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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
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.
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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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