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

NCT04976634 | Active Not Recruiting Phase 2 FDA Drug

• 5 other identifiers: 6482-016MK-6482-0162023-503905-12-00U1111-1288-30202020-005007-40
• Study Type: interventional
• Target: 730
• Locations: 10 countries
• Sites: 57

Brief Summary

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.

Conditions

Neoplasm Malignant

Outcome Measures

Primary Outcomes (4)

• 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 67 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 67 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 with 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) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.

  Up to approximately 67 months

Secondary Outcomes (10)

• Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR

  Up to approximately 67 months

• Disease Control Rate (DCR) Per RECIST 1.1 as Assessed by BICR

  Up to approximately 67 months

• Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by BICR

  Up to approximately 67 months

• Overall Survival (OS)

  Up to approximately 67 months

• ORR Per Modified Response Criteria in Solid Tumors Version 1.1 (mRECIST 1.1) for Hepatocellular Carcinoma (HCC) as Assessed by BICR

  Up to approximately 67 months

Study Arms (2)

Arm 1: Pembrolizumab + Belzutifan + Lenvatinib

EXPERIMENTAL

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; Drug: Belzutifan; Drug: Lenvatinib

Arm 2: Pembrolizumab + Lenvatinib

EXPERIMENTAL

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; Drug: Lenvatinib

Interventions

Pembrolizumab DRUG

Pembrolizumab 400 mg administered Q6W via IV infusion

Also known as: MK-3475, KEYTRUDA®

Arm 1: Pembrolizumab + Belzutifan + Lenvatinib; Arm 2: Pembrolizumab + Lenvatinib

Belzutifan DRUG

Belzutifan 120 mg administered QD via oral tablet

Also known as: MK-6482, PT2977, WELIREG™

Arm 1: Pembrolizumab + Belzutifan + Lenvatinib

Lenvatinib DRUG

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

Also known as: MK-7902, E7080, LENVIMA®

Arm 1: Pembrolizumab + Belzutifan + Lenvatinib; Arm 2: Pembrolizumab + Lenvatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (57)

University of Arizona Cancer Center-University of Arizona Cancer Center - North Campus ( Site 5047)

Tucson, Arizona, 85724, United States

Location

City of Hope Comprehensive Cancer Center ( Site 5002)

Duarte, California, 91010, United States

Location

Cedars-Sinai Medical Center ( Site 5045)

Los Angeles, California, 90048, United States

Location

UCSF Medical Center at Mission Bay ( Site 5021)

San Francisco, California, 94158, United States

Location

Yale-New Haven Hospital-Yale Cancer Center ( Site 5013)

New Haven, Connecticut, 06510, United States

Location

Sibley Memorial Hospital ( Site 5051)

Washington D.C., District of Columbia, 20016, United States

Location

University of Florida College of Medicine ( Site 5015)

Gainesville, Florida, 32610, United States

Location

Johns Hopkins Hospital-Sidney Kimmel Comprehensive Cancer Center - GI and Immunology ( Site 5048)

Baltimore, Maryland, 21287, United States

Location

Brigitte Harris Cancer Pavilion ( Site 5055)

Detroit, Michigan, 48202, United States

Location

Memorial Sloan Kettering Cancer Center ( Site 5050)

New York, New York, 10065, United States

Location

Duke Cancer Institute ( Site 5026)

Durham, North Carolina, 27710, United States

Location

University of Texas MD Anderson Cancer Center-Gastrointestinal Medical Oncology ( Site 5049)

Houston, Texas, 77030, United States

Location

Inova Schar Cancer Institute ( Site 5039)

Fairfax, Virginia, 22031, United States

Location

Blue Ridge Cancer Care ( Site 5053)

Roanoke, Virginia, 24014, United States

Location

Northwest Medical Specialties, PLLC ( Site 5025)

Tacoma, Washington, 98405, United States

Location

University of Wisconsin Hospitals and Clinics ( Site 5037)

Madison, Wisconsin, 53792, United States

Location

Gosford Hospital-Oncology Trials ( Site 4004)

Gosford, New South Wales, 2250, Australia

Location

Westmead Hospital-Department of Medical Oncology ( Site 4001)

Westmead, New South Wales, 2145, Australia

Location

Northern Hospital-Department of Medical Oncology ( Site 4003)

Epping, Victoria, 3076, Australia

Location

Cabrini Hospital - Malvern-Cabrini Institute ( Site 4000)

Malvern, Victoria, 3144, Australia

Location

Antwerp University Hospital-Oncology ( Site 1002)

Edegem, Antwerpen, 2650, Belgium

Location

Cliniques universitaires Saint-Luc-Medical Oncology ( Site 1001)

Brussels, Bruxelles-Capitale, Region de, 1200, Belgium

Location

UZ Leuven ( Site 1000)

Leuven, Vlaams-Brabant, 3000, Belgium

Location

AZ Delta vzw ( Site 1004)

Roeselare, West-Vlaanderen, 8800, Belgium

Location

Université Catholique de Louvain-Namur - Centre Hospitalier -Oncology ( Site 1003)

Namur, 5530, Belgium

Location

Clínica Puerto Montt ( Site 3110)

Port Montt, Los Lagos Region, 5500242, Chile

Location

FALP-UIDO ( Site 3102)

Santiago, Region M. de Santiago, 7500921, Chile

Location

Oncovida ( Site 3108)

Santiago, Region M. de Santiago, 7510032, Chile

Location

Bradfordhill-Clinical Area ( Site 3100)

Santiago, Region M. de Santiago, 8420383, Chile

Location

Centro Investigación del Cáncer James Lind ( Site 3107)

Temuco, Región de la Araucanía, 4800827, Chile

Location

Centre Eugène Marquis Rennes - Centre de Lutte Contre le Cancer ( Site 1103)

Rennes, Brittany Region, 35042, France

Location

CHU Besançon-Medical oncology ( Site 1101)

Besançon, Doubs, 25000, France

Location

CHU Brest Cavale Blanche ( Site 1107)

Brest, Finistere, 29200, France

Location

Institut Regional du Cancer Montpellier ( Site 1106)

Montpellier, Herault, 34298, France

Location

Centre Hospitalier Universitaire de Grenoble-Medical Oncology ( Site 1105)

La Tronche, Isere, 38700, France

Location

Sainte Catherine Institut du Cancer Avignon Provence ( Site 1108)

Avignon, Vaucluse, 84000, France

Location

Hôpital Beaujon-Oncologie Digestive ( Site 1104)

Clichy, Île-de-France Region, 92110, France

Location

Rambam Health Care Campus-Oncology ( Site 1300)

Haifa, 3109601, Israel

Location

Hadassah Medical Center-Oncology ( Site 1303)

Jerusalem, 9112001, Israel

Location

Sheba Medical Center-ONCOLOGY ( Site 1302)

Ramat Gan, 5265601, Israel

Location

Sourasky Medical Center-Oncology ( Site 1301)

Tel Aviv, 6423906, Israel

Location

Maastricht UMC+-Medical Oncology ( Site 1501)

Maastricht, Limburg, 6229 HX, Netherlands

Location

Leids Universitair Medisch Centrum-Medical Oncology ( Site 1504)

Leiden, South Holland, 2333 ZA, Netherlands

Location

Universitair Medisch Centrum Utrecht-Medical Oncology ( Site 1503)

Utrecht, 3584 CX, Netherlands

Location

Auckland City Hospital-Liver Research Unit ( Site 4201)

Grafton, Auckland, 1023, New Zealand

Location

Auckland City Hospital-Cancer & Blood Research ( Site 4200)

Auckland, 1023, New Zealand

Location

Chonnam National University Hwasun Hospital-Hemato-Oncology ( Site 4105)

Hwasun Gun, Jeonranamdo, 58128, South Korea

Location

Keimyung University Dongsan Hospital CRC room 1 ( Site 4104)

Daegu, Taegu-Kwangyokshi, 42601, South Korea

Location

Seoul National University Hospital-Internal Medicine ( Site 4103)

Seoul, 03080, South Korea

Location

Severance Hospital, Yonsei University Health System-Medical oncology ( Site 4100)

Seoul, 03722, South Korea

Location

Asan Medical Center-Department of Oncology ( Site 4101)

Seoul, 05505, South Korea

Location

Samsung Medical Center-Division of Hematology/Oncology ( Site 4102)

Seoul, 06351, South Korea

Location

Hospital Germans Trias i Pujol-Instituto Catalán de Oncología de Badalona ( Site 1806)

Badalona, Barcelona, 08916, Spain

Location

CHUS - Hospital Clinico Universitario-Servicio de Oncologia ( Site 1807)

Santiago de Compostela, La Coruna, 15706, Spain

Location

HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 1801)

Madrid, Madrid, Comunidad de, 28007, Spain

Location

Hospital Universitario Central de Asturias-Medical Oncology ( Site 1802)

Oviedo, Principality of Asturias, 33011, Spain

Location

Hospital Universitari Vall d'Hebron-Oncology ( Site 1800)

Barcelona, 08035, Spain

Location

Related Publications (1)

• Gebrael G, Sahu KK, Agarwal N, Maughan BL. Update on combined immunotherapy for the treatment of advanced renal cell carcinoma. Hum Vaccin Immunother. 2023 Dec 31;19(1):2193528. doi: 10.1080/21645515.2023.2193528. Epub 2023 Apr 16.

  PMID: 37062953 DERIVED

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Neoplasms

Interventions

pembrolizumab; belzutifan; lenvatinib

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2021
• First Posted: July 26, 2021
• Study Start: August 18, 2021
• Primary Completion (Estimated): March 22, 2027
• Study Completion (Estimated): March 22, 2027
• Last Updated: April 6, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share

Locations

BE (5); NL (3); US (16); NZ (2); CL (5); ES (5); IL (4); FR (7); KR (6); AU (4)