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In vivo Evaluation of Ixabepilone (BMS247550), A Novel Epothilone B Derivative, against Pediatric Cancer Models

Authors' Affiliations: Departments of ¹ Molecular Pharmacology and ² Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee; and ³ Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol Myers Squibb, Co., Princeton, New Jersey

Requests for reprints: Peter J. Houghton, Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, P.O. Box 318, Memphis, TN 38105. Phone: 901-495-3463; Fax 901-521-1668; E-mail: peter.houghton{at}stjude.org.

Purpose: Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types. The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an epothilone B derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models.

Experimental Design: Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four), Wilms' tumors (six), osteosarcoma (four), or brain tumors (seven). Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg).

Results: At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved 50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms' tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone. Pharmacokinetics following single i.v. administration of ixabepilone at its MTD (10 mg/kg) were biexponential with C_max of 12.5 µmol/L, elimination half-life of 19.2 hours, and total area under the curve of 5.8 µmol/L-h. The achieved drug exposure of ixabepilone at this efficacious MTD dose level in mice is similar to those achieved in patients given the recommended phase II dose of 40 mg/m² by either 1- or 3-hour infusion every 3 weeks, a regimen that has shown significant anticancer activity in phase II clinical trials in adult patients.

Conclusions: Administered at doses ranging from 66% to 100% of its MTD in mice, the epothilone B derivative ixabepilone shows broad spectrum activity against a panel of pediatric tumor xenograft models. Pharmacokinetic analysis indicates that the systemic ixabepilone exposure achieved in mice at its MTD is similar to that achieved in patients at the recommended phase II dose of 40 mg/m² administered every 3 weeks. Importantly, the present results showed a clear distinction in sensitivity of pediatric solid tumors to this epothilone derivative compared with paclitaxel.

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