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

Albert Lockhart, Mace L. Rothenberg, Jakob Dupont, Wendy Cooper, Paul Chevalier, Lars Sternas, Giliane Buzenet, Elizabeth Koehler, Jeffrey A. Sosman, Lawrence H. Schwartz, David H. Gultekin, Jason A. Koutcher, Edwin F. Donnelly, Ric Andal, Isabelle Dancy, David R. Spriggs, William P. Tew

Research output: Contribution to journalArticle

210 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)207-214
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number2
DOIs
StatePublished - Jan 10 2010
Externally publishedYes

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Vascular Endothelial Growth Factor A
Neoplasms
Pharmacokinetics
aflibercept
Magnetic Resonance Imaging
Vascular Endothelial Growth Factor Receptor-1
Angiogenesis Inhibitors
Proteinuria
Non-Hodgkin's Lymphoma
Permeability
Immunoglobulin G
Hypertension
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. / Lockhart, Albert; Rothenberg, Mace L.; Dupont, Jakob; Cooper, Wendy; Chevalier, Paul; Sternas, Lars; Buzenet, Giliane; Koehler, Elizabeth; Sosman, Jeffrey A.; Schwartz, Lawrence H.; Gultekin, David H.; Koutcher, Jason A.; Donnelly, Edwin F.; Andal, Ric; Dancy, Isabelle; Spriggs, David R.; Tew, William P.

In: Journal of Clinical Oncology, Vol. 28, No. 2, 10.01.2010, p. 207-214.

Research output: Contribution to journalArticle

Lockhart, A, Rothenberg, ML, Dupont, J, Cooper, W, Chevalier, P, Sternas, L, Buzenet, G, Koehler, E, Sosman, JA, Schwartz, LH, Gultekin, DH, Koutcher, JA, Donnelly, EF, Andal, R, Dancy, I, Spriggs, DR & Tew, WP 2010, 'Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors', Journal of Clinical Oncology, vol. 28, no. 2, pp. 207-214. https://doi.org/10.1200/JCO.2009.22.9237
Lockhart, Albert ; Rothenberg, Mace L. ; Dupont, Jakob ; Cooper, Wendy ; Chevalier, Paul ; Sternas, Lars ; Buzenet, Giliane ; Koehler, Elizabeth ; Sosman, Jeffrey A. ; Schwartz, Lawrence H. ; Gultekin, David H. ; Koutcher, Jason A. ; Donnelly, Edwin F. ; Andal, Ric ; Dancy, Isabelle ; Spriggs, David R. ; Tew, William P. / Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 2. pp. 207-214.
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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.",
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T1 - Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors

AU - Lockhart, Albert

AU - Rothenberg, Mace L.

AU - Dupont, Jakob

AU - Cooper, Wendy

AU - Chevalier, Paul

AU - Sternas, Lars

AU - Buzenet, Giliane

AU - Koehler, Elizabeth

AU - Sosman, Jeffrey A.

AU - Schwartz, Lawrence H.

AU - Gultekin, David H.

AU - Koutcher, Jason A.

AU - Donnelly, Edwin F.

AU - Andal, Ric

AU - Dancy, Isabelle

AU - Spriggs, David R.

AU - Tew, William P.

PY - 2010/1/10

Y1 - 2010/1/10

N2 - 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.

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