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.

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Session Type and Session Title: 
Oral Abstract Session, Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Abstract Number: 


J Clin Oncol 34, 2016 (suppl; abstr 2506)
Kevin Dale Courtney, Jeffrey R. Infante, Elaine Tat Lam, Robert A. Figlin, Brian I. Rini, James Brugarolas, Naseem J. Zojwalla, Keshi Wang, Eli Wallace, John A. Josey, Toni K. Choueiri; The University of Texas Southwestern Medical Center, Dallas, TX; Sarah Cannon Research Institute, Nashville, TN; University of Colorado, Denver, Aurora, CO; Cedars-Sinai Medical Center, Los Angeles, CA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Peloton Therapeutics, Dallas, TX; Peloton Therapeutics Inc, Dallas, TX; Dana-Farber/Brigham and Women's Cancer Center, Boston, MA

Abstract Disclosures


Background: 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 therapies was 4. No dose limiting toxicities were observed. Exposure generally increased with dose up to the 800 mg cohort without a further increase from 800 to 1800 mg. At 800 mg, PT2385 was rapidly absorbed (Tmax = 2 h) with a Cmax of 3.1 mg/mL and a half-life of 17 h. Targeted Cmin of 280 ng/mL was exceeded in 15/16 pts receiving ≥ 800 mg. Circulating plasma levels of the HIF-2a transcriptional target erythropoietin (EPO) rapidly decreased within 24 hrs in 15/16 pts receiving ≥ 800 mg and remained suppressed during the 16 wk sampling period. Based on safety, PK, and EPO PD data, 800 mg BID was selected as the RP2D. An additional 17 of 25 planned patients have been enrolled in an expansion cohort. Among the 43 pts, the most common all-grade adverse events (AEs) were anemia (14), fatigue (13) and peripheral edema (10). Grade ≥ 3 treatment related AE’s were anemia (3), pulmonary embolism (1), and lymphopenia (1). To date, 1 CR, 1 PR, and 24 SD have been observed—of these pts, 7 are ongoing > 7 months. Conclusions: Continuous PT2385 administration was safe and tolerable and demonstrated early evidence of clinical activity in heavily pre-treated pts with advanced ccRCC. Clinical trial information: NCT02293980