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
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.
| 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 |
| 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 | Centre Hospitalier Régional Universitaire de Brest - Hôpital Morvan ( 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 ( 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 | 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 |
| Lead Sponsor | Collaborator |
|---|---|
| Merck Sharp & Dohme LLC |
United States, Australia, Belgium, Chile, France, Israel, Korea, Republic of, Netherlands, New Zealand, Spain,
| 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 |
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