PMID- 29744674 OWN - NLM STAT- MEDLINE DCOM- 20190621 LR - 20200721 IS - 1573-7217 (Electronic) IS - 0167-6806 (Print) IS - 0167-6806 (Linking) VI - 171 IP - 1 DP - 2018 Aug TI - Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer. PG - 111-120 LID - 10.1007/s10549-018-4813-z [doi] AB - PURPOSE: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer. METHODS: Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24). RESULTS: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported. CONCLUSIONS: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D. FAU - Bardia, Aditya AU - Bardia A AUID- ORCID: 0000-0003-4885-1157 AD - Division of Hematology and Oncology, Breast Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114-2696, USA. Bardia.Aditya@mgh.harvard.edu. FAU - Gucalp, Ayca AU - Gucalp A AD - Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - DaCosta, Noashir AU - DaCosta N AD - North Shore Hematology Oncology Associates, East Setauket, NY, USA. FAU - Gabrail, Nashat AU - Gabrail N AD - Gabrail Cancer Center, Canton, OH, USA. FAU - Danso, Michael AU - Danso M AD - Virgina Oncology Associates, Norfolk, VA, USA. FAU - Ali, Haythem AU - Ali H AD - Henry Ford Hospital, Detroit, MI, USA. FAU - Blackwell, Kimberly L AU - Blackwell KL AD - Duke University School of Medicine, Durham, NC, USA. FAU - Carey, Lisa A AU - Carey LA AD - Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. FAU - Eisner, Joel R AU - Eisner JR AD - Innocrin Pharmaceuticals, Inc., Durham, NC, USA. FAU - Baskin-Bey, Edwina S AU - Baskin-Bey ES AD - Innocrin Pharmaceuticals, Inc., Durham, NC, USA. FAU - Traina, Tiffany A AU - Traina TA AD - Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. LA - eng GR - K12 CA087723/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article DEP - 20180509 PL - Netherlands TA - Breast Cancer Res Treat JT - Breast cancer research and treatment JID - 8111104 RN - 0 (Androgen Receptor Antagonists) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (Receptors, Androgen) RN - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase) SB - IM MH - Aged MH - Aged, 80 and over MH - Androgen Receptor Antagonists/administration & dosage/adverse effects/pharmacokinetics/*therapeutic use MH - Antineoplastic Agents/administration & dosage/adverse effects/pharmacokinetics/*therapeutic use MH - Biomarkers, Tumor MH - Breast Neoplasms/*drug therapy/metabolism MH - Female MH - Humans MH - Middle Aged MH - Receptors, Androgen/metabolism MH - Steroid 17-alpha-Hydroxylase/*antagonists & inhibitors MH - Treatment Outcome MH - Triple Negative Breast Neoplasms/*drug therapy/metabolism PMC - PMC6226357 MID - NIHMS966623 OTO - NOTNLM OT - Androgen receptor OT - Breast cancer OT - CYP17 lyase OT - Seviteronel COIS- Conflict of Interest This study was funded by Innocrin Pharmaceuticals. E.S.B-B and J.R.E are compensated employees of Innocrin Pharmaceuticals. T.A.T. receives compensation as a Steering Committee member for Innocrin Pharmaceuticals. All other authors declare that they have no conflict of interest. EDAT- 2018/05/11 06:00 MHDA- 2019/06/22 06:00 PMCR- 2019/08/01 CRDT- 2018/05/11 06:00 PHST- 2018/04/17 00:00 [received] PHST- 2018/05/03 00:00 [accepted] PHST- 2018/05/11 06:00 [pubmed] PHST- 2019/06/22 06:00 [medline] PHST- 2018/05/11 06:00 [entrez] PHST- 2019/08/01 00:00 [pmc-release] AID - 10.1007/s10549-018-4813-z [pii] AID - 10.1007/s10549-018-4813-z [doi] PST - ppublish SO - Breast Cancer Res Treat. 2018 Aug;171(1):111-120. doi: 10.1007/s10549-018-4813-z. Epub 2018 May 9.