Clinical trial NCT03006926: A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma
Official title: An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Keywords: hepatocellular carcinoma
E7080
lenvatinib
pembrolizumab
Japan
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2016-12-30
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose until 120 days after the last dose (up to 50.2 months)
measure: Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose until 120 days after the last dose (up to 50.2 months)
measure: DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days)
measure: DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST Version (v) 1.1 Assessed by Independent Imaging Review (IIR)
timeFrame: 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)
measure: DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR
timeFrame: 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)
measure: DLT+Expansion Part: Duration of Response (DOR) Based on RECIST v1.1 Assessed by IIR
timeFrame: 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:
measure: DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review
timeFrame: 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)
measure: DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review
timeFrame: 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)
measure: 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
timeFrame: From the first study dose date to the date of first documentation of PD or death, whichever occurred first (up to 46.2 months)
measure: 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
timeFrame: From date of first dose of study drug until PD (up to 46.2 months)
measure: DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by IIR
timeFrame: From date of first dose of study drug until CR or PR (up to 46.2 months)
measure: DLT+Expansion Part: Time-to-Response (TTR) Based on RECIST v1.1 Assessed by IIR
timeFrame: From date of first dose of study drug until CR or PR (up to 46.2 months)
measure: DLT+Expansion Part: Time-to-Response (TTR) Based on mRECIST Assessed by Investigator Review
timeFrame: From date of first dose of study drug until CR or PR (up to 46.2 months)
measure: DLT+Expansion Part: Overall Survival (OS)
timeFrame: From the date of first dose of study drug until date of death from any cause (up to 48.1 months)
measure: DLT+Expansion Part, Cmax: Maximum Observed Plasma Concentration for Lenvatinib
timeFrame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Tmax: Time to Reach the Cmax for Lenvatinib
timeFrame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib
timeFrame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
measure: 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
timeFrame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib
timeFrame: Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib
timeFrame: Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, CL/F: Apparent Total Clearance for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib
timeFrame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Css,Av: Average Steady State Plasma Concentration for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Vz,ss/F: Apparent Terminal Volume of Distribution at Steady State for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib
timeFrame: Cycle 1 Days 1 and 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Rac (AUC0-8 Hour): Accumulation Ratio of AUC(0-8 Hour) for Lenvatinib
timeFrame: Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, %PTF: Percent (%) Peak-trough Fluctuation for Lenvatinib
timeFrame: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=21 days)
measure: DLT+Expansion Part, Ctrough: Trough (Pre-dose) Serum Concentration for Pembrolizumab
timeFrame: Cycles 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36: Pre-dose (each Cycle length=21 days)
measure: DLT+Expansion Part: Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status
timeFrame: Cycles 1 and 6 Day 1: Pre-dose (each cycle length=21 days)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: California Pacific Medical Center (CPMC)
state: California
city: Santa Monica
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Icahn School of Medicine Mount Sinai
state: New York
city: Edinburg
country: United States
facility: BRCR Global Texas
state: Texas
city: Pessac
country: France
facility: Hôpital Haut-Levêque Centre médico-chirurgical Magellan
state: Bordeaux
city: Rennes
country: France
facility: Centre Eugène Marquis de Rennes
state: Brittany
city: Toulouse
country: France
facility: CHU Toulouse
state: Occitanie
city: Marseille
country: France
facility: Hôpital Timone
state: Provence-Alpes-Côte d'Azur
city: Milan
country: Italy
facility: IRCCS Istituto Clinico Humanitas
state: Lombardy
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
state: Province Of Bologna
city: Kashiwa
country: Japan
facility: Eisai Trial Site 2
state: Chiba
city: Kawasaki
country: Japan
facility: Eisai Trial Site 4
state: Kanagawa
city: Sayama
country: Japan
facility: Eisai Trial Site 3
state: Osaka
city: Chuo-ku
country: Japan
facility: Eisai Trial Site 1
state: Tokyo
city: Ufa
country: Russian Federation
facility: Republican Clinical Oncology Dispensary
state: Bashkortostan
city: Saint Petersburg
country: Russian Federation
facility: St. Petersburg City Clinical Oncology Dispansery
state: Leningrad Oblast
city: Moscow
country: Russian Federation
facility: S.I. Russian Oncological Research Center n.a. N. N. Blokhin RAMS
state: Moscow Oblast
city: Barnaul
country: Russian Federation
facility: Altay Regional Oncology Dispensary
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
state: Community Of Madrid
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
state: Community Of Madrid
city: Badajoz
country: Spain
facility: Hospital Infanta Cristina de Badajoz
state: Province Of Badajoz
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
state: Province Of Salamanca
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Greater London
Study officials:
References:
citation: 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.