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

Kyaw L Aung1, Anthony B El-Khoueiry2, Karen Gelmon3

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

Investigational New Drugs
|April 12, 2018
PubMed

Insights

BMS-986115, a Notch signalling inhibitor, demonstrated safety and biological activity in advanced solid tumour patients. Daily oral dosing showed tolerability and target engagement, supporting its potential as an anti-cancer strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Biology

Background:

  • Notch signalling inhibition is a key anti-cancer strategy targeting cancer stem cells and tumour angiogenesis.
  • BMS-986115 is an oral, selective gamma-secretase inhibitor of Notch signaling.

Purpose of the Study:

  • To determine the safety, tolerability, and Maximum Tolerated Dose (MTD) of BMS-986115.
  • To evaluate two different dosing schedules of BMS-986115 in patients with advanced solid tumours.

Main Methods:

  • A dose escalation study involving two arms: continuous daily dosing (Arm A) and intermittent twice-weekly dosing (Arm B).
  • Thirty-six patients with advanced solid tumours were enrolled and treated.

Main Results:

  • The MTD was established as 1.5 mg daily in Arm A; MTD was not reached in Arm B.
  • Frequent adverse events included diarrhea (72%), hypophosphatemia (64%), and nausea (61%).
  • Biological activity was confirmed by dose-related exposure, target gene inhibition, and stable disease in 5 patients for over 6 months.

Conclusions:

  • Daily oral administration of BMS-986115 is safe and well-tolerated in patients with advanced solid tumours.
  • The study demonstrated biological activity and target engagement of the Notch pathway.
  • Continuous daily dosing showed a defined MTD and supports further investigation.
Keywords:
BMS-986115Gamma-secretase inhibitorOral NOTCH inhibitorPhase I trial

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