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)

• ClinicalTrials.gov Identifier: NCT04246177
• Recruitment Status: Active, not recruiting
• First Posted: January 29, 2020
• Last Update Posted: February 2, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Collaborator: Eisai Inc.
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: January 27, 2020
• First Posted Date: January 29, 2020
• Last Update Posted Date: February 2, 2023
• Actual Study Start Date: May 22, 2020
• Estimated Primary Completion Date: June 30, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 15, 2022)

• Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to ~43 months ]
  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).
• Overall Survival (OS) [ Time Frame: Up to ~95 months ]
  OS is defined as the time from randomization to death due to any cause.

Original Primary Outcome Measures (submitted: January 27, 2020)

• 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). RECIST 1.1 has been modified for this study to define new intrahepatic lesions as meeting Liver Imaging Reporting and Data System version 5 (LI-RADS 5) criteria, and to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
• Overall Survival (OS) [ Time Frame: Up to ~5 years ]
  OS is defined as the time from randomization to death due to any cause.

Current Secondary Outcome Measures (submitted: December 15, 2022)

• PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: Up to ~43 months ]
  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.
• Objective Response Rate (ORR) per mRECIST [ Time Frame: Up to ~95 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). Responses are according to mRECIST as assessed by BICR.
• Disease Control Rate (DCR) per mRECIST [ Time Frame: Up to ~95 months ]
  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.
• Duration of Response (DOR) per mRECIST [ Time Frame: Up to ~95 months ]
  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.
• Time to Progression (TTP) per mRECIST [ Time Frame: Up to ~95 months ]
  TTP is defined as the time from randomization to the first documented disease progression. Responses are according to mRECIST as assessed by BICR.
• Percentage of Participants Who Experience At Least One Adverse Event (AE) [ Time Frame: Up to ~95 months ]
  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.
• Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE) [ Time Frame: Up to ~95 months ]
  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.
• Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI) [ Time Frame: Up to ~95 months ]
  Percentage of participants with Hepatic ECIs not due to disease progression or TACE as assessed by the investigator will be reported.
• Percentage of Participants Who Discontinue Study Drug Due to an AE [ Time Frame: Up to ~95 months ]
  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.
• ORR per RESCIST 1.1 [ Time Frame: Up to ~95 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 of diameters). Responses are according to RECIST 1.1 as assessed by BICR.
• DCR per RECIST 1.1 [ Time Frame: Up to ~95 months ]
  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.
• DOR per RECIST 1.1 [ Time Frame: Up to ~95 months ]
  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.
• TTP per RECIST 1.1 [ Time Frame: Up to ~95 months ]
  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.

Original Secondary Outcome Measures (submitted: January 27, 2020)

• 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. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. New intrahepatic lesions are defined as meeting LI-RADS 5 criteria and a maximum of 10 target lesions and a maximum of 5 target lesions per organ will be included.
• 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. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. New intrahepatic lesions are defined as meeting LI-RADS 5 criteria and a maximum of 10 target lesions and a maximum of 5 target lesions per organ will be included.
• 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). SD must be achieved at ≥6 weeks after randomization to be considered best overall response. 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. New intrahepatic lesions are defined as meeting LI-RADS 5 criteria and a maximum of 10 target lesions and a maximum of 5 target lesions per organ will be included.
• 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. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. New intrahepatic lesions are defined as meeting LI-RADS 5 criteria and a maximum of 10 target lesions and a maximum of 5 target lesions per organ will be included.
• 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. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. New intrahepatic lesions are defined as meeting LI-RADS 5 criteria and a maximum of 10 target lesions and a maximum of 5 target lesions per organ will be included.
• 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.
• 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.
• 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.
• 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.
• 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. RECIST 1.1 has been modified for this study to define new intrahepatic lesions as meeting LI-RADS 5 criteria, and to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
• 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. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. Responses are according to RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to define new intrahepatic lesions as meeting LI-RADS 5 criteria, and to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
• 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. RECIST 1.1 has been modified for this study to define new intrahepatic lesions as meeting LI-RADS 5 criteria, and to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
• 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. RECIST 1.1 has been modified for this study to define new intrahepatic lesions as meeting LI-RADS 5 criteria, and to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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)
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• 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®
• 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).

Study Arms

• 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).
  Interventions:

  • Drug: Lenvatinib
  • Biological: Pembrolizumab
  • Procedure: TACE
• 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).
  Interventions:

  • Drug: Oral Placebo
  • Drug: IV Placebo
  • Procedure: TACE

Publications *

• Verset G, Borbath I, Karwal M, Verslype C, Van Vlierberghe H, Kardosh A, Zagonel V, Stal P, Sarker D, Palmer DH, Vogel A, Edeline J, Cattan S, Kudo M, Cheng AL, Ogasawara S, Daniele B, Chan SL, Knox JJ, Qin S, Siegel AB, Chisamore M, Hatogai K, Wang A, Finn RS, Zhu AX. Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Clin Cancer Res. 2022 Jun 13;28(12):2547-2554. doi: 10.1158/1078-0432.CCR-21-3807.
• Llovet JM, Vogel A, Madoff DC, Finn RS, Ogasawara S, Ren Z, Mody K, Li JJ, Siegel AB, Dubrovsky L, Kudo M. Randomized Phase 3 LEAP-012 Study: Transarterial Chemoembolization With or Without Lenvatinib Plus Pembrolizumab for Intermediate-Stage Hepatocellular Carcinoma Not Amenable to Curative Treatment. Cardiovasc Intervent Radiol. 2022 Apr;45(4):405-412. doi: 10.1007/s00270-021-03031-9. Epub 2022 Feb 4.
• Taylor MH, Schmidt EV, Dutcus C, Pinheiro EM, Funahashi Y, Lubiniecki G, Rasco D. The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Future Oncol. 2021 Feb;17(6):637-648. doi: 10.2217/fon-2020-0937. Epub 2020 Dec 10.
• Kloeckner R, Galle PR, Bruix J. Local and Regional Therapies for Hepatocellular Carcinoma. Hepatology. 2021 Jan;73 Suppl 1:137-149. doi: 10.1002/hep.31424. Epub 2020 Nov 6. No abstract available.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 15, 2022): 450
• Original Estimated Enrollment (submitted: January 27, 2020): 950
• Estimated Study Completion Date: December 31, 2029
• Estimated Primary Completion Date: June 30, 2028 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Chile, China, Colombia, Denmark, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, New Zealand, Norway, Portugal, Puerto Rico, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04246177
• Other Study ID Numbers: 7902-012; 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 ); 2019-002345-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Eisai Inc.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: January 2023