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Br J Cancer. 2018 Mar 20;118(6):793-801. doi: 10.1038/bjc.2017.495. Epub 2018 Feb 13.

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.

Author information

1
Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK.
2
Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK.
3
Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom.
4
Department of Oncology, University of Leicester, Leicester LE2 7LX, UK.
5
Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK.
6
Bart's Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK.
7
Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK.
8
St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK.
9
Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK.
10
Merck & Co., Inc., Kenilworth, NJ 07033, USA.
11
Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA.

Abstract

BACKGROUND:

The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine.

METHODS:

A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour.

RESULTS:

Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response.

CONCLUSIONS:

Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

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