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

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

URL: https://www.ncbi.nlm.nih.gov/pubmed/29438372
DOI: 10.1038/bjc.2017.495

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Notch
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 20 March 2018
Date Deposited: 21 Feb 2018 14:44
Last Modified: 13 Jun 2018 15:52
PMCID: PMC5877439
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36073

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