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Lookup NU author(s): Professor Ruth Plummer
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
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 3-3 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*3*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/m2 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. (C) 2014 AACR.
Author(s): Kendra KL, Plummer R, Salgia R, O'Brien MER, Paul EM, Suttle AB, Compton N, Xu CF, Ottesen LH, Villalona-Calero MA
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Year: 2015
Volume: 14
Issue: 2
Pages: 461-469
Print publication date: 01/02/2015
Online publication date: 10/12/2014
Acceptance date: 25/11/2014
Date deposited: 15/12/2015
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1535-7163.MCT-14-0431
DOI: 10.1158/1535-7163.MCT-14-0431
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