Phase IB study of primary chemotherapy with paclitaxel, gemcitabine, and sunitinib in patients with HER2-negative stage II/III breast cancer.

Abstract

685 Background: The combination of paclitaxel (P) and gemcitabine (G) was previously evaluated in the neoadjuvant setting and showed high efficacy with relatively mild toxicities (Inv New Drugs 2010). For HER2-negative early breast cancer (EBC), a phase IB trial was undertaken to evaluate sunitinib, an oral multi-targeted tyrosine kinase inhibitor, in combination with PG. The primary endpoint was to determine the recommended dose (RD) and maximum tolerable dose (MTD). Secondary endpoints included toxicity, pCR rate, progression-free survival (PFS), and overall survival. Methods: Eligible pts had potentially operable EBC and ECOG PS 0 or 1. Pts enrolled into sequential cohorts of “3 + 3” design. Dose level 1 cohort received paclitaxel 80 mg/m2 and gemcitabine 1,000 mg/m2 IV D1 and D8 with sunitinib 25 mg/day D2-D15 every 3 weeks preoperatively for 6 cycles. The doses of paclitaxel, gemcitabine, and sunitinib were 80/1,200/25 and 80/1,200/37.5 for dose level 2 and dose level 3 cohorts, respectively. We are going to present the outcomes of the primary endpoint. To determine the MTD, only dose limiting toxicity (DLT) occurring during the first cycle of treatment was considered. Results: 15 pts (6-dose level 1, 6-dose level 2, and 3-dose level 3 cohorts) were enrolled between Mar to Nov 2009. Pt characteristics included median age 48 (range 31-67); stage (1-IIB, 8-IIIA and 6-IIIC); ER and/or PR (9-positive and 6-negative); HER2 (1- positive and 14- negative). One HER2+ pt was enrolled based on HER2 immunohistochemistry 1+ positivity which later showed HER2 FISH-positivity. This pt was included in the analysis for the primary endpoint since she completed the first cycle. DLTs were: 1-delayed recovery of G3 neutropenia and 1-G3 febrile neutropenia of 3 pts assigned to dose level 3 cohort; 1-G3 skin rash and 1-G3 febrile neutropenia of 6 pts with dose level 2 cohort; no DLTs observed in 6 pts with dose level 1 cohort. Conclusions: MTD was determined at dose level 2. Based on this phase IB trial, the RD for phase II trials is paclitaxel 80 mg/m2 and gemcitabine 1,000 mg/m2 IV D1 and D8 with sunitinib 25 mg/day D2-D15 every 3 weeks. Supported by NCC Grant No 0910320-1. No significant financial relationships to disclose.