Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors Journal Article

   

Authors:	Lockhart, A. C.; Rothenberg, M. L.; Dupont, J.; Cooper, W.; Chevalier, P.; Sternas, L.; Buzenet, G.; Koehler, E.; Sosman, J. A.; Schwartz, L. H.; Gultekin, D. H.; Koutcher, J. A.; Donnelly, E. F.; Andal, R.; Dancy, I.; Spriggs, D. R.; Tew, W. P.
Article Title:	Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors
Abstract:	Purpose Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. Patients and Methods Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. Results The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) -defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses >= 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. Conclusion IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
Keywords:	bevacizumab; paclitaxel; angiogenesis; biomarker; expression; colorectal-cancer; receptors; permeability; vegf-trap
Journal Title:	Journal of Clinical Oncology
Volume:	28
Issue:	2
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2010-01-01
Start Page:	207
End Page:	214
Language:	English
ACCESSION:	ISI:000273418000008
DOI:	10.1200/jco.2009.22.9237
PROVIDER:	wos
PMCID:	PMC2815710
PUBMED:	19949018
Notes:	--- - Article - "Source: Wos"

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