title: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer.
abstract: OBJECTIVE
  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.
  
  
  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 alpha-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 alpha-tubulin were increased in tumor biopsies performed after ixabepilone therapy.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889-5015, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Suparna B
authors.initials: SB
authors.lastname: Wedam
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Arlene W
authors.initials: AW
authors.lastname: Berman
authors.forename: Adam
authors.initials: A
authors.lastname: Brufsky
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Yang
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Poruchynsky
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Nitin
authors.initials: N
authors.lastname: Mannan
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077143:Docetaxel; D034261:Epothilones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008875:Middle Aged; D009420:Nervous System / Q000187:drug effects / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D043823:Taxoids / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D034261:Epothilones; D043823:Taxoids; D000077143:Docetaxel; C430592:ixabepilone; D017239:Paclitaxel