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|Title:||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|
de Braud, F.
|Citation:||Annals of Oncology, 2011; 22(6):1413-1419|
|Publisher:||Oxford University Press|
|D. J. Jonker, L. S. Rosen, M. B. Sawyer, F. de Braud, G. Wilding, C. J. Sweeney, G. C. Jayson, G. A. McArthur, G. Rustin, G. Goss, J. Kantor, L. Velasquez, S. Syed, O. Mokliatchouk, D. M. Feltquate, G. Kollia, D. S. A. Nuyten, S. Galbraith|
|Abstract:||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.|
|Keywords:||Antiangiogenesis; brivanib; fibroblast growth factor; vascular endothelial growth factor|
|Rights:||© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.|
|Appears in Collections:||Medicine publications|
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