Originally published as JCO Early Release 10.1200/JCO.2005.03.0981 on November 21 2005

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Phase I Dose-Finding Study of Weekly Single-Agent Patupilone in Patients With Advanced Solid Tumors

From the Cancer Institute of New Jersey, New Brunswick; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma Société par Actions Simplifiée, Rueil-Malmaison, France; and Princess Margaret Hospital, Toronto, Ontario, Canada

Address reprint requests to Eric H. Rubin, MD, the Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; e-mail: ehrubin{at}umdnj.edu

PURPOSE: To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients were treated with patupilone (0.3 to 3.6 mg/m²) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration.

RESULTS: Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m² using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m². After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy.

CONCLUSION: Patupilone is well tolerated when administered at a dose of 2.5 mg/m², using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.

Supported by Novartis Pharmaceuticals Corp, East Hanover, NJ.

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

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