Phase 1 Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer

Purpose: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with anti-tumor activity in vitro and in vivo. This open-label phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics (PK) and activity of once daily (QD) seviteronel in male chemotherapy-naïve subjects with castrate-resistant prostate cancer (CRPC). Experimental Design: Seviteronel was administered at 600 mg QD with dose titration (DT) and in modified 3+3 dose escalation QD cohorts at 600 mg, 750 mg, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability and the maximum tolerated dose of seviteronel in chemotherapy-naïve subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA) and enzalutamide (ENZA). Secondary objectives were to assess PK, PSA, tumor response and endocrine results. Results: Twenty-one subjects were enrolled. No dose-limiting toxicities (DLTs) were observed through 750 mg QD. Most treatment-emergent adverse events (AEs) reported at grade1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), vision blurred (38%) and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption. Conclusions: Once-daily seviteronel was generally well tolerated in this phase 1 study of men with CRPC, a majority of which had progressed on prior AA or ENZA, or both. Of the doses evaluated, 600 mg QD was chosen as the recommended phase 2 dose for future studies in subjects with CRPC.

https://ift.tt/2LnteW8