Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes.
OBJECTIVE
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.


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/m(2)/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 alpha-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 alpha-tubulin acetylation after treatment. Baseline or cycle 2 acetylated alpha-tubulin, tau-1, or p53 expression did not correlate with clinical response.


CONCLUSIONS
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.
Denduluri
Neelima
N
Breast Cancer Section, Medical Oncology Branch and Biostatistics, Office of the Clinical Director, Center for Cancer Research, National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, Bethesda, MD, USA.
Low
Jennifer A
JA
Lee
James J
JJ
Berman
Arlene W
AW
Walshe
Janice M
JM
Vatas
Ujala
U
Chow
Catherine K
CK
Steinberg
Seth M
SM
Yang
Sherry X
SX
Swain
Sandra M
SM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D018450:Disease Progression; D034261:Epothilones / Q000737:chemistry* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D043823:Taxoids / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D034261:Epothilones; D043823:Taxoids; C430592:ixabepilone; C093788:epothilone B