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A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer

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Summary

Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1–3, 8–10 and 15–17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2–3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Stephanie Fortier, PhD (Division of Medical Oncology, The Ohio State University) for her assistance in the preparation and editing of this manuscript.

Funding

The project described was supported by the UM1 National Cancer Institute (5UM1CA186712–03), the National Center for Advancing Translational Sciences (UL1TR002733), the CCC Core Grant and the Pharmacoanalytical Shared Resource (P30 CA016058), and the Cancer Clinical Investigator Team Leadership Award (P30CA016058-42S2). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

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Author notes

  1. Sagar Sardesai and Mohamed Badawi contributed equally to this work.

Authors and Affiliations

  1. The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA

    Sagar Sardesai, Evan Morgan, Mahmoud Kassem, Maryam Lustberg, Daniel Stover, Nicole Williams, Raquel Reinbolt, Jeffrey VanDeusen, Mathew Cherian, Bhuvaneswari Ramaswamy & Robert Wesolowski

  2. The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Mohamed Badawi, Mitch Phelps & Yonghua Ling

  3. Medical Oncology, Mercy Health, St. Rita’s Cancer Center, Lima, OH, USA

    Ewa Mrozek & Julie Stephens

  4. The Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA

    Lai Wei

  5. Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rachel Layman

  6. The Division of Hematology, College of Medicine, The Ohio State University, Columbus, OH, USA

    Michael Grever

  7. The Division of Surgical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA

    William Carson

  8. The Ohio State University Comprehensive Cancer Center, Suite 1204, Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA

    Robert Wesolowski

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  1. Sagar Sardesai
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Sagar Sardesai, Mohamed Badawi, Ewa Mrozek, Evan Morgan, Mitch Phelps, Julie Stephens, Lai Wei, Mahmoud Kassem, Yonghua Ling and Robert Wesolowski. The first draft of the manuscript was written by Sagar Sardesai and Mohamed Badawi, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Robert Wesolowski.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of The Ohio State University Comprehensive Cancer Center (OSUCCC), the Human Institutional Review Board at OSUCCC (OSU IRB 2010C0043), and with the 1964 Helsinki declaration and its later amendments.

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Informed consent was obtained from all individual participants included in the study, prior to the initiation of study procedures and treatment.

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Sardesai, S., Badawi, M., Mrozek, E. et al. A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer. Invest New Drugs 38, 1400–1410 (2020). https://doi.org/10.1007/s10637-020-00895-5

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