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 > 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.

Fig 1.

Mean plasma concentration versus time profiles for (A) free and (B) bound vascular endothelial growth factor (VEGF) Trap (log scale). (A) After the first two doses (on days 0 and 14) of intravenous (IV) VEGF Trap, there is a dose-dependent increase in free VEGF Trap maximum plasma concentration, and detectable levels are present at doses of 2.0 mg/kg and greater. (B) At dose levels of 2.0 mg/kg and greater, bound VEGF Trap levels appear to saturate and have no appreciable increase with dose escalation.

Fig 2.

Mean change in volume transfer constant (K^trans) between baseline and 24 hours for each vascular endothelial growth factor (VEGF) Trap dose estimated from a linear analysis of covariance model. The average dose effects (points) and 95% CI (dotted lines) are shown. The decrease in K^trans after 24 hours was significant at all doses except 0.3 and 4.0 mg/kg. Baseline and 24-hour K^trans measurements were significantly different between the 0.3 and 7.0 mg/kg doses (0.98 v 0.22; P = .0276).