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

Abstract

This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3þ3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8 Ã 3 Ã 3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m 2 plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of !12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m 2 every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non-small cell lung cancer that suggest further evaluation of this combination is warranted.

Developments in targeted therapy in melanoma

“…None of the studies published so far reported significant clinical benefit in advanced BRAF wt melanoma patients. 49,50 A recent single-center pilot study investigating the metabolic response, the early cytokine and chemokine profile and the histological findings of metastatic tissue under pazopanib and paclitaxel in the second line setting showed moderate efficacy. 51 17 patients with stage III or IV melanoma were included.…”

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

“…This dosing regimen resulted in an increase of 26 and 31 % in paclitaxel AUC and C max values, respectively [38,49]. Further, in another more recent study, the co-administration of pazopanib and paclitaxel resulted in a 38 % increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the maximum-tolerated dose (MTD) of paclitaxel 150 mg/m 2 plus pazopanib 800 mg [50].…”

PharmGKB summary

“…In addition to being metabolized by CYP3A4, pazopanib also inhibits CYP3A4 [11]. In a phase 1 study of pazopanib plus paclitaxel (which is also metabolized by CYP3A4 and by CYP2C8), authors observed an approximately 40% increase in paclitaxel exposure whereas pazopanib exposure was not related to paclitaxel dose [12]. Furthermore, in the same study of pazopanib plus paclitaxel, one patient who was taking simvastatin (mostly metabolized by CYP3A4 with some involvement of CYP2C8) and had reduced activity of CYP2C8 (CYP2C8*3*3) experienced hepatotoxicity that resolved after simvastatin was withdrawn [12].…”

“…In a phase 1 study of pazopanib plus paclitaxel (which is also metabolized by CYP3A4 and by CYP2C8), authors observed an approximately 40% increase in paclitaxel exposure whereas pazopanib exposure was not related to paclitaxel dose [12]. Furthermore, in the same study of pazopanib plus paclitaxel, one patient who was taking simvastatin (mostly metabolized by CYP3A4 with some involvement of CYP2C8) and had reduced activity of CYP2C8 (CYP2C8*3*3) experienced hepatotoxicity that resolved after simvastatin was withdrawn [12]. This suggests that the hepatotoxicity was most likely related to altered simvastatin metabolism, and that when there is competition for CYP3A4 and CYP2C8 pazopanib metabolism is favored over either paclitaxel or simvastatin.…”