of first documentation of PD, based on mRECIST and RECIST v1.1 assessed by IIR and mRECIST assessed by an investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD, and the increase of LD was at least 5 mm (including new lesions).	From date of first dose of study drug until PD (up to 46.2 months)
DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by IIR	TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.	From date of first dose of study drug until CR or PR (up to 46.2 months)
DLT+Expansion Part: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR	TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to RECIST v1.1 assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.	From date of first dose of study drug until CR or PR (up to 46.2 months)
DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review	TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.	From date of first dose of study drug until CR or PR (up to 46.2 months)
DLT+Expansion Part: Overall Survival (OS)	OS was measured from the date of first dose of study drug until date of death from any cause. Participants who were lost to follow-up or who were alive at the date of data cutoff were censored at the date the participants were last known alive, whichever came earlier.	From the date of first dose of study drug until date of death from any cause (up to 48.1 months)
DLT+Expansion Part, 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 quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). As per pharmacokinetic (PK) planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, AUC(0-ti): Area Under The Plasma Concentration-time Curve From Zero (Pre-Dose) to a Given Sampling Time (ti) for Lenvatinib	AUC(0-ti) was defined as the area under the plasma concentration-time curve from 0 to a given sampling time for lenvatinib. AUC(0-ti) was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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 quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib	AUC(0-tau) was defined as the area under the plasma concentration-time curve over dosing interval for lenvatinib. AUC(0-tau) was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib	Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CLss/F was calculated as (Dose/AUC(0-tau))/F. Where, AUC(0-tau) is the area under the plasma concentration-time curve over the dosing interval and F is the bioavailability of the drug. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib	Css,Av was defined as the average plasma concentration at steady state for lenvatinib. Css,Av was derived by non-compartmental analysis using lenvatinib plasma concentrations quantified by LC-MS/MS. Css,Av was calculated as AUC(0-tau)/tau. Where, AUC(0-tau) is the area under the plasma concentration-time curve over the dosing interval and tau is the length of dosing interval. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib	Volume of distribution at steady state 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,ss/F was calculated as (CLss/F)/Lambda Z. Where, CLss/F is the apparent total clearance following oral administration at steady state and lambda Z is the apparent terminal elimination rate constant. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, 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. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib	Rac(AUC0-8 hour) was calculated as AUC(0-8 hour) at Cycle 1 Day 15/AUC(0-8 hour) at Cycle 1 Day 1. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib	The PTF within complete dosing interval at steady state, calculated as PTF (%) = ([Css,max - Css,min]/Css,Av)* 100. Where, Css,max is the maximum observed plasma concentration at steady state and Css,min is the minimum observed plasma concentration at steady state and Css,Av average steady state plasma concentration. As per PK planned analysis for lenvatinib and as per sponsor's practice, the lenvatinib PK data was collected, analyzed and summarized according to Japanese and non-Japanese population in this study.	Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab	Ctrough was defined as trough (pre-dose) serum concentration for pembrolizumab at steady state.	Cycles 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36: Pre-dose (each Cycle length=21 days)
DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status	ADA positive was defined as participants with at least one pre-treatment or post-dose sample positive in the confirmatory assay for antibodies against pembrolizumab. ADA was assessed using a validated electrochemiluminescence (ECL) immunoassay.	Cycles 1 and 6 Day 1: Pre-dose (each cycle length=21 days)

Collaborators and Investigators

• Sponsor: Eisai Co., Ltd.
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, Pracht M, Mamontov K, Meyer T, Kubota T, Dutcus CE, Saito K, Siegel AB, Dubrovsky L, Mody K, Llovet JM. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020 Sep 10;38(26):2960-2970. doi: 10.1200/JCO.20.00808. Epub 2020 Jul 27.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2017
• Primary Completion (Actual): October 31, 2019
• Study Completion (Actual): November 22, 2022

Study Registration Dates

• First Submitted: December 27, 2016
• First Submitted That Met QC Criteria: December 29, 2016
• First Posted (Estimated): December 30, 2016

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: hepatocellular carcinoma; pembrolizumab; Japan; lenvatinib; 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; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: E7080-J081-116; KEYNOTE 524 (Other Identifier: Merck); 2018-000522-55 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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