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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.

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



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.


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.


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.


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

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