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Background: BMS-247550 is a novel derivative of epothilone B which induces tubulin polymerization and G2/M arrest leading to apoptosis in cancer cells, with preclinical activity in taxane-sensitive and -resistant tumors. Neurotoxicity is common and is dose limiting, generally more pronounced when BMS-247550 is administered on short infusion schedules every 3 weeks (wks). After evaluating a continuous weekly schedule, we introduced a one-week (wk) break in an attempt to reduce fatigue and neurotoxicity. Methods: The primary objective of this phase I study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), recommended phase II dose (RD) and pharmacokinetics of BMS-247550 administered on a novel weekly schedule with a one wk break q 4 wks. Since BMS-247550 is formulated with Cremophor®, potential for hypersensitivity reactions does exist. All patients were premedicated with dexamethasone 20 mg PO 6 and 12 hrs before treatment, as well as diphenhydramine 50 mg IV and ranitidine 50 mg IV 30 min prior to infusion. BMS-247550 was administered as a 1-hr infusion on a weekly for 3 wks followed by a one-wk break schedule. Results: 13 pts were enrolled (6 M/ 7 F), median age 61 (range 34 - 73) and tumor types: hormone refractory prostate cancer (HRPC) (6), breast (5), adrenal (1), and small cell lung cancer (1). A total of 43 courses were given, median 3/pt (range 1-9). All pts had received prior chemotherapy, including taxanes in 11 of them; median no. of prior regimens 4 (range 2-9). BMS-247550 doses were: 15 mg/m2 (7 pts / 27 courses), and 20 mg/m2 (6 pts/16 courses). The starting dose had produced minimal toxicity in a previous trial with a continuous weekly schedule at our institution. Infection with grade (G) 3 neutropenia was the DLT in 1 pt at 15 mg/m2, who experienced G3 sensory-motor neuropathy and G3 fatigue after 4 courses and discontinued therapy. There was no toxicity which precluded weekly treatment on-time during course 1. One pt experienced a brief episode of G3 fatigue after course 2 at 20 mg/m2 and 2 pts had G3 hyperglycemia most probably related to steroid therapy. All other drug-related toxicities were mild-moderate (≤ G2) including nausea, anorexia, diarrhea, alopecia, fatigue, myalgias, anemia, neutropenia and thrombocytopenia. Cumulative sensory neuropathy was the reason for termination of therapy in 2 out of 6 pts who received > 3 courses. The MTD was proposed as 20 mg/m2. One PR according to PSA criteria was observed in a pt with HRPC. Five pts had SD ≥ 4 months: HRPC (4) and breast (1). Conclusions: Prolonging infusion time of weekly BMS-247550 and introducing treatment breaks is associated with tolerable neurotoxicity. This new schedule is active for patients with taxane-resistant tumors and is easily administered.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]