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

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.

Figure 1

Plasma and tumour MK-0752 PK analysis. (A) Plot of area under the curve (AUC_0-t) vs MK-0752 dose (plasma). (B) Plot of C_max (ng ml^-1) vs MK-0752 dose (plasma). (C) Statistical summary of PK parameters at RP2D of MK-0752 (1800 mg). (D) MK-0752 levels in tumour tissue (ng g^-1 tissue) plotted against dose of MK-0752. AUC_0-t=area under the time:plasma concentration curve from time 0 to last measurable time point; C_max=maximum concentration; CV=coefficient of variation as a percentage; ng=nanograms; PK=pharmcokinetics; RE=relative error; SD=standard deviation; T_max= time of maximum concentration.

Figure 2

Notch signature score in hair follicle analysis. (A) Post-dose induced changes in NOTCH signature score in hair follicles of individual patients. Each bar represents individual patient treated with MK-0752 and the height of the bar (Y-axis) is equal to the difference between NOTCH signature score evaluated on patient sample post-treatment minus the baseline (pre-treatment) value of NOTCH signature score measured on a pre-treatment sample from the same patient. Patients are sorted by the post-dose induced changes in NOTCH signature score. Negative values on Y-axis indicate that the signature score was downregulated post-treatment and positive values indicate that signature score increased post-treatment in given patient. Downregulation of NOTCH signalling as captured by NOTCH signature score was observed in 25 out of 29 patients. (B) Scatter plot illustrating dose dependency of post-dose induced changes in NOTCH signature score for individual patients treated with MK-0752 (Y-axis) vs. MK-0752 dose (in mg) on X-axis. Each dot represents a patient. Data are shown for 18 patients with both pre- and post-dose profiling data available in hair follicle samples.