Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Metastatic and Locally Advanced Breast Cancer

Purpose Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Patients and Methods Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated α-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Results Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated α-tubulin were increased in tumor biopsies performed after ixabepilone therapy. Conclusion An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.