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Ixabepilone was approved on October 16, 2007, as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine; and in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
Ixabepilone is a microtubule inhibitor that belongs to the epothilone class of antineoplastic agents. Ixabepilone binds to beta-tubulin subunits on microtubules, suppressing microtubule instability and thereby blocking the mitotic phase of cell division. This agent was approved on October 16, 2007, as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine; and in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
Efficacy. The efficacy of ixabepilone in combination with capecitabine was assessed in an open-label, multicenter, multinational, randomized trial in which patients were assigned to either intravenous (IV) ixabepilone 40 mg/m2 every 3 weeks plus capecitabine 1,000 mg/m2 BID for 2 weeks followed by 1 week of rest or to capecitabine 1,250 mg/m2 BID for 2 weeks followed by 1 week of rest. Eligible patients (N=752) had been treated previously with anthracyclines and taxanes and were required to have demonstrated tumor progression or resistance to these agents. Patients in the combination therapy group received a median of 5 treatment cycles; patients in the monotherapy group received a median of 4 treatment cycles. The primary end point was progression-free survival (PFS). Other end points included objective tumor response, time to response, response duration, and overall survival. Patients treated with combination therapy demonstrated a statistically significant improvement in PFS versus those treated with capecitabine alone (combination therapy, 5.7 mo [median]; monotherapy, 4.1 mo [median]; HR=0.69; 95% CI, 0.58–0.83; P<.0001). The efficacy of ixabepilone as monotherapy was assessed in a multicenter, single-arm trial in which ixabepilone was administered at a dose of 40 mg/m2 over 3 hours every 3 weeks. Eligible patients (N=126) had tumors that had recurred or progressed after ≥2 chemo-therapy regimens including an anthracycline, a taxane, and capecitabine. Patients received a median of 4 treatment cycles. Independent radiologic review demonstrated an objective tumor response rate of 12.4% (95% CI, 6.9%–19.9%) and a median duration of response of 6.0 months (95% CI, 5.0–7.6).
Safety. In clinical trials, peripheral neuro-pathy was observed often in ixabepilone-treated patients. Patients should be monitored for symptoms of neuropathy; those patients experiencing new or worsening symptoms may require a dose reduction or delay. Myelosuppression, primarily manifested as neutropenia, has been observed in patients treated with ixabepilone. In clinical trials, patients with hepatic impairment at baseline experienced greater toxicity with ixabepilone treatment, including occurrences of febrile neutropenia and severe adverse reactions. All patients should be pretreated with a histamine H1 and H2 antagonist approximately 1 hour before ixabepilone infusion to reduce the risk of hypersensitivity reactions. This agent may cause fetal harm in pregnant women. A greater incidence of cardiac adverse reactions, including myocardial ischemia and ventricular dysfunction, was observed among ixabepilone-treated patients than among patients treated with capecitabine alone in clinical trials. The most common adverse events associated with ixabepilone treatment (either as monotherapy or in combination with capecitabine) include peripheral sensory neuropathy, fatigue/ asthenia, nausea, myalgia/arthralgia, alopecia, diarrhea, palmar-plantar erythrodysesthesia syndrome, vomiting, stomatitis/mucositis, anorexia, musculoskeletal pain, constipation, abdominal pain, and nail disorder.