Cancer Res Treat.  2014 Jul;46(3):234-242.

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

• Lee HJ
• Heo DS
• Cho JY
• Han SW
• Chang HJ
• Yi HG
• Kim TE
• Lee SH
• Oh DY
• Im SA
• Jang IJ
• Bang YJ

Abstract

PURPOSE
The 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 METHODS
Patients 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/m2, and the dose of HM30181A was escalated from 30-210 mg/m2.
RESULTS
A total of twenty-four patients were enrolled. Only one patient experienced a dose-limiting toxicity-a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained 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 paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease.
CONCLUSION
The 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/m2.

Keyword

Paclitaxel; P-glycoprotein; Administration; Oral; Clinical Trial; Phase 1; Pharmacokinetics

MeSH Terms

Absorption
Humans
Maximum Tolerated Dose
Neutropenia
P-Glycoprotein*
Paclitaxel*
Pharmacokinetics
Plasma
P-Glycoprotein
Paclitaxel

Figure

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  Fig. 1. Plasma concentration-time curves of paclitaxel at each dose level.

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  Fig. 2. Linear regression profiles of pharmacokinetic parameters. (A) Dose-AUClast linear regression profiles (slope, 0.753; 95% confidence interval [CI], 0.204 to 1.302). (B) Dose-Cmax linear regression profiles (slope, 0.860; 95% CI, 0.414 to 1.305). AUClast, area under the plasma concentration-time curve from 0 to last time to measure plasma concentration; Cmax, maximum plasma concentration.

Reference

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