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

  • 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
Publication Date
Mar 01, 2018
Apollo - University of Cambridge Repository
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Background: The Notch pathway is frequently activated in cancer. Pathway inhibition by GSIs has been shown to be effective in models of PDAC, in combination with gemcitabine (GEM). Methods: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered p.o. weekly (starting dose; 1,200mg), and GEM i.v. on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg/m2, is being performed to determine the safety (using CTCAE v4.02) of combination treatment and recommend a Phase 2 dose (RP2D) combination. Other objectives are tumor response (RECIST 1.1), plasma and tumor MK-0752 concentration, and inhibition of the Notch pathway in hair follicles (expression profiling) and tumor (IHC). Results: 29 patients (pts) were registered on the study, of whom 27 received treatment (17 WHO PS 1; 10 PS 0). All patients received GEM/MK-0752 as first line treatment for metastatic disease. The RP2D of both single agents could be administered in combination (MK-0752 1800mg and GEM 1000 mg/m2). As no DLTs were experienced at this dose combination, the Bayesian algorithm allowed further dose escalation, but dose limiting toxicity (G3 hypokalaemia) was observed at MK-0752 2,400mg in 1 pt. Gastrointestinal related adverse events (AEs) were common (diarrhoea 18 pts; nausea 19 pts; vomiting 17 pts). Other (>10% pts) AEs included fatigue, thrombocytopenia (G4 in 1 pt) and transaminitis. Tumor response evaluation was available after 10 weeks of treatment in 18 pts (6 withdrew early due to AEs, 1 pt was not evaluable, 2 pts still on treatment): 11/18 achieved stable disease and a confirmed partial response was observed at 12 weeks (time to subsequent progression 38 weeks). Plasma PK analysis revealed Cmax at 1,800mg of 61-104 µg/mL (n=7, Tmax, 4-8 hours) with a long half-life: quantifiable (>50 ng/mL) MK-0752 in plasma, 7 days after a single administration in 5/7 pts. A signature of Notch pathway inhibition was observed in 16/18 pts in hair follicles and paired biopsies (20 pts) are being analysed for tumor PK and Hes1 IHC. Conclusions: GEM and MK-0752, can be combined at full, single agent RP2Ds and the regimen is well tolerated. Clinical activity was seen, which will require confirmation in a Phase II trial. Clinical trial information: NCT01098344.

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