Mullaney, Brian P.

660 Background: Patients (pts) with MBC previously treated with an anthracycline, a taxane and capecitabine have very limited treatment options. Ixabepilone is the first semi-synthetic analog in a new class of cytotoxic agents, the epothilones. It has shown activity in breast and other tumors. Methods: This single-arm Phase II trial was designed to assess the objective response rate (ORR) of ixabepilone in MBC pts resistant to an anthracycline, a taxane and capecitabine. Pts had to be resistant to each regimen as defined by progression within 8 wks in the metastatic setting or recurrence within 6 months (mo) of adjuvant anthracycline/taxane. Capecitabine must have been given in the metastatic setting. Response was assessed by an independent radiology review committee (IRRC; primary analysis) and by each investigator per RECIST. Ixabepilone was administered IV at 40 mg/m2 over 3 h every 3 wks. Results: A total of 126 pts were treated: median age 51 yrs (range 30–78), Karnofsky PS range 70–100% and 70% pts had baseline liver metastases. 88% pts had received ≥2 prior metastatic regimens. 113 pts were response evaluable (had target disease by IRRC and met eligibility criteria for prior therapy). Median duration of response was 5.3 mo. Stable disease (SD) was the best response in 50% pts and 14% pts had SD ≥6 mo duration. Median PFS was 3.1 mo. Pts received a median of 4 cycles (range 1–16). The most common Grade 3/4 treatment-related adverse events were sensory peripheral neuropathy (14%), fatigue (10%), myalgia (7%), and stomatitis (6%). The neuropathy was cumulative and reversible. Time to resolution (to Grade 1 or baseline) for Grade 3/4 neuropathy was 5.4 wks by Kaplan-Meier analysis. Grade 3/4 neutropenia and thrombocytopenia occurred in 54% and 7% of pts, respectively. Febrile neutropenia was reported in 3% pts. Conclusions: Ixabepilone demonstrates promising clinical activity and a manageable safety profile in patients highly resistant to standard chemotherapy. [Table: see text] [Table: see text]

Purpose To evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study. Patients and Methods Patients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m2 monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF). Results A total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD ≥ 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received ≥ eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks. Conclusion Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.