A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.
Steward, William P
Anthoney, D Alan
Hampson, Lisa V
British journal of cancer
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Cook, N., Basu, B., Smith, D., Gopinathan, A., Evans, J., Steward, W. P., Palmer, D., et al. (2018). A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.. British journal of cancer, 118 (6), 793-801. https://doi.org/10.1038/bjc.2017.495
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.
Humans, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Propionates, Benzene Derivatives, Sulfones, Deoxycytidine, Antineoplastic Combined Chemotherapy Protocols, Infusions, Intravenous, Drug Administration Schedule, Bayes Theorem, Signal Transduction, Adult, Aged, Middle Aged, Female, Male, Receptors, Notch, Amyloid Precursor Protein Secretases
Cancer Research UK (C96/A25177)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cancer Research UK (15678)
External DOI: https://doi.org/10.1038/bjc.2017.495
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280412
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Licence URL: https://creativecommons.org/licenses/by-nc-sa/4.0/