Originally published as JCO Early Release 10.1200/JCO.2006.10.0784 on July 2 2007

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Phase II Trial of Ixabepilone, an Epothilone B Analog, in Patients With Metastatic Breast Cancer Previously Untreated With Taxanes

Neelima Denduluri, Jennifer A. Low, James J. Lee, Arlene W. Berman, Janice M. Walshe, Ujala Vatas, Catherine K. Chow, Seth M. Steinberg, Sherry X. Yang, Sandra M. Swain

From the Breast Cancer Section, Medical Oncology Branch and Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis; Diagnostic Radiology Department, Warrant G. Magnuson Clinical Center; National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, Bethesda, MD; Washington Cancer Institute, Washington Hospital Center, Washington, DC; and Yale Cancer Center, Yale University School of Medicine, New Haven, CT

Address reprint requests to Sandra M. Swain, MD, Washington Cancer Institute, Washington Hospital Center, 110 Irving St NW, Washington, DC 20010; e-mail: sandra.m.swain{at}medstar.net

Purpose: Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer.

Patients and Methods: Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m²/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated -tubulin, tau-1, and p53 expression when possible.

Results: Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor -tubulin acetylation after treatment. Baseline or cycle 2 acetylated -tubulin, tau-1, or p53 expression did not correlate with clinical response.

Conclusion: Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.

published online ahead of print at www.jco.org on July 2, 2007.

Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

Presented in part at the 41st and 42nd Annual Meetings of the America Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and June 2-6, 2006, Atlanta, GA, respectively.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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