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Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037836/ https://www.ncbi.nlm.nih.gov/pubmed/24800949 http://dx.doi.org/10.1038/bjc.2014.233 |
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author | Tan, A R Dowlati, A Stein, M N Jones, S F Infante, J R Bendell, J Kane, M P Levinson, K T Suttle, A B Burris III, H A |
author_facet | Tan, A R Dowlati, A Stein, M N Jones, S F Infante, J R Bendell, J Kane, M P Levinson, K T Suttle, A B Burris III, H A |
author_sort | Tan, A R |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4037836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-40378362015-05-27 Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies Tan, A R Dowlati, A Stein, M N Jones, S F Infante, J R Bendell, J Kane, M P Levinson, K T Suttle, A B Burris III, H A Br J Cancer Clinical Study 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. Nature Publishing Group 2014-05-27 2014-05-06 /pmc/articles/PMC4037836/ /pubmed/24800949 http://dx.doi.org/10.1038/bjc.2014.233 Text en Copyright © 2014 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Clinical Study Tan, A R Dowlati, A Stein, M N Jones, S F Infante, J R Bendell, J Kane, M P Levinson, K T Suttle, A B Burris III, H A Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
title | Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
title_full | Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
title_fullStr | Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
title_full_unstemmed | Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
title_short | Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
title_sort | phase i study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies |
topic | Clinical Study |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037836/ https://www.ncbi.nlm.nih.gov/pubmed/24800949 http://dx.doi.org/10.1038/bjc.2014.233 |
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