A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors
| Autor: | Grant A. McArthur, George Wilding, L. S. Rosen, Georgia Kollia, Christopher Sweeney, S. Galbraith, D. Feltquate, D. S. A. Nuyten, Derek J. Jonker, Linda M. Velasquez, Michael B. Sawyer, Samira Syed, F. de Braud, J Kantor, Glenwood D. Goss, O. Mokliatchouk, G.J.S. Rustin, Gordon C Jayson |
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| Rok vydání: | 2010 |
| Předmět: |
Sorafenib
Adult Male medicine.medical_specialty Bevacizumab Maximum Tolerated Dose Phases of clinical research Angiogenesis Inhibitors Antineoplastic Agents Pharmacology Metastasis chemistry.chemical_compound Pharmacokinetics Internal medicine Neoplasms medicine Humans Neoplasm Metastasis Aged Aged 80 and over Alanine Dose-Response Relationship Drug Neovascularization Pathologic business.industry Triazines Hematology Original Articles Middle Aged medicine.disease Receptors Fibroblast Growth Factor Endocrinology Brivanib alaninate Receptors Vascular Endothelial Growth Factor Oncology chemistry Pharmacodynamics Toxicity Female business medicine.drug |
| Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology. 22(6) |
| ISSN: | 1569-8041 |
| Popis: | Background: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. Patients and methods: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. Results: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180–800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly £1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ‡600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. Conclusion: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses £800 mg orally q.d., the recommended phase II study dose. |
| Databáze: | OpenAIRE |
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