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Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Lenvatinib as First-line Therapy in Participants With Advanced Hepatocellular Carcinoma (MK-7902-002/LEAP-002)

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ClinicalTrials.gov Identifier: NCT03713593
Recruitment Status : Not yet recruiting
First Posted : October 22, 2018
Last Update Posted : October 22, 2018
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

The purpose of this study is to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3745) versus lenvatinib in combination with placebo as first-line therapy for the treatment of advanced hepatocellular carcinoma in adult participants.

The primary hypotheses of this study are that lenvatinib plus pembrolizumab is superior to lenvatinib plus placebo with respect to progression-free survival (PFS) and overall survival (OS).


Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Drug: lenvatinib Biological: pembrolizumab Drug: saline placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Lenvatinib in First-line Therapy of Participants With Advanced Hepatocellular Carcinoma (LEAP-002)
Estimated Study Start Date : December 20, 2018
Estimated Primary Completion Date : July 23, 2022
Estimated Study Completion Date : July 23, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: lenvatinib plus pembrolizumab
Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
Drug: lenvatinib
Administered orally once a day during each 21-day cycle
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®

Biological: pembrolizumab
Administered as an IV infusion on Day 1 Q3W
Other Names:
  • MK-3475
  • KEYTRUDA®

Active Comparator: lenvatinib plus placebo
Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
Drug: lenvatinib
Administered orally once a day during each 21-day cycle
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®

Drug: saline placebo
Administered as an IV infusion on Day 1 Q3W




Primary Outcome Measures :
  1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 44 months ]
    PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to the RECIST 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

  2. Overall Survival (OS) [ Time Frame: Up to approximately 44 months ]
    OS is the time from randomization to death due to any cause.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 44 months ]
    ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

  2. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 44 months ]
    DOR is determined by disease assessment and is defined as the time from the first documented evidence of a response of CR or PR, per RECIST 1.1 as assessed by BICR, until the first documented disease progression or death due to any cause, whichever occurs first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

  3. Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 44 months ]
    DCR is defined as the percentage of participants who have a best overall response of CR, PR, or stable disease (SD) per RECIST 1.1 as assessed by BICR. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

  4. Percentage of Participants Who Experience At Least One Adverse Event (AE) [ Time Frame: Up to approximately 44 months ]
    Percentage of participants experiencing an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study treatment

  5. Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE) [ Time Frame: Up to approximately 44 months ]
    Percentage of participants experiencing a SAE defined as an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose, or is another important medical event

  6. Percentage of Participants Who Experience At Least One Immune-related Adverse Event (irAE) of Clinical Interest [ Time Frame: Up to approximately 44 months ]
    Percentage of participants experiencing an AE representing an immunologic etiology and considered to be causally related to drug exposure

  7. Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI) [ Time Frame: Up to approximately 44 months ]
    Percentage of participants experiencing a hepatic ECI not due to disease progression as judged by the investigator.

  8. Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event [ Time Frame: Up to approximately 44 months ]
    Percentage of participants discontinuing study treatment due to an AE

  9. Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf) [ Time Frame: At designated time points on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) ]
    Blood samples will be obtained on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) for pharmacokinetic (PK) analysis to determine the AUC of lenvatinib.

  10. Time to Disease Progression (TTP) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 44 months ]
    TTP is defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

  11. Progression-free Survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to approximately 44 months ]
    PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ will be followed.

  12. Objective Response Rate (ORR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to approximately 44 months ]
    ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of any intratumoral arterial enhancement in all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of viable [enhancement in the arterial phase] target lesions, taking as reference the baseline sum of the diameters of target lesions) per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ will be followed.

  13. Duration of Response (DOR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to approximately 44 months ]
    DOR is determined by disease assessment and is defined as the time from the first documented evidence of a response of CR or PR, per mRECIST as assessed by BICR, until the first documented disease progression or death due to any cause, whichever occurs first. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ will be followed.

  14. Disease Control Rate (DCR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to approximately 44 months ]
    DCR is defined as the percentage of participants who have a best overall response of CR, PR, or SD per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. A maximum of 10 target lesions and a maximum of 5 target lesions per organ will be followed.

  15. Time to Disease Progression (TTP) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to approximately 44 months ]
    TTP is defined as the time from randomization to the first documented disease progression per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ will be followed.



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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:

  • Is male or female and ≥18 years of age at the time of signing the informed consent
  • Has a diagnosis of hepatocellular carcinoma confirmed by radiology, histology, or cytology
  • Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach
  • Has a Child-Pugh class A liver score
  • Has a predicted life expectancy of >3 months
  • Has at least one measurable lesion based on RECIST 1.1 as confirmed by BICR
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
  • Has controlled hepatitis B virus (HBV)

Exclusion Criteria:

  • Has had esophageal or gastric variceal bleeding within the last 6 months
  • Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
  • Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula
  • Has clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior to the first dose of study intervention
  • Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability
  • Has had major surgery to the liver within 4 weeks prior to the first dose of study intervention
  • Has had a minor surgery (ie, simple excision) within 7 days prior to the first dose of study intervention
  • Has serious non-healing wound, ulcer, or bone fracture
  • Has received any systemic chemotherapy for HCC or chemotherapy for any malignancy in the past 3 years
  • Has received prior therapy with an anti-programmed cell death 1 (ant-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti- programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, or CD137)
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exceptions of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that has undergone potentially curative therapy
  • Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator
  • Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of their excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • Has urine protein ≥1 grams/24 hours
  • Prolongation of corrected QT (QTc) interval to >480 milliseconds (corrected by Fridericia Formula)
  • Has left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
  • Has an active infection requiring systemic therapy with the exceptions of HBV or HCV
  • Has a known history of human immunodeficiency virus (HIV) infection
  • Has a known history of active tuberculosis (Bacillus tuberculosis)
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
  • Has had an allogenic tissue/solid organ transplant

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): NCT03713593


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Eisai Inc.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03713593     History of Changes
Other Study ID Numbers: 7902-002
MK-7902-002 ( Other Identifier: Merck Protocol Number )
2018-002983-26 ( EudraCT Number )
E7080-G000-311 ( Other Identifier: Eisai Protocol Number )
First Posted: October 22, 2018    Key Record Dates
Last Update Posted: October 22, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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

Keywords provided by Merck Sharp & Dohme Corp.:
receptor tyrosine kinase inhibitor
programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
programmed cell death ligand 2 (PD-L2, PDL2)

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