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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.
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
Abstracts by Kevin Dale Courtney:
Aberrant tumor metabolism to enable glucocorticoid receptor takeover in enzalutamide-resistant prostate cancer.Meeting: 2017 Genitourinary Cancers Symposium | Abstract No: 157
Phase II trial of high-dose interleukin-2 (IL-2) and stereotactic Radiation therapy (SABR) for metastatic clear cell renal cell carcinoma (ccRCC): Interim analysis.Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 532Category: Genitourinary Cancer - Renal Cell Cancer
Presentations by Kevin Dale Courtney:
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.Meeting: 2016 ASCO Annual Meeting Abstract No: 2506Session: Developmental Therapeutics-Clinical Pharmacology and Experimental Therapeutics (Oral Abstract Session)