Phase 2 Study to evaluate Pembrolizumab Plus Lenvatinib in Combo w/ Belzutifan in 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.

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 20% over approximately 3 months before first dose of study therapy