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A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma

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ClinicalTrials.gov Identifier: NCT03006926
Recruitment Status : Active, not recruiting
First Posted : December 30, 2016
Results First Posted : December 31, 2020
Last Update Posted : December 31, 2020
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 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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: N/A
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 13, 2017
Actual Primary Completion Date : October 31, 2019
Estimated Study Completion Date : August 31, 2021

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. DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose until 30 days after the last dose (up to approximately 2 years 9 months) ]
  2. Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose until 30 days after the last dose (up to approximately 2 years 9 months) ]
  3. DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days) ]
    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 >=75 percent (%) 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) >2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria.

  4. DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST 1.1 Assessed by Independent Imaging Review (IIR) [ Time Frame: From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first (up to approximately 2 years and 9 months) ]
    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) 1.1 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.

  5. DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR [ Time Frame: From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months) ]
    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).

  6. DLT+Expansion Part: Duration of Response (DOR) Based on RECIST 1.1 Assessed by IIR [ Time Frame: From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months) ]
    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 1.1 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).


Secondary Outcome Measures :
  1. DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review [ Time Frame: From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first (up to approximately 2 years and 9 months) ]
    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.

  2. DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review [ Time Frame: From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months) ]
    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).

  3. DLT+Expansion Part: Progression-free Survival (PFS) Based on mRECIST and RECIST 1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review [ Time Frame: From the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) (up to approximately 2 years 9 months) ]
    PFS was defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) based on mRECIST and RECIST 1.1 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).

  4. DLT+Expansion Part: Time-to Progression (TTP) Based on mRECIST and RECIST 1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review [ Time Frame: From date of first dose of study drug until disease progression (up to approximately 2 years 9 months) ]
    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 1.1 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).

  5. DLT+Expansion Part: Time-to Response (TTR) Based on mRECIST Assessed by IIR [ Time Frame: From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months) ]
    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.

  6. DLT+Expansion Part: Time-to Response (TTR) Based on RECIST 1.1 Assessed by IIR [ Time Frame: From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months) ]
    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 1.1 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.

  7. DLT+Expansion Part: Time-to Response (TTR) Based on mRECIST Assessed by Investigator Review [ Time Frame: From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months) ]
    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.

  8. DLT+Expansion Part: Overall Survival (OS) [ Time Frame: From the date of first dose of study drug until date of death from any cause (up to approximately 2 years 9 months) ]
    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 and the participants who were alive at the date of data cutoff was censored at the date the participant was last known alive, whichever came earlier.

  9. Cmax: Maximum Observed Plasma Concentration for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  10. Tmax: Time to Reach the Cmax for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  11. AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  12. AUC(0-ti): Area Under The Plasma Concentration-time Curve From Zero (Pre-Dose) to a Given Sampling Time (ti) for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  13. AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  14. t1/2: Terminal Elimination Phase Half-Life for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  15. CL/F: Apparent Total Clearance for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  16. Vz/F: Apparent Volume of Distribution at Terminal Phase for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  17. Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  18. Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  19. Tss,Max: Time to Maximum Concentration at Steady State For Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  20. AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  21. Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  22. Css,Av: Average Steady State Plasma Concentration for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  23. Rac (Cmax): Accumulation Index of Cmax for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Rac (Cmax) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  24. Rac (AUC): Accumulation Index of AUC for Lenvatinib and Pembrolizumab [ Time Frame: Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days) ]
    Rac (AUC) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

  25. Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status for Pembrolizumab [ Time Frame: Cycles 1 and 6 Day 1: Pre-dose (cycle length=21 days) ]
    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).



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.


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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
  • 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


Locations
Show Show 26 study locations
Sponsors and Collaborators
Eisai Co., Ltd.
  Study Documents (Full-Text)

Documents provided by Eisai Inc. ( Eisai Co., Ltd. ):
Study Protocol  [PDF] January 17, 2019
Statistical Analysis Plan  [PDF] October 22, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eisai Co., Ltd.
ClinicalTrials.gov Identifier: NCT03006926    
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
Results First Posted: December 31, 2020
Last Update Posted: December 31, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action