An open-label phase II study to evaluate PT2977 for the treatment of von Hippel-Lindau disease-associated renal cell carcinoma.

Abstract

TPS680 Background: In von Hippel-Lindau (VHL), renal cell carcinomas (RCC) are 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, 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. Management of VHL-associated renal tumors most often involves active surveillance until surgery is recommended for tumors larger than 3 cm to reduce the risk of metastasis. Repeated surgical procedures, which are often required, can carry significant morbidity. Systemic therapy options that can delay or obviate the need for surgery by reducing tumor size are needed. Methods: This open-label Phase 2 study will evaluate the efficacy and safety of PT2977, a highly selective small molecule inhibitor of HIF-2α, in VHL patients who have at least 1 measurable ccRCC (per RECIST 1.1). PT2977 will be administered orally at 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 requiring immediate surgical intervention. Patients may have VHL-associated tumors in other organ systems. Key exclusion criteria include prior systemic therapy for VHL, evidence of metastatic disease, and history of a non-VHL-associated invasive malignancy in the past 2 years. The primary endpoint is objective response rate (ORR) of ccRCC tumors per RECIST 1.1. Secondary endpoints include duration of response (DOR), time to response (TTR), progression-free survival (PFS), time to surgery (TTS) for ccRCC tumors, and efficacy evaluations for non-ccRCC tumors. Safety and pharmacokinetics of PT2977 will also be evaluated. Patient recruitment is ongoing. Funding: Peloton Therapeutics, Inc. Clinical trial information: NCT03401788.