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

Natalie Cook, Bristi Basu, Donna Michelle Smith, Aarthi Gopinathan, Jeffry Evans, William P. Steward, Daniel Palmer, David Propper, Balaji Venugopal, Mirela Hategan, D. Alan Anthoney, Lisa V. Hampson, Michael Nebozhyn, David Tuveson, Hayley Farmer-Hall, Helen Turner, Robert McLeod, Sarah Halford, Duncan Jodrell

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The Notch pathway is frequently activated in cancer. Pathway inhibition by g-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 1000mgm-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 1800mg 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 g-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

Original languageEnglish
Pages (from-to)793-801
Number of pages9
JournalBritish Journal of Cancer
Volume118
Issue number6
DOIs
Publication statusPublished - 20 Mar 2018

Keywords

  • G-secretase
  • Gemcitabine
  • Notch pathway
  • Pancreatic cancer

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