This phase I study determined the maximum tolerated regimen and dose-limiting toxicities of pazopanib in combination with weekly paclitaxel, assessed the effect of pazopanib on the pharmacokinetic profile of paclitaxel, and evaluated antitumor activity.
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/m2) 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.
Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m2 paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m2. At the MTR, coadministration of 800 mg pazopanib and 80 mg/m2 paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.
Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m2 when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.