A Phase 2 Trial Of Bms-247550 (Ixabepilone), An Epothilone B Analog, Given Daily X 5 In Breast Cancer

545 Background: The epothilones are nontaxane microtubule stabilizers which have shown promising activity in 1- and 3-hour infusions every 3 weeks. Grade 3 neuropathy was reported in 12–37% of breast cancer patients. Methods: Patients with metastatic or locally advanced breast cancer and measurable disease were stratified by prior taxane therapy. Patients were treated with BMS-247550 at 6 mg/m2/d IV d1–5, every 3 weeks. A novel battery of tests to assess neurotoxicity included subjective questionnaires, balance testing, Semmes-Weinstein monofilaments, the Jebsen Test of Hand Function, the Grooved Peg Board Test, and nerve conduction studies. Results: Forty-two patients received 174 cycles. Prior taxane-treated patients received 0–10 (median 2) prior chemo regimens; taxane naïve patients received 0–1 (median 0) prior chemo regimens. Grade 3 and 4 toxicities per patient: neutropenia (32%, grade 4: 20%), febrile neutropenia (10%, all grade 3), thrombocytopenia (5%), fatigue (15%), diarrhea (12%), nausea/vomiting (5%), constipation (2%), myalgia/arthralgia (2%), sensory neuropathy (grade 3: 2%, all grades: 40%). Of the 33 prior taxane-treated patients, there are 6 (18%) PR, 12 (40%) SD, 12 (40%) PD, 3 (9%) too early to evaluate (TE). Of the 9 taxane-naive patients, 4 (44%) PR, 4 (44%) SD, and 1 (11%) TE. One patient was removed from study due to grade 3 neurotoxicity, and 2 pts for other grade 3/4 toxicities. Eleven of 30 (37%) patients with no baseline neuropathy developed grade 1; 3 (10%) of 30 developed grade 2; 1 (3%) developed grade 3. Only 1 of 12 (8%) patients with baseline grade 1 developed grade 2 neuropathy. Increased sensory neuropathy was associated with self-reported worsening of pain intensity (p<0.01), but not with the other neurotoxicity tests evaluated, and further analyses are ongoing. Eight patients have had pre- and post-treatment biopsies. Tubulin stabilization will be assessed by examining post-translational modifications of tubulin on pre- and post-therapy biopsies by Western blot. Conclusions: Responses are seen in both prior taxane-treated and taxane naïve patients. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb