Abstract 2532
Background
In VHL disease, renal cell carcinomas (RCC) are known to be of clear cell histology (ccRCC). HIF-2α has been established as an oncogenic driver in ccRCC, where VHL deficiency is the underlying genomic alteration. In this setting of VHL gene inactivation, HIF-2α accumulates under normoxic conditions, driving the expression of genes associated with progression of ccRCC, including vascular endothelial growth factor A (VEGFA), cyclin D1 and other factors that contribute to tumor growth and proliferation. Clinical management of VHL disease-associated renal tumors involves active surveillance until surgery is required for tumors larger than 3 cm to prevent metastasis. Repeated surgical procedures can carry significant morbidity. Systemic therapy options that can delay or obviate the need for surgery by reducing tumor size are needed.
Trial design
This open-label Phase 2 study will evaluate the efficacy and safety of PT2977, a highly selective small molecule inhibitor of HIF-2α, in patients with VHL disease who have at least 1 measurable ccRCC (as defined by RECIST 1.1). PT2977 will be administered orally at a dosage of 120 mg once daily. Key inclusion criteria include a germline VHL alteration and at least 1 measurable solid ccRCC but no tumor >3.0 cm that requires immediate surgical intervention. Patients may have VHL disease-associated tumors in other organ systems. Key exclusion criteria include prior systemic therapy for VHL disease, an immediate need for surgical intervention, evidence of metastatic disease, and history of a non-VHL disease-associated invasive malignancy in the past 2 years. The primary efficacy endpoint is objective response rate (ORR) of ccRCC tumors per RECIST 1.1. Secondary efficacy endpoints include duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) for ccRCC tumors as well as efficacy evaluations for non-ccRCC VHL disease-associated tumors. Safety/tolerability and pharmacokinetics of PT2977 in this trial will also be evaluated. Patient recruitment is ongoing.
Clinical trial identification
NCT03401788; EudraCT: 2018-000125-30.
Legal entity responsible for the study
Peloton Therapeutics, Inc.
Funding
Peloton Therapeutics, Inc.
Editorial Acknowledgement
Disclosure
E. Jonasch, R. Srinivasan: Research support: Peloton Inc. E. Park, S. Thamake, M. Hirmand: Employee of Peloton Inc.