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Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer

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Abstract

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.

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Funding

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.

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    Authors and Affiliations

    1. Division of Hematology and Oncology, Breast Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114-2696, USA

      Aditya Bardia

    2. Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

      Ayca Gucalp & Tiffany A. Traina

    3. North Shore Hematology Oncology Associates, East Setauket, NY, USA

      Noashir DaCosta

    4. Gabrail Cancer Center, Canton, OH, USA

      Nashat Gabrail

    5. Virgina Oncology Associates, Norfolk, VA, USA

      Michael Danso

    6. Henry Ford Hospital, Detroit, MI, USA

      Haythem Ali

    7. Duke University School of Medicine, Durham, NC, USA

      Kimberly L. Blackwell

    8. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

      Lisa A. Carey

    9. Innocrin Pharmaceuticals, Inc., Durham, NC, USA

      Joel R. Eisner & Edwina S. Baskin-Bey

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    1. Aditya Bardia
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    Correspondence to Aditya Bardia.

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    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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    Aditya Bardia and Ayca Gucalp contributed equally to this work.

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    Bardia, A., Gucalp, A., DaCosta, N. et al. Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer. Breast Cancer Res Treat 171, 111–120 (2018). https://doi.org/10.1007/s10549-018-4813-z

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