ClinicalTrials.gov
ClinicalTrials.gov Menu

A Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03006926
Recruitment Status : Recruiting
First Posted : December 30, 2016
Last Update Posted : August 6, 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 (mRECIST) for HCC and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 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 2019
Estimated Study Completion Date : December 2020

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 3 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"

  3. Expansion part: Objective response rate (ORR) by mRECIST and RECIST 1.1 based on IIR analysis [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination (up to approximately 3 years) ]
    ORR is defined as the percentage of participants who have best overall response (BOR) of complete response (CR) or partial response (PR) at the time of data cutoff as assessed by mRECIST and RECIST 1.1 based on IIR analysis. Responses (PR or CR) should be confirmed no less than 4 weeks after the initial response.

  4. Expansion part: Duration of response (DOR) by mRECIST and RECIST 1.1 based on IIR analysis [ Time Frame: From the first documentation of CR or PR to the first date of documentation of disease progression or death whichever occurs first (up to approximately 3 years) ]
    DOR is defined as the time from the first documentation of CR or PR to the date of first documentation of disease progression or death (whichever occurs first) as assessed by mRECIST and RECIST 1.1 based on IIR analysis.


Secondary Outcome Measures :
  1. DLT Evaluation Part: ORR by mRECIST and RECIST 1.1 Based on IIR Analysis [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination (up to approximately 3 years) ]
    ORR is defined as the percentage of participants who have BOR of CR or PR at the time of data cutoff as assessed by mRECIST based on investigator review and IIR, and by RECIST 1.1 based on IIR. Responses (PR or CR) should be confirmed no less than 4 weeks after the initial response.

  2. DLT Evaluation Part: DOR by mRECIST and RECIST 1.1 Based on IIR Analysis [ Time Frame: From the first documentation of CR or PR to the date of first documentation of disease progression or death, whichever occurs first (up to approximately 3 years) ]
    DOR is defined as the time from the first documentation of CR or PR to the date of first documentation of disease progression or death (whichever occurs first) as assessed by mRECIST based on investigator review and IIR, and by RECIST 1.1 based on IIR. Responses (PR or CR) should be confirmed no less than 4 weeks after the initial response.

  3. Expansion part: ORR by mRECIST Based on Investigator Review [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination (up to approximately 3 years) ]
    ORR is defined as the percentage of participants who have BOR of CR or PR at the time of data cutoff as assessed by mRECIST based on investigator review. Responses (PR or CR) should be confirmed no less than 4 weeks after the initial response.

  4. Expansion part: DOR by mRECIST Based on Investigator Review [ Time Frame: From the first documentation of CR or PR to the date of first documentation of disease progression or death, whichever occurs first (up to approximately 3 years) ]
    DOR is defined as the time from the first documentation of CR or PR to the date of first documentation of disease progression or death (whichever occurs first) as assessed by mRECIST based on investigator review. Responses (PR or CR) should be confirmed no less than 4 weeks after the initial response.

  5. Progression-free Survival (PFS) by mRECIST and RECIST 1.1 Based on IIR Analysis [ Time Frame: From date of first dose of study drug to the date of first documentation of disease progression or death, whichever occurs first (up to approximately 3 years) ]
    PFS is defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurs first) as assessed by mRECIST based on investigator review and IIR, and RECIST 1.1 based on IIR.

  6. Time to Progression (TTP) by RECIST 1.1 Based on IIR analysis [ Time Frame: From date of first dose of study drug to the date of first documentation of disease progression (up to approximately 3 years) ]
    TTP is defined as the time from the first study dose date to the date of first documentation of disease progression as assessed by mRECIST based on investigator review and IIR, and RECIST 1.1 based on IIR.

  7. Time to Response (TTR) by mRECIST and RECIST 1.1 Based on IIR Analysis [ Time Frame: From the date of first study dose to the date of first documentation of CR or PR (up to approximately 3 years) ]
    TTR is defined as the time from the date of first study dose to the date of first documentation of CR or PR as assessed by mRECIST based on investigator review and IIR, and RECIST 1.1 based on IIR.

  8. Overall survival (OS) [ Time Frame: From the start date of the Treatment Phase until date of death from any cause (up to approximately 3 years) ]
    OS is measured from the start date of the Treatment Phase until date of death from any cause. Participants who are lost to follow-up and the participants who are alive at the date of data cutoff will be censored at the date the participant was last known alive or the cut-off date, whichever comes earlier.

  9. Mean maximum concentration (Cmax) of lenvatinib [ Time Frame: DLT Part: Cycle1 Day1 (C1D1)(predose pembrolizumab), D15(predose lenvatinib),1,2,4,8,24 hours postdose lenvatinib; Expansion Part: C1 D1,15(predose lenvatinib),0.5-4,6-10 hours postdose lenvatinib; C2,4,6 D1 predose prembrolizumab; (cycle length=21 days) ]
    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.

  10. Mean time to reach maximum concentration (Tmax) of lenvatinib [ Time Frame: DLT Part: Cycle1 Day1 (C1D1)(predose pembrolizumab), D15(predose lenvatinib),1,2,4,8,24 hours postdose lenvatinib; Expansion Part: C1 D1,15(predose lenvatinib),0.5-4,6-10 hours postdose lenvatinib; C2,4,6 D1 predose prembrolizumab; (cycle length=21 days) ]
    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.

  11. Mean terminal half-life (t1/2) of lenvatinib [ Time Frame: DLT Part: Cycle1 Day1 (C1D1)(predose pembrolizumab), D15(predose lenvatinib),1,2,4,8,24 hours postdose lenvatinib; Expansion Part: C1 D1,15(predose lenvatinib),0.5-4,6-10 hours postdose lenvatinib; C2,4,6 D1 predose prembrolizumab; (cycle length=21 days) ]
    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.

  12. Mean area under the drug concentration-time curve (AUC) of lenvatinib [ Time Frame: DLT Part: Cycle1 Day1 (C1D1)(predose pembrolizumab), D15(predose lenvatinib),1,2,4,8,24 hours postdose lenvatinib; Expansion Part: C1 D1,15(predose lenvatinib),0.5-4,6-10 hours postdose lenvatinib; C2,4,6 D1 predose prembrolizumab; (cycle length=21 days) ]
    Blood samples will be collected at the designated time points. AUC represents the overall amount of drug in the plasma after dosing.

  13. Mean apparent total clearance (CL/F) of lenvatinib [ Time Frame: DLT Part: Cycle1 Day1 (C1D1)(predose pembrolizumab), D15(predose lenvatinib),1,2,4,8,24 hours postdose lenvatinib; Expansion Part: C1 D1,15(predose lenvatinib),0.5-4,6-10 hours postdose lenvatinib; C2,4,6 D1 predose prembrolizumab; (cycle length=21 days) ]
    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.

  14. Mean apparent volume of distribution (Vz/F) of lenvatinib [ Time Frame: DLT Part: Cycle1 Day1 (C1D1)(predose pembrolizumab), D15(predose lenvatinib),1,2,4,8,24 hours postdose lenvatinib; Expansion Part: C1 D1,15(predose lenvatinib),0.5-4,6-10 hours postdose lenvatinib; C2,4,6 D1 predose prembrolizumab; (cycle length=21 days) ]
    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.

  15. Mean measured concentration at the end of a dosing interval (Ctrough) of pembrolizumab [ Time Frame: Day1 (D1) of Cycle(C) 1,2,4,6,8 and D1 in every 4 cycles after C8:predose of pembrolizumab, (cycle length=21 days); End of treatment: 30 days after discontinuation or until initiation of other anticancer treatment, whichever is earlier (up to 3 years) ]
    Blood samples will be collected at the designated time points. Ctrough is the minimum concentration at the end of the dosing interval.

  16. Mean clearance (CL) of pembrolizumab [ Time Frame: Day1 (D1) of Cycle(C) 1,2,4,6,8 and D1 in every 4 cycles after C8:predose of pembrolizumab, (cycle length=21 days); End of treatment: 30 days after discontinuation or until initiation of other anticancer treatment, whichever is earlier (up to 3 years) ]
    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.

  17. Number of participants with anti-drug antibodies (ADA) for pembrolizumab [ Time Frame: Day 1 of Cycle 1 and 6: predose of pembrolizumab, (cycle length=21 days) ]
    Blood samples will be collected and analyzed. Serum ADA will be detected by using validated methods.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

  Show 30 Study Locations
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: August 6, 2018
Last Verified: July 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