A Phase I Dose Escalation Trial Of Pt2385, A First-In-Class Oral Hif-2a Inhibitor, In Patients With Advanced Clear Cell Renal Cell Carcinoma.

2506Background: Inactivation of the von Hippel Lindau (VHL) tumor suppressor occurs in the majority of clear cell renal cell carcinomas (ccRCC). VHL deficiency stabilizes the transcription factor hypoxia-inducible factor (HIF)-2a, an oncogenic driver of ccRCC. PT2385 is a first-in-class, orally administered selective small molecule inhibitor of HIF-2a that disrupts the heterodimerization of HIF-2a with HIF-1b and blocks the transcription of several genes involved in oncogenesis. PT2385 demonstrated anti-tumor efficacy in mouse xenograft models of ccRCC. Methods: Patients (pts) with advanced ccRCC and at least one prior therapy with a VEGF inhibitor were treated with PT2385 twice daily (BID) in a 3+3 Phase I design to determine the recommended Phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). Plasma PK were measured on days 1 and 15 and PD weekly. Results: 26 pts were enrolled in dose escalation receiving PT2385 from 100 to 1800 mg BID. Median number of prior therap...