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Type: Journal article
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
Author: Jonker, D.
Rosen, L.
Sawyer, M.
de Braud, F.
Wilding, G.
Sweeney, C.
Jayson, G.
McArthur, G.
Rustin, G.
Goss, G.
Kantor, J.
Velasquez, L.
Syed, S.
Mokliatchouk, O.
Feltquate, D.
Kollia, G.
Nuyten, D.
Galbraith, S.
Citation: Annals of Oncology, 2011; 22(6):1413-1419
Publisher: Oxford University Press
Issue Date: 2011
ISSN: 0923-7534
Statement of
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.
RMID: 0030047851
DOI: 10.1093/annonc/mdq599
Appears in Collections:Medicine publications

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