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A Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma

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ClinicalTrials.gov Identifier: NCT03006926
Recruitment Status : Recruiting
First Posted : December 30, 2016
Last Update Posted : March 27, 2018
Sponsor:
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Co., Ltd. )

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 Expansion part of the study will evaluate objective response rate and duration of response by modified Response Evaluation Criteria In Solid Tumors for HCC (mRECIST) and RECIST 1.1 based on independent imaging review

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: lenvatinib Drug: pembrolizumab (200 mg) Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma
Actual Study Start Date : February 28, 2017
Estimated Primary Completion Date : August 31, 2018
Estimated Study Completion Date : February 28, 2019

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Number of participants with any serious adverse event and number of participants with any non-serious adverse event. [ Time Frame: For each participant, from the first participant first dose until 30 days after the last dose (up to approximately 2 years) ]
    An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect.

  2. Dose-limiting toxicity (DLT) of lenvatinib and pembrolizumab during Cycle 1 [ Time Frame: Up to 21 Days (Cycle 1) ]
    A DLT is defined as any of the following: (1) any of the hematological or nonhematological toxicities specified in the protocol that are considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; (2) failure to administer greater than or equal to 75% of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; (3) participants who discontinue 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 does not meet DLT criteria"


Secondary Outcome Measures :
  1. Objective response rate (ORR) based on modified Response Evaluation Criteria In Solid Tumors (mRECIST) [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years ]
    ORR is defined as the proportion of participant who have BOR of CR or PR at the time of data cutoff. Responses (PR or CR) should be confirmed no less than 4 weeks after the initial response. Assessment and definition of BOR is based on mRECIST.

  2. Duration of response (DOR) based on mRECIST [ Time Frame: From the first documentation of complete response (CR) or partial response (PR) to the date of first documentation of disease progression or death (whichever occurs first), or up to approximately 2 years ]
    From the first documentation of complete response (CR) or partial response (PR) to the date of first documentation of disease progression or death (whichever occurs first). Assessment and definition of PD is based on mRECIST

  3. Mean maximum concentration (Cmax) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. Cmax is the highest concentration of drug in the plasma that is measured after a dose.

  4. Mean time to reach maximum concentration (Tmax) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. Tmax is the time to the highest concentration of lenvatinib in the plasma that is measured after a dose.

  5. Mean terminal half-life (t1/2) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. t1/2 is the time taken for the plasma concentration to fall to half its original value.

  6. Mean area under the drug concentration-time curve (AUC) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. AUC represents the overall amount of drug in the plasma after dosing.

  7. Mean apparent total clearance (CL/F) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. Apparent clearance is defined as the rate of lenvatinib elimination divided by plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time.

  8. Mean apparent volume of distribution (Vz/F) of lenvatinib [ Time Frame: Cycle 1, Day 1: predose of pembrolizumab; 1, 2, 4, 8, and 24 hours postdose of lenvatinib. Cycle 1, Day 15: predose of lenvatinib; 1, 2, 4, 8, and 24 hours postdose of lenvatinib ]
    Blood samples will be collected at the designated time points. The apparent volume of distribution gives information about the amount of lenvatinib distributed in body tissue rather than the blood/plasma.

  9. Mean measured concentration at the end of a dosing interval (Ctrough) of pembrolizumab [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, and 8 and Day 1 in every 4 cycles after Cycle 8: predose of pembrolizumab. End of treatment: within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier ]
    Blood samples will be collected at the designated time points. Ctrough is the minimum concentration at the end of the dosing interval.

  10. Mean clearance (CL) of pembrolizumab [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, and 8 and Day 1 in every 4 cycles after Cycle 8: predose of pembrolizumab. End of treatment: within 30 days after discontinuation or until the initiation of other anticancer treatment, whichever is earlier ]
    Blood samples will be collected at the designated time points. Apparent clearance is defined as the rate of pembrolizumab elimination divided by serum concentration, giving a volume of plasma from which drug is completely removed per unit of time.

  11. Number of participants with anti-drug antibodies (ADA) for pembrolizumab [ Time Frame: Day 1 of Cycles 1 and 6: predose of pembrolizumab ]
    Blood samples will be collected and analyzed. Serum ADA will be detected by using validated methods.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Any current brain or subdural metastases
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03006926


Contacts
Contact: Customer Joy Department. EJ 81-120-161-454 esi_medinfo@eisai.com

Locations
United States, California
Pacific Hematology and Oncology Associates Recruiting
San Francisco, California, United States, 94115
Ronald Reagan UCLA Medical Center Recruiting
Santa Monica, California, United States, 90095
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
United States, New York
Icahn School of Medicine Mount Sinai Recruiting
New York, New York, United States, 10029
Japan
Eisai Trial Site Active, not recruiting
Kashiwa, Chiba, Japan
Eisai Trial Site Active, not recruiting
Kawasaki, Kanagawa, Japan
Eisai Trial Site Active, not recruiting
Sayama, Osaka, Japan
Eisai Trial Site Active, not recruiting
Chuo-ku, Tokyo, Japan
Sponsors and Collaborators
Eisai Co., Ltd.

Responsible Party: Eisai Co., Ltd.
ClinicalTrials.gov Identifier: NCT03006926     History of Changes
Other Study ID Numbers: E7080-J081-116
KEYNOTE 524 ( Other Identifier: Merck )
2018-000522-55 ( EudraCT Number )
First Posted: December 30, 2016    Key Record Dates
Last Update Posted: March 27, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc. ( Eisai Co., Ltd. ):
hepatocellular carcinoma
E7080
lenvatinib
pembrolizumab
Japan

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Pembrolizumab
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action