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Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors
The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemore...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541958/ https://www.ncbi.nlm.nih.gov/pubmed/34180036 http://dx.doi.org/10.1007/s10637-021-01138-x |
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author | Kummar, Shivaani Srivastava, Apurva K. Navas, Tony Cecchi, Fabiola Lee, Young H. Bottaro, Donald P. Park, Sook Ryun Do, Khanh T. Jeong, Woondong Johnson, Barry C. Voth, Andrea R. Rubinstein, Larry Wright, John J. Parchment, Ralph E. Doroshow, James H. Chen, Alice P. |
author_facet | Kummar, Shivaani Srivastava, Apurva K. Navas, Tony Cecchi, Fabiola Lee, Young H. Bottaro, Donald P. Park, Sook Ryun Do, Khanh T. Jeong, Woondong Johnson, Barry C. Voth, Andrea R. Rubinstein, Larry Wright, John J. Parchment, Ralph E. Doroshow, James H. Chen, Alice P. |
author_sort | Kummar, Shivaani |
collection | PubMed |
description | The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-021-01138-x. |
format | Online Article Text |
id | pubmed-8541958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-85419582021-10-27 Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors Kummar, Shivaani Srivastava, Apurva K. Navas, Tony Cecchi, Fabiola Lee, Young H. Bottaro, Donald P. Park, Sook Ryun Do, Khanh T. Jeong, Woondong Johnson, Barry C. Voth, Andrea R. Rubinstein, Larry Wright, John J. Parchment, Ralph E. Doroshow, James H. Chen, Alice P. Invest New Drugs Phase I Studies The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-021-01138-x. Springer US 2021-06-28 2021 /pmc/articles/PMC8541958/ /pubmed/34180036 http://dx.doi.org/10.1007/s10637-021-01138-x Text en © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Phase I Studies Kummar, Shivaani Srivastava, Apurva K. Navas, Tony Cecchi, Fabiola Lee, Young H. Bottaro, Donald P. Park, Sook Ryun Do, Khanh T. Jeong, Woondong Johnson, Barry C. Voth, Andrea R. Rubinstein, Larry Wright, John J. Parchment, Ralph E. Doroshow, James H. Chen, Alice P. Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
title | Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
title_full | Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
title_fullStr | Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
title_full_unstemmed | Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
title_short | Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
title_sort | combination therapy with pazopanib and tivantinib modulates vegf and c-met levels in refractory advanced solid tumors |
topic | Phase I Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541958/ https://www.ncbi.nlm.nih.gov/pubmed/34180036 http://dx.doi.org/10.1007/s10637-021-01138-x |
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