A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma

NCT03006926 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: E7080-J081-116KEYNOTE 5242018-000522-55
• Study Type: interventional
• Target: 104
• Locations: 7 countries
• Sites: 26

Brief Summary

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).

Conditions

Hepatocellular Carcinoma

Keywords

hepatocellular carcinoma; E7080; lenvatinib; pembrolizumab; Japan

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (28)

• DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review

  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

  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

  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

  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

  From date of first dose of study drug until CR or PR (up to 46.2 months)

Study Arms (1)

lenvatinib 8 or 12 mg plus pembrolizumab 200 mg

EXPERIMENTAL

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; Drug: pembrolizumab (200 mg)

Interventions

lenvatinib DRUG

4 mg capsules

lenvatinib 8 or 12 mg plus pembrolizumab 200 mg

pembrolizumab (200 mg) DRUG

30-minute intravenous infusion

lenvatinib 8 or 12 mg plus pembrolizumab 200 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Eisai Co., Ltd.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (26)

California Pacific Medical Center (CPMC)

San Francisco, California, 94115, United States

Location

Ronald Reagan UCLA Medical Center

Santa Monica, California, 90095, United States

Location

Mercy Medical Center

Baltimore, Maryland, 21202, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Icahn School of Medicine Mount Sinai

New York, New York, 10029, United States

Location

BRCR Global Texas

Edinburg, Texas, 78539, United States

Location

Hôpital Haut-Levêque Centre médico-chirurgical Magellan

Pessac, Bordeaux, 33604, France

Location

Centre Eugène Marquis de Rennes

Rennes, Brittany Region, 35042, France

Location

CHU Toulouse

Toulouse, Occitanie, 31059, France

Location

Hôpital Timone

Marseille, Provence-Alpes-Côte d'Azur Region, 13005, France

Location

IRCCS Istituto Clinico Humanitas

Milan, Lombardy, 20089, Italy

Location

Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi

Bologna, Province of Bologna, 15-40138, Italy

Location

Eisai Trial Site 2

Kashiwa, Chiba, Japan

Location

Eisai Trial Site 4

Kawasaki, Kanagawa, Japan

Location

Eisai Trial Site 3

Sayama, Osaka, Japan

Location

Eisai Trial Site 1

Chuo-ku, Tokyo, Japan

Location

Republican Clinical Oncology Dispensary

Ufa, Bashkortostan Republic, Russia

Location

St. Petersburg City Clinical Oncology Dispansery

Saint Petersburg, Leningradskaya Oblast', Russia

Location

S.I. Russian Oncological Research Center n.a. N. N. Blokhin RAMS

Moscow, Moscow Oblast, Russia

Location

Altay Regional Oncology Dispensary

Barnaul, Russia

Location

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, 39008, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, Madrid, 28007, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Madrid, 28041, Spain

Location

Hospital Infanta Cristina de Badajoz

Badajoz, Province of Badajoz, 06080, Spain

Location

Hospital Universitario de Salamanca

Salamanca, Province of Salamanca, 37007, Spain

Location

Royal Free Hospital

London, Greater London, NW3 2QG, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32716739 DERIVED

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

lenvatinib; pembrolizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Results Point of Contact

• Title: Eisai Inquiry Service
• Organization: Eisai Co., Ltd.

eisai-chiken_hotline@hhc.eisai.co.jp

none

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2016
• First Posted: December 30, 2016
• Study Start: February 13, 2017
• Primary Completion: October 31, 2019
• Study Completion: November 22, 2022
• Last Updated: December 13, 2023
• Results First Posted: December 31, 2020

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (6); JP (4); IT (2); RU (4); FR (4); GB (1); ES (5)