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Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer

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Summary

Introduction Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3 + 3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47–73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1–2 nausea (n = 4) and bone pain (n = 3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n = 2). The only grade 3 AE was hypertension (n = 2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer.

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Acknowledgments

The authors would like to thank all of the participants enrolled in this trial, the UW research staff, and the physicians who participated.

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Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    Murtuza Rampurwala, Kari B. Wisinski, Mark E. Burkard, Sima Ehsani, Ruth M. O’Regan, KyungMann Kim, Jill Kolesar & Amye J. Tevaarwerk

  2. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Murtuza Rampurwala, Kari B. Wisinski, Mark E. Burkard, Sima Ehsani, Ruth M. O’Regan & Amye J. Tevaarwerk

  3. Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA

    Lakeesha Carmichael & KyungMann Kim

  4. University of Wisconsin School of Pharmacy, Madison, WI, USA

    Jill Kolesar

  5. Department of Medicine, Hematology/Oncology, University of Wisconsin, 1111 Highland Ave, WIMR Rm 6037, Madison, WI, 53705, USA

    Amye J. Tevaarwerk

Authors
  1. Murtuza Rampurwala
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  2. Kari B. Wisinski
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Corresponding author

Correspondence to Amye J. Tevaarwerk.

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Conflict of interest

Murtuza Rampurwala declares that he has no conflict of interest.

Kari B Wisinski declares that she has no conflict of interest.

Mark E Burkard declares that he has no conflict of interest.

Sima Ehsani declares that she has no conflict of interest.

Ruth M O’Regan declares that she has no conflict of interest.

Lakeesha Carmichael declares that she has no conflict of interest.

KyungMann Kim declares that he has no conflict of interest.

Jill Kolesar declares that she has no conflict of interest.

Amye J Tevaarwerk declares that she has no conflict of interest.

Funding

This study was funded by Millennium Pharmaceuticals. This work was supported by the NCI Cancer Center Support Grant P30 CA014520 and NCI U01CA062491 Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis. AJT and MEB have received support from the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grants UL1TR000427and KL2TR000428, while MR has received support from T32 CA009614.

Ethical approval

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Rampurwala, M., Wisinski, K.B., Burkard, M.E. et al. Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Invest New Drugs 35, 87–94 (2017). https://doi.org/10.1007/s10637-016-0403-2

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  • DOI: https://doi.org/10.1007/s10637-016-0403-2

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