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

Colorectal Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04976634
• Other study ID #: 6482-016
• Secondary ID: MK-6482-0162020-
• Status: Recruiting
• Phase: Phase 2
• Start date: August 18, 2021
• Est. completion date: March 22, 2027

Study information

• Verified date: June 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 730
• Est. completion date: March 22, 2027
• Est. primary completion date: March 22, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 2a (HIF-2a)

• 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

Related Conditions & MeSH terms

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

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Australia	Northern Hospital-Department of Medical Oncology ( Site 4003)	Epping	Victoria
Australia	Gosford Hospital-Oncology Trials ( Site 4004)	Gosford	New South Wales
Australia	Cabrini Hospital - Malvern-Cabrini Institute ( Site 4000)	Malvern	Victoria
Australia	Westmead Hospital-Department of Medical Oncology ( Site 4001)	Westmead	New South Wales
Belgium	Cliniques universitaires Saint-Luc-Medical Oncology ( Site 1001)	Brussels	Bruxelles-Capitale, Region De
Belgium	Antwerp University Hospital-Oncology ( Site 1002)	Edegem	Antwerpen
Belgium	UZ Leuven ( Site 1000)	Leuven	Vlaams-Brabant
Belgium	AZ Delta vzw ( Site 1004)	Roeselare	West-Vlaanderen
Belgium	Université Catholique de Louvain-Namur - Centre Hospitalier -Oncology ( Site 1003)	Yvoir	Namur
Chile	Clínica Puerto Montt ( Site 3110)	Puerto Montt	Los Lagos
Chile	Bradfordhill-Clinical Area ( Site 3100)	Santiago	Region M. De Santiago
Chile	FALP-UIDO ( Site 3102)	Santiago	Region M. De Santiago
Chile	Oncovida ( Site 3108)	Santiago	Region M. De Santiago
Chile	Centro Investigación del Cáncer James Lind ( Site 3107)	Temuco	Araucania
France	Sainte Catherine Institut du Cancer Avignon Provence ( Site 1108)	Avignon	Vaucluse
France	CHU Besançon-Medical oncology ( Site 1101)	Besançon	Doubs
France	CHU Brest Cavale Blanche ( Site 1107)	Brest	Finistere
France	Hôpital Beaujon-Oncologie Digestive ( Site 1104)	Clichy	Ile-de-France
France	Centre Hospitalier Universitaire de Grenoble-Medical Oncology ( Site 1105)	La Tronche	Isere
France	Institut Régional du Cancer Montpellier ( Site 1106)	Montpellier	Herault
France	Centre Eugène Marquis Rennes - Centre de Lutte Contre le Cancer ( Site 1103)	Rennes	Bretagne
Israel	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	Sourasky Medical Center-Oncology ( Site 1301)	Tel Aviv
Korea, Republic of	Keimyung University Dongsan Hospital CRC room 1 ( Site 4104)	Daegu	Taegu-Kwangyokshi
Korea, Republic of	Chonnam National University Hwasun Hospital-Hemato-Oncology ( Site 4105)	Hwasun Gun	Jeonranamdo
Korea, Republic of	Asan Medical Center-Department of Oncology ( Site 4101)	Seoul
Korea, Republic of	Samsung Medical Center-Division of Hematology/Oncology ( Site 4102)	Seoul
Korea, Republic of	Seoul National University Hospital-Internal Medicine ( Site 4103)	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System-Medical oncology ( Site 4100)	Seoul
Netherlands	Leids Universitair Medisch Centrum-Medical Oncology ( Site 1504)	Leiden	Zuid-Holland
Netherlands	Maastricht UMC+-Medical Oncology ( Site 1501)	Maastricht	Limburg
Netherlands	Universitair Medisch Centrum Utrecht-Medical Oncology ( Site 1503)	Utrecht
New Zealand	Auckland City Hospital-Cancer & Blood Research ( Site 4200)	Auckland
New Zealand	Auckland City Hospital-Liver Research Unit ( Site 4201)	Grafton	Auckland
Spain	Hospital Germans Trias i Pujol-Instituto Catalán de Oncología de Badalona ( Site 1806)	Badalona	Barcelona
Spain	Hospital Universitari Vall d'Hebron-Oncology ( Site 1800)	Barcelona
Spain	HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 1801)	Madrid	Madrid, Comunidad De
Spain	Hospital Universitario Central de Asturias-Medical Oncology ( Site 1802)	Oviedo	Asturias
Spain	CHUS - Hospital Clinico Universitario-Servicio de Oncologia ( Site 1807)	Santiago de Compostela	La Coruna
United States	Johns Hopkins Hospital-Sidney Kimmel Comprehensive Cancer Center - GI and Immunology ( Site 5048)	Baltimore	Maryland
United States	Brigitte Harris Cancer Pavilion ( Site 5055)	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center ( Site 5002)	Duarte	California
United States	Duke Cancer Institute ( Site 5026)	Durham	North Carolina
United States	Inova Schar Cancer Institute ( Site 5039)	Fairfax	Virginia
United States	University of Florida College of Medicine ( Site 5015)	Gainesville	Florida
United States	University of Texas MD Anderson Cancer Center-Gastrointestinal Medical Oncology ( Site 5049)	Houston	Texas
United States	Cedars-Sinai Medical Center ( Site 5045)	Los Angeles	California
United States	University of Wisconsin Hospitals and Clinics ( Site 5037)	Madison	Wisconsin
United States	Yale-New Haven Hospital-Yale Cancer Center ( Site 5013)	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center ( Site 5050)	New York	New York
United States	Blue Ridge Cancer Care ( Site 5053)	Roanoke	Virginia
United States	UCSF Medical Center at Mission Bay ( Site 5021)	San Francisco	California
United States	Northwest Medical Specialties, PLLC ( Site 5025)	Tacoma	Washington
United States	University of Arizona Cancer Center-University of Arizona Cancer Center - North Campus ( Site 5047)	Tucson	Arizona
United States	Sibley Memorial Hospital ( Site 5051)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Chile,  France,  Israel,  Korea, Republic of,  Netherlands,  New Zealand,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary