Cook, N. et al. (2018) A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. British Journal of Cancer, 118(6), pp. 793-801. (doi: 10.1038/bjc.2017.495) (PMID:29438372) (PMCID:PMC5877439)
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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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Venugopal, Dr Balaji and Evans, Professor Jeff |
Authors: | Cook, N., Basu, B., Smith, D.-M., Gopinathan, A., Evans, T.R. J., Steward, W. P., Palmer, D., Propper, D., Venugopal, B., Hategan, M., Anthoney, D. A., Hampson, L. V., Nebozhyn, M., Tuveson, D., Farmer-Hall, H., Turner, H., McLeod, R., Halford, S., and Jodrell, D. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | British Journal of Cancer |
Publisher: | Cancer Research UK |
ISSN: | 0007-0920 |
ISSN (Online): | 1532-1827 |
Published Online: | 13 February 2018 |
Copyright Holders: | Copyright © 2018 The Authors |
First Published: | First published in British Journal of Cancer 118(6): 793-801 |
Publisher Policy: | Reproduced under a Creative Commons License |
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