$Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors$
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Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors

Summary 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...

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Published in:	Investigational new drugs Vol. 39; no. 6; pp. 1577 - 1586
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-12-2021 Springer Nature B.V
Subjects:	Adverse events Angiogenesis Angiogenesis Inhibitors - administration & dosage Angiogenesis Inhibitors - adverse effects Angiogenesis Inhibitors - pharmacology Angiogenesis Inhibitors - therapeutic use Antineoplastic Combined Chemotherapy Protocols Area Under Curve Biopsy c-Met protein Chemoresistance Combination therapy Dose-Response Relationship, Drug Drug Administration Schedule Growth factors Health services Hepatocyte growth factor Hepatocyte Growth Factor - metabolism Humans Hypertension Indazoles - administration & dosage Indazoles - adverse effects Indazoles - pharmacokinetics Indazoles - therapeutic use Inhibitor drugs Maximum Tolerated Dose Medicine Medicine & Public Health Mesenchyme Middle Aged Neoplasms - drug therapy Neoplasms - pathology Oncology Patients Pharmacodynamics Pharmacokinetics Pharmacology Pharmacology/Toxicology Phase I Studies Proto-Oncogene Proteins c-met - antagonists & inhibitors Pyrimidines - administration & dosage Pyrimidines - adverse effects Pyrimidines - pharmacokinetics Pyrimidines - therapeutic use Pyrrolidinones - administration & dosage Pyrrolidinones - adverse effects Pyrrolidinones - pharmacokinetics Pyrrolidinones - therapeutic use Quinolines - administration & dosage Quinolines - adverse effects Quinolines - pharmacokinetics Quinolines - therapeutic use Solid tumors Sulfonamides - administration & dosage Sulfonamides - adverse effects Sulfonamides - pharmacokinetics Sulfonamides - therapeutic use Targeted cancer therapy Toxicity Tumors Vascular endothelial growth factor Vascular Endothelial Growth Factor A - drug effects Vascular endothelial growth factor receptors Biomarkers Angiogenesis Pharmacodynamics Pazopanib Tivantinib
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Summary:	Summary 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0167-6997 1573-0646 1573-0646
DOI:	10.1007/s10637-021-01138-x