Phase I Dose-Finding Study Of The Gamma Secretase Inhibitor Pf-03084014 (Pf-4014) In Combination With Docetaxel In Patients (Pts) With Advanced Triple-Negative Breast Cancer (Tnbc).

1068 Background: Gamma secretase is a key component of the Notch signaling pathway, which is involved in cancer cell biology and survival in various tumor types including breast cancer. PF-4014 demonstrated synergistic anti-tumor activity with docetaxel in preclinical models, supporting clinical development of this combination. Methods: Pts received PF-4014 orally, twice daily (BID) in combination with docetaxel Q3W, following a matrix design with the modified toxicity probability interval method. The purpose was to estimate the maximum tolerated dose (MTD); the primary endpoint was first-cycle dose-limiting toxicity (DLT). The MTD was defined as the highest, tested dose with a first-cycle DLT rate u003c 0.33. Results: In all, 22 female pts received treatment; mean age 50 yrs (27-76 yrs). The most common treatment-related adverse events (AEs) were neutropenia (91%), fatigue (77%), leukopenia (68%), nausea (64%), alopecia (59%), diarrhea (59%), and anemia (50%), which were generally mild to moderate in severit...