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

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Cook N, Basu B, Smith DM, Gopinathan A, Evans J, Steward WP, Palmer D, Propper D, Venugopal B, Hategan M, Anthoney DA, Hampson LV, Nebozhyn M, Tuveson D, Farmer-Hall H, Turner H, McLeod R, Halford S, Jodrell D

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

Br J Cancer. 2018 Mar 20;118(6):793-801. doi: 10.1038/bjc.2017.495. Epub 2018 Feb 13.

PubMed ID

29438372 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
MK-0752	Gamma-secretase subunit APH-1A	Protein	Humans	Unknown	Inhibitor	Details