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

  • Kyaw L. Aung
  • Anthony B. El-Khoueiry
  • Karen Gelmon
  • Ben Tran
  • Gaurav Bajaj
  • Bing He
  • Tian Chen
  • Lili Zhu
  • Sharath Poojary
  • Shashwati Basak
  • Zhenhao Qi
  • Anna Spreafico
  • Bruce S. Fischer
  • Jayesh Desai
PHASE I STUDIES
  • 27 Downloads

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.

Keywords

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

Notes

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.

Compliance with ethical standards

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.

Supplementary material

10637_2018_597_MOESM1_ESM.docx (59 kb)
ESM 1 (DOCX 59 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kyaw L. Aung
    • 1
  • Anthony B. El-Khoueiry
    • 2
  • Karen Gelmon
    • 3
  • Ben Tran
    • 4
  • Gaurav Bajaj
    • 5
  • Bing He
    • 5
  • Tian Chen
    • 6
  • Lili Zhu
    • 6
  • Sharath Poojary
    • 7
  • Shashwati Basak
    • 7
  • Zhenhao Qi
    • 8
  • Anna Spreafico
    • 1
  • Bruce S. Fischer
    • 9
  • Jayesh Desai
    • 4
  1. 1.Drug Development Program, Princess Margaret Cancer Centre, University Health NetworkUniversity of TorontoTorontoCanada
  2. 2.Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.British Columbia Cancer AgencyVancouverCanada
  4. 4.Peter MacCallum Cancer Centre and Royal Melbourne HospitalUniversity of MelbourneMelbourneAustralia
  5. 5.Clinical Pharmacology & Pharmacometrics, Bristol-Myers SquibbLawrencevilleUSA
  6. 6.Global Biometric Sciences, Bristol-Myers SquibbPrincetonUSA
  7. 7.Biocon BMS R&D Centre, Syngene International LtdBangaloreIndia
  8. 8.Clinical Genomics and Genetics, Translational Medicine, Bristol-Myers SquibbPrincetonUSA
  9. 9.Oncology Early Clinical Development, Bristol-Myers SquibbLawrencevilleUSA

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