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Safety and Efficacy of Lenvatinib (E7080/MK-7902) With Pembrolizumab (MK-3475) in Combination With Transarterial Chemoembolization (TACE) in Participants With Incurable/Non-metastatic Hepatocellular Carcinoma (MK-7902-012/E7080-G000-318/LEAP-012)

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ClinicalTrials.gov Identifier: NCT04246177
Recruitment Status : Recruiting
First Posted : January 29, 2020
Last Update Posted : July 29, 2021
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
The purpose of this study is to evaluate the efficacy and safety of lenvatinib and pembrolizumab in combination with TACE versus TACE plus oral and intravenous (IV) placebos in participants with incurable, non-metastatic hepatocellular carcinoma (HCC). The primary hypotheses are that pembrolizumab plus lenvatinib in combination with TACE is superior to placebo plus TACE with respect to progression-free survival (PFS) and overall survival (OS).

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Drug: Lenvatinib Biological: Pembrolizumab Drug: Oral Placebo Drug: IV Placebo Procedure: TACE Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 950 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) With Pembrolizumab (MK-3475) in Combination With Transarterial Chemoembolization (TACE) Versus TACE in Participants With Incurable/Non-metastatic Hepatocellular Carcinoma (LEAP-012)
Actual Study Start Date : May 22, 2020
Estimated Primary Completion Date : April 25, 2025
Estimated Study Completion Date : December 31, 2029

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lenvatinib plus Pembrolizumab plus TACE
Participants will receive a combination of lenvatinib, pembrolizumab, and TACE. Lenvatinib will be administered at a dose of 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 during each 21-day cycle until progressive disease or unacceptable toxicity (up to 2 years [~35 cycles] or longer with Sponsor approval). Pembrolizumab will be administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W) for up to 2 years (~17 doses). Participants will undergo TACE as a background procedure of chemotherapeutic and embolic agent(s).
Drug: Lenvatinib
Administered at a dose of 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) via oral capsules once a day during each 21-day cycle.
Other Names:
  • MK-7902
  • E7080
  • LENVIMA®

Biological: Pembrolizumab
Administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W).
Other Names:
  • MK-3475
  • KEYTRUDA®

Procedure: TACE
Conducted as a background procedure of chemotherapeutic and embolic agent(s).

Active Comparator: Oral Placebo plus IV Placebo plus TACE
Participants will receive a combination of lenvatinib-matching oral placebo, pembrolizumab-matching IV placebo, and TACE. Lenvatinib-matching oral placebo will be administered once a day during each 21-day cycle for up to 2 years (~35 cycles) or longer with Sponsor approval and pembrolizumab-matching IV placebo will be administered once every 6 weeks (Q6W) for up to 2 years (~17 doses). Participants will undergo TACE as a background procedure of chemotherapeutic and embolic agent(s).
Drug: Oral Placebo
Lenvatinib-matching placebo administered via oral capsules once a day during each 21-day cycle.

Drug: IV Placebo
Pembrolizumab-matching placebo administered via IV infusion once every 6 weeks (Q6W).

Procedure: TACE
Conducted as a background procedure of chemotherapeutic and embolic agent(s).




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 ~5 years ]
    PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by blinded independent central review (BICR).

  2. Overall Survival (OS) [ Time Frame: Up to ~5 years ]
    OS is defined as the time from randomization to death due to any cause.


Secondary Outcome Measures :
  1. PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to ~5 years ]
    PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to mRECIST as assessed by BICR.

  2. Objective Response Rate (ORR) per mRECIST [ Time Frame: Up to ~5 years ]
    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). Responses are according to mRECIST as assessed by BICR.

  3. Disease Control Rate (DCR) per mRECIST [ Time Frame: Up to ~5 years ]
    DCR is defined as the percentage of participants who have a best overall response of CR (disappearance of any intratumoral arterial enhancement in all target lesions), 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), or stable disease (SD). Responses are according to mRECIST as assessed by BICR.

  4. Duration of Response (DOR) per mRECIST [ Time Frame: Up to ~5 years ]
    DOR is determined by disease assessment and is defined as the time from the first documented evidence of a response of CR (disappearance of any intratumoral arterial enhancement in all target lesions) or 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) until the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to mRECIST as assessed by BICR.

  5. Time to Progression (TTP) per mRECIST [ Time Frame: Up to ~5 years ]
    TTP is defined as the time from randomization to the first documented disease progression. Responses are according to mRECIST as assessed by BICR.

  6. Percentage of Participants Who Experience At Least One Adverse Event (AE) [ Time Frame: Up to ~5 years ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience at least one AE will be reported.

  7. Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE) [ Time Frame: Up to ~5 years ]
    An SAE is an AE that results in death, is life threatening, requires or prolongs a hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose, or is another important medical event. The percentage of participants who experience at least one SAE will be reported.

  8. Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI) [ Time Frame: Up to ~5 years ]
    Percentage of participants with Hepatic ECIs not due to disease progression or TACE as assessed by the investigator will be reported.

  9. Percentage of Participants Who Discontinue Study Drug Due to an AE [ Time Frame: Up to ~5 years ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinue study drug due to an AE will be reported.

  10. ORR per RESCIST 1.1 [ Time Frame: Up to ~5 years ]
    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 of diameters). Responses are according to RECIST 1.1 as assessed by BICR.

  11. DCR per RECIST 1.1 [ Time Frame: Up to ~5 years ]
    DCR is defined as the percentage of participants who have a best overall response of CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters), or SD. Responses are according to RECIST 1.1 as assessed by BICR.

  12. DOR per RECIST 1.1 [ Time Frame: Up to ~5 years ]
    DOR is determined by disease assessment and is defined as the time from the first documented evidence of a response of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) until the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by BICR.

  13. TTP per RECIST 1.1 [ Time Frame: Up to ~5 years ]
    TTP is defined as the time from randomization to the first documented disease progression. Responses are according to RECIST 1.1 as assessed by BICR.



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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:

  • Has a diagnosis of HCC confirmed by radiology, histology, or cytology
  • Has HCC localized to the liver and not amenable to curative treatment
  • Participants with Hepatitis C virus (HCV) are eligible if treatment was completed at least 1 month prior to starting study intervention
  • Participants with Hepatitis B virus (HBV) are eligible
  • Has adequately controlled blood pressure with or without antihypertensive medications
  • Has adequate organ function

Exclusion Criteria:

  • Is currently a candidate for liver transplantation
  • Has had gastric bleeding within the last 6 months
  • Has ascites that is not controlled with medication
  • Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as congestive heart failure
  • Has a serious nonhealing wound, ulcer, or bone fracture
  • Has received locoregional therapy to existing liver lesions

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): NCT04246177


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Eisai Inc.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT04246177    
Other Study ID Numbers: 7902-012
2019-002345-37 ( EudraCT Number )
MK-7902-012 ( Other Identifier: Merck Protocol Number )
LEAP-012 ( Other Identifier: Merck )
E7080-G000-318 ( Other Identifier: Eisai Protocol Number )
205286 ( Registry Identifier: JAPIC-CTI )
First Posted: January 29, 2020    Key Record Dates
Last Update Posted: July 29, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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