title: Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  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 > or = 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.
  
  
  CONCLUSIONS
  IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
authors: Vanderbilt University Medical Center, Nashville, TN, USA. alockhar@dom.wustl.edu
authors: A Craig
authors: AC
authors: Lockhart
authors: Mace L
authors: ML
authors: Rothenberg
authors: Jakob
authors: J
authors: Dupont
authors: Wendy
authors: W
authors: Cooper
authors: Paul
authors: P
authors: Chevalier
authors: Lars
authors: L
authors: Sternas
authors: Giliane
authors: G
authors: Buzenet
authors: Elizabeth
authors: E
authors: Koehler
authors: Jeffrey A
authors: JA
authors: Sosman
authors: Lawrence H
authors: LH
authors: Schwartz
authors: David H
authors: DH
authors: Gultekin
authors: Jason A
authors: JA
authors: Koutcher
authors: Edwin F
authors: EF
authors: Donnelly
authors: Ric
authors: R
authors: Andal
authors: Isabelle
authors: I
authors: Dancy
authors: David R
authors: DR
authors: Spriggs
authors: William P
authors: WP
authors: Tew
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor