P1-17-09: A Phase 1/2 Dose-Escalation Study of SAR245408 (S08) or SAR245409 (S09) in Combination with Letrozole (L) in Subjects with Hormone Receptor-Positive and HER2−Negative (HR+/HER2−) Breast Cancer (BC) Refractory to a Nonsteroidal Aromatase Inhibitor (AI).

Background: Upregulation of PI3K activity is a common molecular mechanism involved in resistance to AIs. S08 is a potent, orally bioavailable, pan-PI3K inhibitor. S09 is a potent, orally bioavailable inhibitor of PI3K which also possesses mTOR inhibitory activity. Both compounds exhibit robust PI3K and ERK pathway inhibition in paired human tumor biopsy samples from phase 1 studies (Edelman G, et al . ASCO 2010; Brana I, et al . ASCO 2010). Methods: This ongoing, open-label, multicenter, phase 1/2 study (NCT01082068) was designed to evaluate the safety and tolerability of L in combination with either S08 (Arm 1) or S09 (Arm 2). Eligible female patients (pts) were ≥18 yrs, ECOG PS 0–1, with advanced or recurrent HR+/HER2− BC whose disease is refractory to nonsteroidal AIs. Phase 1 used an ascending 3+3 dose-escalation design and pts were accrued to each arm until no more than 1/3 pts or ≥33% of 3–6 pts at a given dose level experienced a dose-limiting toxicity (DLT) during the first 28-day cycle. Pts were alternately assigned to Arm 1 or Arm 2 and received 2.5 mg L PO (qd) in combination with different dose levels of either S08 (Arm 1; starting dose 200 mg tablets, PO, qd) or S09 (Arm 2; starting dose of 30 mg capsules, PO, bid). After reaching a preliminary maximum tolerated dose (MTD) for each combination, pts will accrue to the phase 2 portion of the study. A two-stage design will be used evaluate the phase 2 co-primary endpoints of ORR and PFS. Each arm will be evaluated independently and no formal comparisons between arms are planned. Results: As of June 1 st 2011, 17 pts were enrolled to Arm 1 (8 pts) or Arm 2 (9 pts). Median age was 54 yrs. Based on preliminary data, the adverse event profile in both arms were similar to those reported in the single agent phase I studies for S08 and S09 respectively. SAEs reported in Arm 1 (2 subjects) included 2 cases of Gr1 pneumothorax and 1 Gr4 pneumonitis; in Arm 2 (2 subjects) included Gr4 lumbar pain and Gr4 elevation of ALT and AST. No DLTs were reported in Arm 1 while one DLT (Gr3 skin rash) was reported in Arm 2 at a dose level of S09 50 mg bid (table 1). Arm 1 dosing data from S08 400 mg qd + L 2.5 mg qd dose level (maximum dose level allowed per protocol) will be completed by August 2011. For Arm 2, the MTD was S09 50 mg bid + L 2.5 mg, qd. Discussion. Both S08 and S09 can be combined with L, and maximal doses for both combinations were established. Additional safety, PK and efficacy data will be presented from phase 1. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-09.