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.2018-06-122018-06-122011Annals of Oncology, 2011; 22(6):1413-14190923-75341569-8041http://hdl.handle.net/2440/112788Background: 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.en© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.Antiangiogenesis; brivanib; fibroblast growth factor; vascular endothelial growth factorJournal article003004785110.1093/annonc/mdq5990002910608000232-s2.0-79952967812186445Sweeney, C. [0000-0002-0398-6018]