Phase I trial of vinorelbine and sorafenib in metastatic breast cancer (MBC).

Abstract

e13576 Background: Vinorelbine, a semisynthetic vinca alkaloid, at 20–25 mg/m2 has a response rate of 15–30% for second line therapy of MBC. Sorafenib is an oral multi-kinase inhibitor against the tyrosine kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Flt-3 and c-Kit receptors. In preclinical studies, sorafenib demonstrated antitumor activity by inducing complete tumor stasis in a variety of tumor types through the Raf/MEK/ERK pathway. In the NCI H460 cell line for NSCLC tumor xenograft, synergy between vinorelbine and sorafenib were observed. Methods: Eligibility include: MBC with adequate end-organ function and performance status (<2) with up to two lines of prior chemotherapy regimens. Intravenous vinorelbine on days 1, 8, 15 and oral sorafenib twice daily each 28-day cycle were given. Dose escalation using 3+3 design was determined based on course 1 toxicities. Vinorelbine was started at 20 mg/m2 and sorafenib at 200 mg. Tumor response was evaluated every two cycles by RECIST. Results: 11 patients were enrolled from 1/09 to 6/09 with a median age of 59 years (range 39–70). Prior chemotherapy regimens were 1/6/4 patients with 0/1/2 prior regimens. Dose limiting toxicities (DLT) on the second dose level, vinorelbine 25 mg/m2 and sorafenib 200 mg twice daily, were grade 3 hand-foot skin reactions in 1 and grade 3 febrile neutropenia in 2 out of 5 patients, establishing the maximum tolerated dose (MTD) as vinorelbine 20 mg/m2 and sorafenib 200 mg twice daily. At the MTD, 6 patients were treated with 1 patient having grade 3 treatment-related toxicities (low sodium, neutropenia) during course 1. Additional grade 3 or 4 toxicities noted (in subsequent cycles) at the MTD include hypertension (2), neutropenia (1), and fatigue (1). The median number of cycles delivered at the MTD was 7 (range 2- 12+). We observed 1 partial response (PR) and 3 stable diseases (>4 months) at the MTD, with 1 additional stable disease at the DLT level. Conclusions: We established the phase II MTD as vinorelbine 20 mg/m2 and sorafenib 200 mg twice daily. With acceptable toxicity and encouraging initial response, a phase II trial is now on-going. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx