Abstract P6-15-03: Phase Ib Trial of the Gamma Secretase Inhibitor (GSI), MK-0752 Followed by Docetaxel in Locally Advanced or Metastatic Breast Cancer

Abstract

Abstract Background: The cancer stem cell hypothesis asserts that there is a small population of cells within a tumor that has the ability to self renew and differentiate, and that these cells drive tumor growth and metastasis but are resistant to conventional cytotoxic chemotherapy. Pathways involved in stem cell growth and differentiation are viable targets for new anticancer therapies. One such pathway, Notch, is inhibited by GSIs which prevent translocation of Notch intracellular domain to the nucleus. Inhibition of GS concurrent with chemotherapy might improve disease control by targeting both stem cells and differentiated cells within the tumor. This Phase Ib clinical trial was designed to determine the MTD of the GSI, MK-0752, in combination with docetaxel, and to evaluate an effect on stem cell markers in serial tumor biopsies. Methods: Eligible subjects had metastatic breast cancer or locally advanced breast cancer that did not respond to anthracycline therapy. Patients with disease that progressed on a taxane, or who had received a taxane within 6 months were excluded. MK-0752 was administered orally on days 1-3 of each 21-day cycle of therapy, in escalating doses. Dose levels (mg/day) 1=300; 2=450; 3=600; and 4=800. Docetaxel 80 mg/m2 IV was administered day 8, with pegfilgrastim day 9 each cycle. Treatment was continued until disease progression, unacceptable toxicity, or symptomatic deterioration. The trial was monitored using the Time to Event Continual Reassessment Method, targeting a 20% toxicity rate. Tumor biopsies were performed at baseline, after 1 cycle, and at treatment completion in a subset of patients. Results: 30 patients were enrolled between Mar 2008 and Jan 2010. Dose limiting toxicities of the combination included diarrhea, hand-foot syndrome, and LFT elevation. 20/30 patients experienced Grade 1 or 2 fatigue. The final estimates and confidence intervals for the probability of dose limiting toxicity at each dose level are summarized in the table: Probability = probability of dose-limiting toxicity 20 enrolled patients had measurable disease by RECIST criteria. Of these, 9 had PR, 8 SD, and 3 PD, for an estimated RR of 45% to the combination. 2 patients have been maintained on therapy in excess of 22 cycles. Conclusions: Dose level 3 was identified for further study in a Phase II randomized trial. Efficacy of docetaxel was not inhibited by MK-0752, as a 45% RR in patients with measurable disease was observed. There is intriguing long term disease stabilization in 2 patients. Evidence of an effect of the combination on the stem cell population was apparent on serial biopsies as presented at SABCS Dec 2009 (Abstract # 48); additional biopsy data will be presented. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-03.