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

J Clin Oncol. 2010 Jan 10;28(2):207-14. doi: 10.1200/JCO.2009.22.9237. Epub 2009 Nov 30.

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 > 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.

Conclusion: IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects*
  • Angiogenesis Inhibitors / therapeutic use*
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / therapeutic use*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiogenesis Inhibitors
  • Protein Kinase Inhibitors
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor