Epothilone B analog (BMS-247550) at the recommended phase II dose (RPTD) in patients (pts) with gynecologic (gyn) and breast cancers

Abstract

2115 Background & Methods: Epothilones differ from taxanes in biodistribution and mechanisms of resistance. Our prior phase I study (ASCO 2002, abstract#409) established the RPTD of BMS-247550 to be 40mg/m2 as a 1hour infusion every 3 weeks. 42 pts (21 gyn, 13 breast, 8 other) were entered at this dose level: male/female 4/38, median age 56 years (range 29–81), performance status 0–1, median # prior cytotoxic regimens 3 (range 0–8). Results: Neutropenia and neuropathy were the most frequent toxicities. Grade ≥3 neutropenia occurred in 19 pts (4 with fever on cycle(C)1 day(D)14, C5D6, C2D8, and fatal sepsis in an 81 y/o on C1D7) leading to 8 dose reductions. 10 pts (9 on prior taxanes or cisplatin) developed new onset grade ≥2 neuropathy (2 grade 3) after a median of 3 cycles (range 2–8). 1 previously untreated pt developed neuropathy after 8 cycles. All resolved to grade ≤ 1 by the next cycle, including 1 who refused further therapy. Other toxicities: thrombocytopenia, anemia, fatigue, alopecia, and gastrointestinal (e.g. nausea, vomiting, abdominal pain, diarrhea) were rarely grade 3. Hypersensitivity reaction occurred in 2 pts on cycles 2 and 3 with successful rechallenge. Pharmacokinetic/toxicity and other lab correlates (e.g. microtubule bundling) are under analysis. Median cycle # was 3 (gyn), 3 (breast), and 2.5 (other). Gyn (all taxane pretreated) partial response (PR)= 2 (1/14 ovarian, 1/3 endometrial primaries); breast (11/13 taxane pretreated) PR= 4 (all taxane pretreated). Conclusion: BMS-247550 is tolerated at 40mg/m2 every 3 weeks as a 1hr infusion, and has activity in gyn and breast cancers pretreated with taxanes. Supported in part by N01-CM17103, U01-CA76642, M01 RR00096, & P30 CA16087 No significant financial relationships to disclose.