Phase I Study of Pazopanib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumors

Abstract

Purpose. To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.Patients and Methods. Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m 2 ) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

“…A drug-drug interaction was expected, because paclitaxel is a substrate for CYP2C8 and CYP3A4, and pazopanib is a weak inhibitor of CYP3A4 and CYP2C8. The extent of the interaction observed in this study appears similar to that previously reported for pazopanib in combination with paclitaxel administered on a weekly schedule (25), and in combination with paclitaxel and carboplatin (23) administered with various doses of pazopanib. Collectively, these studies suggest that coadministration of pazopanib results in a consistent increase in systemic exposure to paclitaxel regardless of the paclitaxel dose regimen and pazopanib doses investigated.…”

“…Previous studies demonstrated that pazopanib could not be readily combined with paclitaxel 175 mg/m 2 and carboplatin area under the plasma drug concentration curve (AUC) 5 administered every 3 weeks at doses higher than pazopanib 200 mg (23,24). However, it was feasible to administer pazopanib 800 mg with a weekly regimen of paclitaxel 80 mg/m 2 , which resulted in a 26% higher geometric mean paclitaxel AUC that was similar to the systemic exposure of a paclitaxel dose of 100 mg/m 2 (25). This study was designed to evaluate the safety of pazopanib in combination with paclitaxel administered every 3 weeks, and to determine the recommended phase II dose for this combination in the first-line setting in patients with advanced solid tumors.…”

Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors

“…Coadministration of pazopanib 200 mg (n ¼ 14) and 400 mg (n ¼ 8) once daily with paclitaxel 175 mg/m 2 and carboplatin every 21 days decreased paclitaxel clearance by 30% and 17%, respectively, and increased paclitaxel C max by approximately 40%. Mean paclitaxel clearance decreased by 14% and mean paclitaxel C max increased by 36% after administration of pazopanib 800 mg once daily and paclitaxel 80 mg/m 2 in a weekly regimen (18). These results indicate that maximal inhibition of paclitaxel clearance is achieved at pazopanib doses at or below 200 mg.…”

“…A phase I trial had previously shown that administration of pazopanib at 800 mg once daily reduced paclitaxel clearance by approximately 14% (18). Therefore, paclitaxel 175 mg/m 2 and carboplatin AUC6 administered intravenously every 21 days and pazopanib 800 mg once daily were chosen as the starting doses to achieve a predicted systemic exposure to paclitaxel similar to that following administration of paclitaxel 200 mg/m 2 and carboplatin in the absence of pazopanib.…”

First line treatment of advanced non-small-cell lung cancer – specific focus on albumin bound paclitaxel

“…Moreover, the drug-drug interaction may not always be clinically relevant (eg, minimal pharmacokinetic changes from clindamycin-paclitaxel combination and minimally increased plasma paclitaxel when given in combination with pazopanib). 52,53 In patients with hepatic dysfunction, the same dose modification scheme recommended for sb-paclitaxel is safe and feasible for nab-paclitaxel. 54 …”