Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
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Authors: | A R Tan A Dowlati M N Stein S F Jones J R Infante J Bendell M P Kane K T Levinson A B Suttle H A Burris III |
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Affiliation: | 1.Rutgers Cancer Institute of New Jersey,195 Little Albany Street, New Brunswick, NJ 08903, USA;2.University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, USA;3.Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Nashville, TN 37203, USA;4.GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA |
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Abstract: | Background: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.Methods: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m−2)/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.Results: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).Conclusions: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m−2 in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance. |
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Keywords: | pazopanib lapatinib paclitaxel vascular endothelial growth factor receptor tyrosine kinase inhibitor EGFR and HER2 tyrosine kinase inhibitor |
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