Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors.
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.
Lockhart
A Craig
AC
Vanderbilt University Medical Center, Nashville, TN, USA. alockhar@dom.wustl.edu
Rothenberg
Mace L
ML
Dupont
Jakob
J
Cooper
Wendy
W
Chevalier
Paul
P
Sternas
Lars
L
Buzenet
Giliane
G
Koehler
Elizabeth
E
Sosman
Jeffrey A
JA
Schwartz
Lawrence H
LH
Gultekin
David H
DH
Koutcher
Jason A
JA
Donnelly
Edwin F
EF
Andal
Ric
R
Dancy
Isabelle
I
Spriggs
David R
DR
Tew
William P
WP
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
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