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

Abstract

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.

Preclinical efficacy spectrum and pharmacokinetics of ixabepilone

“…This is supported by the favorable half-life of ixabepilone in humans (35 h) seen in a phase I dose-finding study [33]. The favorable clinical pharmacokinetic characteristics of ixabepilone are further demonstrated by the finding in phase I clinical studies that AUC of ixabepilone at the approved dose of 40 mg/m 2 (1,760-2,560 ng h/ml, 3.5-5.1 lM h) was higher than that of patupilone (204-237 ng h/mL, over a range of administration schedules) [33][34][35]38]. It is also worth noting that this exposure level is similar to those produced in mice at therapeutically efficacious doses (Fig.…”

Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: results of a phase I trial

“…Diarrhoea has rarely been reported with sagopilone treatment, although it is a DLT of patupilone and is frequently observed with ixabepilone (Low et al, 2005;Rubin et al, 2005). Nausea and vomiting were mild-to-moderate and easily manageable with standard antiemetics.…”

The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

“…Patupilone has been shown to have clinical activity in patients with advanced solid tumors [58] and is being evaluated in CRPC patients. In a phase II study, 45 patients who were chemotherapy naïve or had received one prior chemotherapy regimen for metastatic CRPC were treated with patupilone, 2.5 mg/m 2 administered as a 5-minute i.v.…”