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

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)

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
• 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