A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer
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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 paclitaxeland HM30181A, which is an inhibitor of P-glycoprotein, in patients with advancedcancers. Materials and MethodsPatients with advanced solid tumors received standard therapy were given the studydrug at escalating doses, using a 3+3 design. The study drug was orally administeredon days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel wasescalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from30-210 mg/m2. ResultsA total of twenty-four patients were enrolled. Only one patient experienced a doselimitingtoxicity—a grade 3 neutropenia that persisted for more than 2 weeks, at 240mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration wasobtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration-time from 0 to the most recent plasma concentration measurement of paclitaxelwas reached at a dose level of 420 mg/m2. The absorption of paclitaxel tendsto be limited at doses that exceed 300 mg/m2. The effective plasma concentrationof paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients wereevaluated; 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 concentrationof paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300mg/m2.
Abstract
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 paclitaxeland HM30181A, which is an inhibitor of P-glycoprotein, in patients with advancedcancers. Materials and MethodsPatients with advanced solid tumors received standard therapy were given the studydrug at escalating doses, using a 3+3 design. The study drug was orally administeredon days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel wasescalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from30-210 mg/m2. ResultsA total of twenty-four patients were enrolled. Only one patient experienced a doselimitingtoxicity—a grade 3 neutropenia that persisted for more than 2 weeks, at 240mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration wasobtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration-time from 0 to the most recent plasma concentration measurement of paclitaxelwas reached at a dose level of 420 mg/m2. The absorption of paclitaxel tendsto be limited at doses that exceed 300 mg/m2. The effective plasma concentrationof paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients wereevaluated; 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 concentrationof paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300mg/m2.
참고문헌 (24)
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