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Investigational New Drugs
Published in: Investigational New Drugs 6/2018

01-12-2018 | PHASE I STUDIES

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

Authors: 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

Published in: Investigational New Drugs | Issue 6/2018

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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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Metadata
Title
A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours
Authors
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
Publication date
01-12-2018
Publisher
Springer US
Published in
Investigational New Drugs / Issue 6/2018
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-018-0597-6

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