Pembrolizumab: Pembrolizumab 400 mg administered Q6W via IV infusion
Belzutifan: Belzutifan 120 mg administered QD via oral tablet
Lenvatinib: 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
Study 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.
Eligibility
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
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 outcome measure(s)
Arm 1: Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT) — Up to approximately 21 days 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.
Arm 1: Number of Participants Who Experience at Least One Adverse Event (AE) — Up to approximately 67 months 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.
Arm 1: Number of Participants Who Discontinue Study Treatment Due to an AE — Up to approximately 67 months 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.
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) — Up to approximately 67 months 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.
Trial sites (57)
Facility
City
Region
Status
University of Arizona Cancer Center-University of Arizona Cancer Center - North Campus ( Site 5047)
Tucson
Arizona
City of Hope Comprehensive Cancer Center ( Site 5002)
Duarte
California
Cedars-Sinai Medical Center ( Site 5045)
Los Angeles
California
UCSF Medical Center at Mission Bay ( Site 5021)
San Francisco
California
Yale-New Haven Hospital-Yale Cancer Center ( Site 5013)
New Haven
Connecticut
Sibley Memorial Hospital ( Site 5051)
Washington D.C.
District of Columbia
University of Florida College of Medicine ( Site 5015)
Gainesville
Florida
Johns Hopkins Hospital-Sidney Kimmel Comprehensive Cancer Center - GI and Immunology ( Site 5048)
Baltimore
Maryland
Brigitte Harris Cancer Pavilion ( Site 5055)
Detroit
Michigan
Memorial Sloan Kettering Cancer Center ( Site 5050)
New York
New York
Duke Cancer Institute ( Site 5026)
Durham
North Carolina
University of Texas MD Anderson Cancer Center-Gastrointestinal Medical Oncology ( Site 5049)
Houston
Texas
Inova Schar Cancer Institute ( Site 5039)
Fairfax
Virginia
Blue Ridge Cancer Care ( Site 5053)
Roanoke
Virginia
Northwest Medical Specialties, PLLC ( Site 5025)
Tacoma
Washington
University of Wisconsin Hospitals and Clinics ( Site 5037)
Madison
Wisconsin
Gosford Hospital-Oncology Trials ( Site 4004)
Gosford
New South Wales
Westmead Hospital-Department of Medical Oncology ( Site 4001)
Westmead
New South Wales
Northern Hospital-Department of Medical Oncology ( Site 4003)
Epping
Victoria
Cabrini Hospital - Malvern-Cabrini Institute ( Site 4000)
Malvern
Victoria
Antwerp University Hospital-Oncology ( Site 1002)
Edegem
Antwerpen
Cliniques universitaires Saint-Luc-Medical Oncology ( Site 1001)
Brussels
Bruxelles-Capitale, Region de
UZ Leuven ( Site 1000)
Leuven
Vlaams-Brabant
AZ Delta vzw ( Site 1004)
Roeselare
West-Vlaanderen
Université Catholique de Louvain-Namur - Centre Hospitalier -Oncology ( Site 1003)
Namur
Belgium
Centro Investigación del Cáncer James Lind ( Site 3107)
Temuco
Araucania
Clínica Puerto Montt ( Site 3110)
Port Montt
Los Lagos Region
FALP-UIDO ( Site 3102)
Santiago
Region M. de Santiago
Oncovida ( Site 3108)
Santiago
Region M. de Santiago
Bradfordhill-Clinical Area ( Site 3100)
Santiago
Region M. de Santiago
Centre Eugène Marquis Rennes - Centre de Lutte Contre le Cancer ( Site 1103)
Rennes
Brittany Region
CHU Besançon-Medical oncology ( Site 1101)
Besançon
Doubs
CHU Brest Cavale Blanche ( Site 1107)
Brest
Finistere
Institut Regional du Cancer Montpellier ( Site 1106)
Montpellier
Herault
Centre Hospitalier Universitaire de Grenoble-Medical Oncology ( Site 1105)
La Tronche
Isere
Sainte Catherine Institut du Cancer Avignon Provence ( Site 1108)
Avignon
Vaucluse
Hôpital Beaujon-Oncologie Digestive ( Site 1104)
Clichy
Île-de-France Region
Rambam Health Care Campus-Oncology ( Site 1300)
Haifa
Israel
Hadassah Medical Center-Oncology ( Site 1303)
Jerusalem
Israel
Sheba Medical Center-ONCOLOGY ( Site 1302)
Ramat Gan
Israel
+ 17 more sites — see the full list on the official registry below.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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