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

Abstract

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

ARe we there yet? Understanding androgen receptor signaling in breast cancer

“…Clinical trials for patients with ER+ or TNBC indicated that seviteronel was well-tolerated in women, with the majority of adverse events (AEs) being Grade 1/2, in addition to four Grade 3/4 AEs that may be related to seviteronel treatment 171 . Phase I trials in CRPC patients suggest that seviteronel may be an effective treatment alternative for men who are not responsive on other therapies with most reported AEs being Grade 1/2 172 . Preclinical work in AR+ TNBC demonstrates that seviteronel inhibits cell proliferation and growth on soft agar 173 .…”

Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells

“…Seviteronel has been shown to be more effective than abiraterone acetate at inhibiting CYP17 lyase (23), and seviteronel also possesses some antagonistic effects against AR, potentially rendering it a dual-AR inhibitor. In phase I studies, seviteronel has been well-tolerated both in men with castration-resistant prostate cancer (CRPC) (24) and in women with ER+ breast cancer or TNBC (25). There is hope that these novel agents, including seviteronel, will be effective in patients with AR+ cancers, including TNBC.…”

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

“…Unlike abiraterone acetate, VT464, selectively inhibits the 17,20-lyase rather than 17α-hydroxylase reactions, so it is proposed that the combination with prednisone is not necessary. However, phase 1 testing of VT464 suggested that there is minor inhibition of CYP17 hydroxylase ( 52 ), so low-dose dexamethasone is being administered with VT464 in ongoing trials with prostate cancer patients ( 53 , 54 ). Abiraterone acetate and VT464 both also function as competitive AR antagonists, including of AR mutants, with VT464 more potent than abiraterone in cells with the T878A AR mutation ( 55 – 58 ).…”