Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors
| العنوان: | Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors |
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| المؤلفون: | Donald P. Bottaro, Ralph E. Parchment, Larry Rubinstein, Barry C. Johnson, Woondong Jeong, Young H. Lee, Khanh T. Do, Apurva K. Srivastava, James H. Doroshow, John Wright, Alice P. Chen, S. Kummar, Tony Navas, Andrea Regier Voth, Fabiola Cecchi, Sook Ryun Park |
| المصدر: | Investigational New Drugs |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Vascular Endothelial Growth Factor A, 0301 basic medicine, Indazoles, C-Met, Maximum Tolerated Dose, Combination therapy, Angiogenesis, Phases of clinical research, Angiogenesis Inhibitors, Context (language use), Drug Administration Schedule, Pazopanib, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phase I Studies, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Pharmacology (medical), Tivantinib, Pharmacology, Sulfonamides, Dose-Response Relationship, Drug, Hepatocyte Growth Factor, business.industry, Middle Aged, Proto-Oncogene Proteins c-met, Pyrrolidinones, Vascular endothelial growth factor, Pyrimidines, 030104 developmental biology, Pharmacodynamics, Oncology, chemistry, Area Under Curve, 030220 oncology & carcinogenesis, Quinolines, Cancer research, business, Biomarkers, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1573-0646 0167-6997 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e83a5914e623f2c8c7a0c52fc6852c8Test https://doi.org/10.1007/s10637-021-01138-xTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8e83a5914e623f2c8c7a0c52fc6852c8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15730646 01676997 |
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