Authors:
N Cook, B Basu, D-M Smith, A Gopinathan, J Evans, WP Steward, D Palmer, D Propper, B Venugopal, M Hategan, DA Anthoney, LV Hampson, M Nebozhyn, D Tuveson, H Farmer-Hall, H Turner, R McLeod, S Halford, D Jodrell
Journal name: 
Br J Cancer
Citation info: 
118(6):793-801
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.
DOI: 
http://doi.org/10.1038/bjc.2017.495
Research group: 
Jodrell Group
E-pub date: 
20 Mar 2018