A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer.

purposeThe purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. MATERIALS AND

methodsPatients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m(2), and the dose of HM30181A was escalated from 30-210 mg/m(2).

resultsA total of twenty-four patients were enrolled. Only one patient experienced a doselimiting toxicity-a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m(2) of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m(2) and the area under the curve of plasma concentration- time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m(2). The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m(2). The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m(2). Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease.

conclusionThe study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m(2).