Neoplasm Malignant
Conditions
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.
Interventions
DRUGPembrolizumab
Pembrolizumab 400 mg administered Q6W via IV infusion
DRUGBelzutifan
Belzutifan 120 mg administered QD via oral tablet
DRUGLenvatinib
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
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | ORR, per mRECIST 1.1, is defined as the percentage of participants with CR (disappearance of any intratumoral arterial enhancement in all target lesions) or PR (at least a 30% decrease in the sum of diameters of viable \[contrast enhancement in the arterial phase\] target lesions, taking as reference the baseline sum of diameters of target lesions) as assessed by BICR. For participants with HCC, mRECIST1.1 allows assessment of treatment-related tumor necrosis and assessment of viable tumor by assessment with arterial phase imaging. ORR as assessed by BICR will be presented. |
| DOR Per mRECIST 1.1 for HCC as Assessed by BICR | Up to approximately 67 months | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in sum of diameters of target lesions) per mRECIST 1.1, DOR is defined as time from first documented evidence of CR or PR until progressive disease (PD) or death. Per mRECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. The mRECIST 1.1 this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For participants with HCC, mRECIST1.1 allows assessment of treatment-related tumor necrosis and assessment of viable tumor by assessment with arterial phase imaging. DOR as assessed by BICR will be presented. |
| DCR Per mRECIST 1.1 for HCC as Assessed by BICR | Up to approximately 67 months | DCR is defined, per mRECIST 1.1, as the percentage of participants who have a CR (Disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD\]). For participants with HCC, mRECIST1.1 allows assessment of treatment-related tumor necrosis and assessment of viable tumor by assessment with arterial phase imaging. The best overall response of CR, PR, or SD after ≥ 6 weeks per mRECIST 1.1 for HCC will be assessed by BICR. |
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 67 months | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented. |
| Arm 2: Number of Participants Who Experience 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 experience an AE after administration of pembrolizumab plus lenvatinib will be presented. |
| Arm 2: Number of Participants Who Discontinued 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 of pembrolizumab plus lenvatinib after an AE will be presented. |
| PFS Per mRECIST 1.1 for HCC as Assessed by BICR | Up to approximately 67 months | PFS, per mRECIST 1.1, is defined as the time from first dose of study treatment to the first documented PD or death due to any cause, whichever occurs first as assessed by mRECIST1.1 to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Per mRECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. For participants with HCC, mRECIST1.1 allows assessment of treatment-related tumor necrosis and assessment of viable tumor by assessment with arterial phase imaging. PFS as assessed by BICR will be presented. |
| Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by BICR | Up to approximately 67 months | PFS is defined as the time from first day of study intervention to the first documented PD or death due to any cause, whichever occurs first as assessed by RECIST 1.1. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented. |
| Disease Control Rate (DCR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 67 months | DCR is defined as the percentage of participants who have a CR, PR, or Stable Disease (SD). Per RECIST 1.1, CR = disappearance of all target lesions, PR = ≥30% decrease in the sum of product diameters (SPD) of target lesions, compared to baseline SPD, and SD = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. The best overall response of CR, PR, or SD after ≥ 6 weeks will be assessed per RECIST 1.1 by BICR. |
| Overall Survival (OS) | Up to approximately 67 months | OS is defined as the time from the first day of study intervention to death due to any cause. |
Countries
Australia, Belgium, Chile, France, Israel, Netherlands, New Zealand, South Korea, Spain, United States
Outcome results
None listed