Ixempra (ixabepilone)

Ixempra (ixabepilone) is a semi-synthetic analog of epothilone B. It binds to tubulin and promotes tubulin polymerization and microtubule stabilization, thereby arresting cells in the G2-M phase of the cell cycle and inducing tumor cell apoptosis.

Ixempra is specifically indicated 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. Ixempra monotherapy is specifically indicated for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Ixempra is supplied as as a solution designed for intravenous administration. The recommended initial dose is is 40 mg/m2 administered intravenously over 3 hours every three weeks. Doses for patients with body surface area greater than 2.2 m2 should be calculated based on 2.2 m2.

FDA Approval
FDA approval of Ixempra was based on the results of two clinical trials.

Combination Therapy
This open-label trial enrolled 752 subjects whose disease had rapidly progressed through at least two prior therapies (anthracycline and taxane). Subjects were randomized to receive ixabepilone (40 mg/m2 every 3 weeks) in combination with capecitabine (1000 mg/m2 twice daily for 2 weeks followed by 1 week rest) or capecitabine alone. The combination treatment prolonged progression free survival compared to capecitabine alone (5.7 months vs. 4.1 months), with a statistically significant 25% decrease in the risk of disease progression. An objective response rate was observed in more than twice as many subjects in the combination group compared to control (34.7% vs. 14.3%). The median duration of response was 6.4 months versus 5.6 months.

Monotherapy
This single-arm trial enrolled 126 women who had heavily pretreated, advanced metastatic breast cancer, which had progressed through following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Ixempra was administered at a dose of 40 mg/m2 intravenously over 3 hours every 3 weeks, for a median of 4 cycles. The primary endpoint was objective response rate. Secondary endpoints included duration of response and time to response. Of the enrolled subjects, 113 were response-evaluable. Response results were determined by an independent radiology facility (IRF) and study investigators. The objective response rate was 12.4% determined by the IRF and 18.3% determined by the investigators. Median duration of response was 6.0 months and median time to response was 6.1 weeks.

Adverse events associated with the use of Ixempra monotherapy may include, but are not limited to, the following:

• Peripheral sensory neuropathy
• Fatigue
• Asthenia
• Myalgia/arthralgia
• Alopecia
• Nausea
• Vomiting
• Stomatitis/mucositis
• Diarrhea
• Musculoskeletal pain
• Hematologic abnormalities

The adverse events associated with the use of Ixempra/capecitabine combination treatment may include, but are not limited to, the following:

• Palmarplantar erythrodysesthesia (hand-foot) syndrome
• Anorexia
• Abdominal pain
• Nail disorder
• Constipation
• Hematologic abnormalities

Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to ß-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of aß-II and aß-II microtubules. This arrests the cells in the G2-M phase of the cell cycle and induces tumor cell apoptosis.

Thomas E, Tabernero J, Fornier M, Conté P, Fumoleau P, Lluch A, Vahdat LT, Bunnell CA, Burris HA, Viens P, Baselga J, Rivera E, Guarneri V, Poulart V, Klimovsky J, Lebwohl D, Martin M Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007 Aug 10;25(23):3399-406

Roché H, Yelle L, Cognetti F, Mauriac L, Bunnell C, Sparano J, Kerbrat P, Delord JP, Vahdat L, Peck R, Lebwohl D, Ezzeddine R, Curé H Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007 Aug 10;25(23):3415-20

Denduluri N, Low JA, Lee JJ, Berman AW, Walshe JM, Vatas U, Chow CK, Steinberg SM, Yang SX, Swain SM Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007 Aug 10;25(23):3421-7

Low JA, Wedam SB, Lee JJ, Berman AW, Brufsky A, Yang SX, Poruchynsky MS, Steinberg SM, Mannan N, Fojo T, Swain SM Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology2005 Apr 20;23(12):2726-34

Zhuang SH, Agrawal M, Edgerly M, Bakke S, Kotz H, Thambi P, Rutt A, Balis FM, Bates S, Fojo T A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days. Cancer 2005 May 1;103(9):1932-8

Abraham J, Agrawal M, Bakke S, Rutt A, Edgerly M, Balis FM, Widemann B, Davis L, Damle B, Sonnichsen D, Lebwohl D, Bates S, Kotz H, Fojo T Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003 May 1;21(9):1866-73

For additional information regarding Ixempra or breast cancer, please visit the Ixempra web page.