Abstract OT2-3-02: Phase Ib/II study of an oral PI3K/mTOR inhibitor plus letrozole compared with letrozole (L) in pre-operative setting in patients with Estrogen Receptor-positive, HER2-negative early breast cancer (BC): Phase Ib preliminary data.

Background: Acquired hormone independent BC cell growth is associated with upregulation of the PI3K/mTOR pathway in vitro and in neo-adjuvant studies of aromatase inhibition (Ghazoui AACR Breast Cancer Symposium, 2011). Preclinical and clinical studies suggest that the combination of hormone therapy and a PI3K/mTOR inhibitor can restore sensitivity to hormone resistant tumours. Luminal B BCs are more frequently associated with endocrine resistance, hyperactivation of the PI3K signaling pathway, and increased expression of the Ki-67 proliferation marker than Luminal A BCs. This particular population may be a suitable target for PI3K directed therapy. A reduction in Ki-67 in the neo-adjuvant setting by endocrine therapy has been shown to correlate with efficacy of that same therapeutic in the adjuvant setting. Thus, a pre-operative study in high Ki-67-expressing BCs with short term reduction in Ki-67 as a primary endpoint could be used to support a study in the adjuvant setting with a conventional disease free endpoint. Study Design: The study is conducted in 2 phases, a Phase Ib followed by a randomized Phase II. The Phase Ib is designed to assess the tolerability of PF-04691502, an oral PI3K/mTOR antagonist, combined with L in postmenopausal women with ER positive, HER-2 negative advanced BC. A total of 10 patients will be enrolled in this portion of the study. PF-04691502+L will be administered until progression of disease. After up to 2 months of treatment, the safety profile of PF-04691502+L will be evaluated prior to the initiation of the Phase II portion in a pre-operative setting. A total of 204 postmenopausal women with ER positive, HER-2 negative early BC selected based on a high level of Ki-67 (>10%) will be enrolled in the Phase II portion. Patients will be randomized to receive PF-04691502+L or L alone for 6 weeks. The Phase II is designed to test the hypothesis that the addition of PF-04691502 to L can reduce Ki-67 levels after 6 weeks of administration to a greater degree than L alone, thus supporting the concept that the compound might mitigate the intrinsic or acquired resistance to hormonal therapy in a high risk patient population in the adjuvant setting. Patients will undergo 3 sequential core-biopsies (baseline, weeks 2 and 6) to compare the changes in Ki-67 value from baseline to the end of the treatments and to test pharmacodynamic effects associated with PI3K/mTOR pathway modulation. Results: As of May 2012, 8 postmenopausal women with advanced BC were enrolled in the phase Ib. All patients received PF-04691502 8 mg/day and L 2.5 mg/day. Treatment is ongoing in all patients. The combination has a manageable safety profile although the median time of observation is short (47 days). A full set of safety data of patients enrolled in the Phase Ib will be presented. Also pharmacokinetic profile of L alone and in combination with PF-04691502 will be shown. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-02.