Pembrolizumab Plus Lenvatinib in Combination With Belzuti... | NCT04976634

ID	Type	Description
MK-6482-016	Other Identifier	MSD
2023-503905-12-00	EU Trial (CTIS) Number
U1111-1288-3020	Registry Identifier	UTN
2020-005007-40	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm 1: Pembrolizumab + Belzutifan + Lenvatinib	Experimental	Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg (For HCC: 8 mg [body weight <60kg] or 12 mg [body weight ≥ 60 kg]). Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Belzutifan and lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.	Drug: Pembrolizumab Drug: Belzutifan Drug: Lenvatinib
Arm 2: Pembrolizumab + Lenvatinib	Experimental	Participants with IO resistant ESCC will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.	Drug: Pembrolizumab Drug: Lenvatinib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Pembrolizumab	Drug	Pembrolizumab 400 mg administered Q6W via IV infusion	Arm 1: Pembrolizumab + Belzutifan + Lenvatinib Arm 2: Pembrolizumab + Lenvatinib

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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
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 67 months
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 67 months
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)

Secondary Outcomes

Measure	Description	Time Frame
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR	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.

Eligibility Module

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](streamdown:incomplete-link)