Cook, N., Basu, B., Smith, D. M., Gopinathan, A., Evans, 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., Jodrell, D. (March 2018) A phase I trial of the gamma-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer, 118 (6). pp. 793-801. ISSN 0007-0920
Abstract
BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by gamma-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 gamma-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.British Journal of Cancer advance online publication, 13 February 2018; doi:10.1038/bjc.2017.495 www.bjcancer.com.
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