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)

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Lenvatinib
* Biological: Pembrolizumab
* Drug: Oral Placebo
* Drug: IV Placebo
* Procedure: TACE


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenvatinib plus Pembrolizumab plus TACE<br>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<br>* 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.<br>* Other names: LENVIMA®;Biological: Pembrolizumab<br>* Administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W).<br>* Other names: KEYTRUDA®;Procedure: TACE<br>* Conducted as a background procedure of chemotherapeutic and embolic agent(s).<br>|
| Active Comparator: Oral Placebo plus IV Placebo plus TACE<br>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<br>* Lenvatinib-matching placebo administered via oral capsules once a day during each 21-day cycle.<br>Drug: IV Placebo<br>* Pembrolizumab-matching placebo administered via IV infusion once every 6 weeks (Q6W).<br>Procedure: TACE<br>* Conducted as a background procedure of chemotherapeutic and embolic agent(s).<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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receptor tyrosine kinase inhibitor, programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)