Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016)

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of belzutifan in combination with pembrolizumab and lenvatinib in multiple solid tumors including hepatocellular carcinoma (HCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), endometrial cancer (EC),and esophageal squamous cell carcinoma (ESCC). There is no formal hypothesis testing in this study.

Official Title
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An Open-label, Multicenter, Phase 2 Study to Evaluate the Efficacy and Safety of Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Multiple Solid Tumors

Conditions
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Carcinoma, Hepatocellular, Colorectal Neoplasms, Pancreatic Ductal Adenocarcinoma, Biliary Tract Neoplasms, Endometrial Neoplasms, Esophageal Neoplasms

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Belzutifan
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of one of the following advanced (unresectable and/or metastatic) solid tumors, documented by histopathology or cytopathology: Hepatocellular carcinoma (HCC) Colorectal cancer (CRC) (non-microsatellite instability-high [non-MSI-H]/deficient mismatch repair [dMMR]) Pancreatic ductal adenocarcinoma (PDAC). Biliary tract cancer (BTC) (includes intrahepatic, extrahepatic cholangiocarcinoma [CCA] and gall bladder cancer) Endometrial cancer (EC) Esophageal squamous cell carcinoma (ESCC) Disease progression on or since the most recent treatment (does not apply to newly diagnosed unresectable or metastatic HCC or EC). Measurable disease per RECIST v1.1 as assessed locally (by investigator) and verified by BICR Submission of an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated Male participants are abstinent from heterosexual intercourse or agree to follow contraceptive guidance during and for at least 7 days after last dose of study intervention with belzutifan and lenvatinib Female participants are not pregnant or breastfeeding, not a woman of child-bearing potential (WOCBP), or is a WOCBP and agrees to follow contraceptive guidance during the intervention period and and for at least 120 days after the last dose of pembrolizumab or for at least 30 days after last dose of lenvatinib or belzutifan, whichever occurs last Adequate organ function Adequately controlled blood pressure with or without antihypertensive medications HCC Specific Inclusion Criteria: No prior systemic chemotherapy, including anti-VEGF therapy, anti-programmed cell-death (PD-1)/PD-L1 or any systemic investigational anticancer agents for advanced/unresectable HCC (1L) CRC ([non-MSI-H/dMMR) Specific Inclusion Criteria: Received at least 2 prior lines of systemic therapy for unresectable or metastatic disease which includes fluoropyrimidine, irinotecan and oxaliplatin PDAC Specific Inclusion Criteria: Prior therapy with at least 1 (platinum or gemcitabine containing regimen) but no more than 2 prior systemic therapies for unresectable or metastatic pancreatic cancer BTC Specific Inclusion Criteria: Received at least 1 prior line of systemic therapy (containing gemcitabine or fluoropyrimidine) for unresectable or metastatic disease EC Specific Inclusion Criteria: Study treatment is for 1L therapy of EC and participants should not have received prior systemic chemotherapy. Exception: May have received 1 prior line of line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of a curative-intent resection, if the recurrence occurred ≥6 months after the last dose of chemotherapy or may have received prior radiation with or without chemotherapy ESCC Specific Inclusion Criteria: Have experienced radiographic or clinical progression on one prior line of standard systemic therapy (immune oncology (IO) naïve participants) or an anti-PD-1/PD-L1 (IO resistant participants) Exclusion Criteria: Unable to swallow orally administered medication or presence of a gastrointestinal (GI) disorder that may affect study intervention absorption History of a second malignancy that is progressing or has required active treatment within 3 years A pulse oximeter reading <92% at rest, or requirement of intermittent supplemental oxygen/ chronic supplemental oxygen Presence of central nervous system (CNS) metastases and/or carcinomatous meningitis Clinically significant cardiovascular disease within 6 months of first dose of study intervention Symptomatic pleural effusion, unless clinically stable after treatment Preexisting ≥ Grade 3 gastrointestinal (GI) or non-GI fistula Moderate to severe hepatic impairment Clinically significant history of bleeding within 3 months before screening Presence of serious active nonhealing wound/ulcer/bone fracture Requirement for hemodialysis or peritoneal dialysis History of human immunodeficiency virus (HIV) infection History of Hepatitis B or active Hepatis C virus infections. with exceptions for HCC and BTC Prior therapy with a PD-1, anti-PD-L1, anti-PD-L2 agent, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) or hypoxia-inducible factor 2α (HIF-2α) Radiographic evidence of intratumoral cavitation, or invasion/infiltration of a major blood vessel EC specific exclusion criteria: History of carcinosarcoma, endometrial leiomyosarcoma or other high-grade sarcomas, or endometrial stromal sarcomas ESCC specific exclusion criteria: Has clinically apparent ascites or pleural effusion or experienced weight loss >20% over approximately 3 months before first dose of study therapy

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Pembrolizumab + Belzutifan + Lenvatinib<br>Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg (For HCC: 8 mg [body weight <60kg] or 12 mg [body weight ≥ 60 kg]). Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Belzutifan and lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation. | Drug: Pembrolizumab<br>* Pembrolizumab 400 mg administered Q6W via IV infusion<br>* Other names: KEYTRUDA®;Drug: Belzutifan<br>* Belzutifan 120 mg administered QD via oral tablet<br>* Other names: WELIREG™;Drug: Lenvatinib<br>* Lenvantinib dose for HCC is 8 mg QD for body weight <60 kg and 12 mg QD for body weight ≥ 60 kg administered via oral capsule. For all other tumors, the lenvatinib dose is 20 mg QD administered via oral capsule<br>* Other names: LENVIMA®;|
| Experimental: Arm 2: Pembrolizumab + Lenvatinib<br>Participants with IO resistant ESCC will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation. | Drug: Pembrolizumab<br>* Pembrolizumab 400 mg administered Q6W via IV infusion<br>* Other names: KEYTRUDA®;Drug: Lenvatinib<br>* Lenvantinib dose for HCC is 8 mg QD for body weight <60 kg and 12 mg QD for body weight ≥ 60 kg administered via oral capsule. For all other tumors, the lenvatinib dose is 20 mg QD administered via oral capsule<br>* Other names: LENVIMA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm 1: Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT) | Occurrence of any of the following will be considered a DLT if possibly, probably, or definitely related to study treatment administration: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting >7 days; Grade 4 thrombocytopenia-any duration; Grade 3 thrombocytopenia if associated with clinically significant hemorrhage; Febrile neutropenia Grade 3 or Grade 4; Grade 3 nonhematologic toxicity lasting >5 days despite optimal supportive care; Grade 3 hypertension not controlled by antihypertensive medication(s); Grade 3 or Grade 4 nonhematologic laboratory abnormality (if medical intervention is required, or leads to hospitalization, or persists for >1 week) ; Elevated bilirubin if persists >4 weeks (for HCC and BTC participants only); Designated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver test abnormalities; Treatment-related toxicity resulting in participant discontinuation of study intervention during the DLT window; Grade 5 toxicity. | Up to approximately 21 days | 
| Arm 1: Number of Participants Who Experience at Least One Adverse Event (AE) | An AE is defined as 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 number of participants who experience one or more AEs will be presented. | Up to approximately 60 months | 
| Arm 1: Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is defined as 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 number of participants who discontinue study treatment due to an AE will be presented separately for the safety lead-in phase (up to 21 days) and the main study. | Up to approximately 59 months | 
| Confirmed Objective Response Rate (ORR) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | ORR is defined as the percentage of participants who have a Complete Response (CR) or a Partial Response (PR) per RECIST 1.1, as assessed by blinded independent central review (BICR). | Up to approximately 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. The DOR per RECIST 1.1 will be assessed by BICR. | Up to approximately 60 months | 
| Disease Control Rate (DCR) Per RECIST 1.1 as Assessed by BICR | DCR is defined as the percentage of participants who have a CR, PR, or Stable Disease (SD). The best overall response of CR, PR, or SD after ≥ 6 weeks will be assessed per RECIST 1.1 by BICR. | Up to approximately 60 months | 
| Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by BICR | PFS is defined as the time from first day of study intervention to the first documented progressive disease (PD) per RECIST1.1 as assessed by BICR, or death due to any cause, whichever occurs first. | Up to approximately 60 months | 
| Overall Survival (OS) | OS is defined as the time from the first day of study intervention to death due to any cause. | Up to approximately 60 months | 
| ORR Per Modified Response Criteria in Solid Tumors Version 1.1 (mRECIST 1.1) for Hepatocellular Carcinoma (HCC) as Assessed by BICR | ORR is defined as the percentage of participants who have a CR or a PR per mRECIST 1.1 for HCC, as assessed by BICR. | Up to approximately 60 months | 
| DOR Per mRECIST 1.1 for HCC as Assessed by BICR | DOR is defined as the time from the first documented evidence of CR or PR until either progressive disease (PD) or death due to any cause, whichever occurs first. The DOR per mRECISIT 1.1 for HCC willl be assessed by BICR. | Up to approximately 60 months | 
| DCR Per mRECIST 1.1 for HCC as Assessed by BICR | DCR is defined as the percentage of participants who have a CR or PR or SD. The best overall response of CR, PR, or SD after ≥ 6 weeks per mRECIST 1.1 for HCC will be assessed by BICR. | Up to approximately 60 months | 
| PFS Per mRECIST 1.1 for HCC as Assessed by BICR | PFS is defined as the time from first day of study intervention to the first documented PD per mRECIST 1.1 for HCC as assessed by BICR, or death due to any cause, whichever occurs first. | Up to approximately 60 months | 
| Arm 2: Number of Participants Who Experienced an Adverse Event (AE) | An AE is defined as 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 number of participants who experience an AE after administration of pembrolizumab plus lenvatinib will be presented. | Up to approximately 60 months | 
| Arm 2: Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is defined as 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 number of participants who discontinue study treatment of pembrolizumab plus lenvatinib after an AE will be presented. | Up to approximately 59 months |