A phase I trial of the γ-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.

Abstract

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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Bayes Theorem
  • Benzene Derivatives / administration & dosage
  • Benzene Derivatives / adverse effects
  • Benzene Derivatives / pharmacokinetics
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacokinetics
  • Drug Administration Schedule
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Propionates / administration & dosage
  • Propionates / adverse effects
  • Propionates / pharmacokinetics
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • Sulfones / administration & dosage
  • Sulfones / adverse effects
  • Sulfones / pharmacokinetics

Substances

  • 3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
  • Benzene Derivatives
  • Propionates
  • Receptors, Notch
  • Sulfones
  • Deoxycytidine
  • gemcitabine
  • Amyloid Precursor Protein Secretases