Phase I/II study of sunitinib (SU) in combination with metronomic dosing of cyclophosphamide (C) and methotrexate (M) in patients (pts) with metastatic breast cancer (MBC).

Abstract

1067 Background: Metronomic chemotherapy has demonstrated antitumor activity in preclinical and clinical studies in a number of solid tumors. The effects of metronomic chemotherapy appear to be enhanced when combined with targeted antiangiogenic agents in vivo, and with bevacizumab in women with MBC. We conducted a phase 1/2 clinical study of daily SU, a potent oral multi- targeted tyrosine kinase inhibitor, in combination with metronomic dosing of oral C and M in patients with MBC. Methods: Pts were treated with a 2-week course of SU monotherapy followed by combination treatment consisting of daily SU, C (50 mg/day), and M (2.5 mg/bid on days 1-2 each week). Eligibility included MBC with any number of prior therapies. In phase 1, SU was dose-escalated in 3 cohorts (12.5, 25, and 37.5 mg/day). In phase 2, all patients received SU 37.5 mg/day in combination with CM. Serial blood work for circulating tumor cells (CTCs) and circulating endothelial cells (CECs) was collected for all patients. Results: A total of 28 pts have been enrolled to date (21 in phase 1; 7 in phase 2). The most common adverse events in phase 1 were grade 3 neutropenia and thrombocytopenia. Other grade 3 toxicities included liver function abnormalities, mucositis, and foot pain. Dose-limiting toxicity at 37.5 mg/day consisted of one grade 4 thrombocytopenia. Of 7 pts enrolled in phase 2, two discontinued treatment due to unacceptable toxicity (treatment delay due to grade 3 neutropenia and thrombocytopenia). Two pts required dose-reductions (grade 3 foot pain; and grade 3 neutropenia and thrombocytopenia). Of the 19 pts receiving either SU 25 mg/day or 37.5 mg/day that were evaluable for response, one (5%) had a confirmed partial response, 9 (47%) had stable disease (3 for greater than 11 months), and 9 (47%) had progressive disease at first restaging. Conclusions: Continuous daily SU 37.5 mg/day in combination with metronomic dosing of CM is associated with hematologic toxicity requiring dose reduction in heavily pretreated pts with MBC. Preliminary data indicate significant clinical activity despite extensive prior therapy. Additional patients will be enrolled at SU 25 mg/d with CM. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer