Clinical trial NCT04976634: Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016)
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Neoplasm Malignant
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-07-26
Enrollment: 730
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Effective as of Amendment 3 (26 Mar 2025), enrollment of participants with ESCC will be closed.

Eligibility criteria: 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

Primary outcomes:
measure: Arm 1: Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT)
timeFrame: Up to approximately 21 days
measure: Arm 1: Number of Participants Who Experience at Least One Adverse Event (AE)
timeFrame: Up to approximately 67 months
measure: Arm 1: Number of Participants Who Discontinue Study Treatment Due to an AE
timeFrame: Up to approximately 67 months
measure: 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)
timeFrame: Up to approximately 67 months
Secondary outcomes:
measure: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: Disease Control Rate (DCR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 67 months
measure: ORR Per Modified Response Criteria in Solid Tumors Version 1.1 (mRECIST 1.1) for Hepatocellular Carcinoma (HCC) as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: DOR Per mRECIST 1.1 for HCC as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: DCR Per mRECIST 1.1 for HCC as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: PFS Per mRECIST 1.1 for HCC as Assessed by BICR
timeFrame: Up to approximately 67 months
measure: Arm 2: Number of Participants Who Experience an AE
timeFrame: Up to approximately 67 months
measure: Arm 2: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 67 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center-University of Arizona Cancer Center - North Campus ( Site 5047)
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center ( Site 5002)
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center ( Site 5045)
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center at Mission Bay ( Site 5021)
state: California
city: New Haven
country: United States
facility: Yale-New Haven Hospital-Yale Cancer Center ( Site 5013)
state: Connecticut
city: Washington
country: United States
facility: Sibley Memorial Hospital ( Site 5051)
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida College of Medicine ( Site 5015)
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Hospital-Sidney Kimmel Comprehensive Cancer Center - GI and Immunology ( Site 5048)
state: Maryland
city: Detroit
country: United States
facility: Brigitte Harris Cancer Pavilion ( Site 5055)
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 5050)
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute ( Site 5026)
state: North Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center-Gastrointestinal Medical Oncology ( Site 5049)
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 5039)
state: Virginia
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care ( Site 5053)
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties, PLLC ( Site 5025)
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospitals and Clinics ( Site 5037)
state: Wisconsin
city: Gosford
country: Australia
facility: Gosford Hospital-Oncology Trials ( Site 4004)
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital-Department of Medical Oncology ( Site 4001)
state: New South Wales
city: Epping
country: Australia
facility: Northern Hospital-Department of Medical Oncology ( Site 4003)
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital - Malvern-Cabrini Institute ( Site 4000)
state: Victoria
city: Edegem
country: Belgium
facility: Antwerp University Hospital-Oncology ( Site 1002)
state: Antwerpen
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc-Medical Oncology ( Site 1001)
state: Bruxelles-Capitale, Region De
city: Leuven
country: Belgium
facility: UZ Leuven ( Site 1000)
state: Vlaams-Brabant
city: Roeselare
country: Belgium
facility: AZ Delta vzw ( Site 1004)
state: West-Vlaanderen
city: Namur
country: Belgium
facility: Université Catholique de Louvain-Namur - Centre Hospitalier -Oncology ( Site 1003)
city: Temuco
country: Chile
facility: Centro Investigación del Cáncer James Lind ( Site 3107)
state: Araucania
city: Puerto Montt.
country: Chile
facility: Clínica Puerto Montt ( Site 3110)
state: Los Lagos
city: Santiago
country: Chile
facility: FALP-UIDO ( Site 3102)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Oncovida ( Site 3108)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill-Clinical Area ( Site 3100)
state: Region M. De Santiago
city: Rennes
country: France
facility: Centre Eugène Marquis Rennes - Centre de Lutte Contre le Cancer ( Site 1103)
state: Bretagne
city: Besançon
country: France
facility: CHU Besançon-Medical oncology ( Site 1101)
state: Doubs
city: Brest
country: France
facility: CHU Brest Cavale Blanche ( Site 1107)
state: Finistere
city: Montpellier
country: France
facility: Institut Regional du Cancer Montpellier ( Site 1106)
state: Herault
city: Clichy
country: France
facility: Hôpital Beaujon-Oncologie Digestive ( Site 1104)
state: Ile-de-France
city: La Tronche
country: France
facility: Centre Hospitalier Universitaire de Grenoble-Medical Oncology ( Site 1105)
state: Isere
city: Avignon
country: France
facility: Sainte Catherine Institut du Cancer Avignon Provence ( Site 1108)
state: Vaucluse
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology ( Site 1300)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center-Oncology ( Site 1303)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center-ONCOLOGY ( Site 1302)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center-Oncology ( Site 1301)
city: Hwasun Gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital-Hemato-Oncology ( Site 4105)
state: Jeonranamdo
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital CRC room 1 ( Site 4104)
state: Taegu-Kwangyokshi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital-Internal Medicine ( Site 4103)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System-Medical oncology ( Site 4100)
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center-Department of Oncology ( Site 4101)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center-Division of Hematology/Oncology ( Site 4102)
city: Maastricht
country: Netherlands
facility: Maastricht UMC+-Medical Oncology ( Site 1501)
state: Limburg
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum-Medical Oncology ( Site 1504)
state: Zuid-Holland
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht-Medical Oncology ( Site 1503)
city: Grafton
country: New Zealand
facility: Auckland City Hospital-Liver Research Unit ( Site 4201)
state: Auckland
city: Auckland
country: New Zealand
facility: Auckland City Hospital-Cancer & Blood Research ( Site 4200)
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias-Medical Oncology ( Site 1802)
state: Asturias
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol-Instituto Catalán de Oncología de Badalona ( Site 1806)
state: Barcelona
city: Santiago de Compostela
country: Spain
facility: CHUS - Hospital Clinico Universitario-Servicio de Oncologia ( Site 1807)
state: La Coruna
city: Madrid
country: Spain
facility: HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 1801)
state: Madrid, Comunidad De
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron-Oncology ( Site 1800)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: