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A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours

Investigational New Drugs volume 36, pages 1026–1036 (2018)Cite this article

Summary

Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling. Method Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115. Results Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months. Conclusion The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.

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Acknowledgements

Authors would like to thank the patients and study teams at each participating site; Dr. Lillian Siu from the Princess Margaret Cancer Centre, Toronto, Canada; Lisu Wang and John Cogswell from Bristol-Myers Squibb, Hopewell, New Jersey, USA; Sumitha Kurian, Shweta Ramayya, Ankit Jinager, and Deepa Joshi from Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India.

Funding

This study was sponsored and funded by Bristol-Myers Squibb.

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Authors and Affiliations

  1. Drug Development Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada

    Kyaw L. Aung & Anna Spreafico

  2. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 900333, USA

    Anthony B. El-Khoueiry

  3. British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 4E6, Canada

    Karen Gelmon

  4. Peter MacCallum Cancer Centre and Royal Melbourne Hospital, University of Melbourne, 305 Grattan St, Melbourne, VIC, 3000, Australia

    Ben Tran & Jayesh Desai

  5. Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Lawrenceville, NJ, 08648, USA

    Gaurav Bajaj & Bing He

  6. Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, 08540, USA

    Tian Chen & Lili Zhu

  7. Biocon BMS R&D Centre, Syngene International Ltd, Bangalore, 560 099, India

    Sharath Poojary & Shashwati Basak

  8. Clinical Genomics and Genetics, Translational Medicine, Bristol-Myers Squibb, Princeton, NJ, 08540, USA

    Zhenhao Qi

  9. Oncology Early Clinical Development, Bristol-Myers Squibb, Lawrenceville, NJ, 08648, USA

    Bruce S. Fischer

Authors
  1. Kyaw L. Aung
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  2. Anthony B. El-Khoueiry
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  3. Karen Gelmon
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  7. Tian Chen
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  10. Shashwati Basak
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  11. Zhenhao Qi
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  14. Jayesh Desai
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Corresponding author

Correspondence to Jayesh Desai.

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Conflict of interest

Gaurav Bajaj, Bing He, Tian Chen, Lili Zhu, Zhenhao Qi, and Bruce S. Fischer are employees and stockholders of Bristol-Myers Squibb. Sharath Poojary and Shashwati Basak are employees of Syngene International Ltd., which has business relationship with Bristol-Myers Squibb. Other authors declare no conflict of interest.

Ethical approval

This article does not contain any studies with animals performed by any of the authors. All procedures performed in this study 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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Aung, K.L., El-Khoueiry, A.B., Gelmon, K. et al. A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours. Invest New Drugs 36, 1026–1036 (2018). https://doi.org/10.1007/s10637-018-0597-6

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  • DOI: https://doi.org/10.1007/s10637-018-0597-6

Keywords

  • BMS-986115
  • Oral NOTCH inhibitor
  • Gamma-secretase inhibitor
  • Phase I trial