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

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, a...

Full description

Saved in:
Bibliographic Details
Published in:British journal of cancer 2018-03, Vol.118 (6), p.793
Main Authors: Cook, Natalie, Basu, Bristi, Smith, Donna-michelle, Gopinathan, Aarthi, Evans, Jeffry, Steward, William P, Palmer, Daniel, Propper, David, Venugopal, Balaji, Hategan, Mirela, Anthoney, D Alan, Hampson, Lisa V, Nebozhyn, Michael, Tuveson, David, Farmer-hall, Hayley, Turner, Helen, Mcleod, Robert, Halford, Sarah, Jodrell, Duncan
Format: Article
Language:English
Subjects:
Adenocarcinoma
Bayesian analysis
Follicles
Gemcitabine
Inhibition
Mathematical models
Notch protein
Pancreatic cancer
Patients
Secretase
Tumors
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2017.495