A Phase I Trial of an IV-Administered Vascular Endothelial Growth Factor Trap for Treatment in Patients with Choroidal Neovascularization due to Age-Related Macular Degeneration

Quan Dong Nguyen, Syed Mahmood Shah, Gulnar Hafiz, Edward Quinlan, Jennifer Sung, Karen Chu, Jesse M. Cedarbaum, Peter A. Campochiaro

Research output: Contribution to journalArticle

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Abstract

Objectives: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). Design: Randomized, multicenter, placebo-controlled clinical trial. Participants: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. Methods: Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap-a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. Main Outcome Measures: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. Results: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12%, -10%, -66%, and -60%, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P<0.02 by analysis of covariance [ANCOVA]) and -5.6%, +47.1%, and -63.3% for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P<0.02, ANCOVA). A significant change in VA was not noted in this small study. Conclusions: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60% of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.

Original languageEnglish (US)
Pages (from-to)1522.e1-1522.e14
JournalOphthalmology
Volume113
Issue number9
DOIs
StatePublished - Sep 2006

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Choroidal Neovascularization
Macular Degeneration
Vascular Endothelial Growth Factor A
Placebos
Visual Acuity
Therapeutics
Safety
Vascular Endothelial Growth Factor Receptor
Maximum Tolerated Dose
Controlled Clinical Trials
Optical Coherence Tomography
Diabetic Retinopathy
Proteinuria
Recombinant Proteins
Protein Binding
Pharmacokinetics
Observation
Outcome Assessment (Health Care)
Hypertension
Population

ASJC Scopus subject areas

  • Ophthalmology

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A Phase I Trial of an IV-Administered Vascular Endothelial Growth Factor Trap for Treatment in Patients with Choroidal Neovascularization due to Age-Related Macular Degeneration. / Nguyen, Quan Dong; Shah, Syed Mahmood; Hafiz, Gulnar; Quinlan, Edward; Sung, Jennifer; Chu, Karen; Cedarbaum, Jesse M.; Campochiaro, Peter A.

In: Ophthalmology, Vol. 113, No. 9, 09.2006, p. 1522.e1-1522.e14.

Research output: Contribution to journalArticle

Nguyen, Quan Dong ; Shah, Syed Mahmood ; Hafiz, Gulnar ; Quinlan, Edward ; Sung, Jennifer ; Chu, Karen ; Cedarbaum, Jesse M. ; Campochiaro, Peter A. / A Phase I Trial of an IV-Administered Vascular Endothelial Growth Factor Trap for Treatment in Patients with Choroidal Neovascularization due to Age-Related Macular Degeneration. In: Ophthalmology. 2006 ; Vol. 113, No. 9. pp. 1522.e1-1522.e14.
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abstract = "Objectives: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). Design: Randomized, multicenter, placebo-controlled clinical trial. Participants: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. Methods: Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap-a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. Main Outcome Measures: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. Results: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12{\%}, -10{\%}, -66{\%}, and -60{\%}, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P<0.02 by analysis of covariance [ANCOVA]) and -5.6{\%}, +47.1{\%}, and -63.3{\%} for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P<0.02, ANCOVA). A significant change in VA was not noted in this small study. Conclusions: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60{\%} of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.",
author = "Nguyen, {Quan Dong} and Shah, {Syed Mahmood} and Gulnar Hafiz and Edward Quinlan and Jennifer Sung and Karen Chu and Cedarbaum, {Jesse M.} and Campochiaro, {Peter A.}",
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AU - Nguyen, Quan Dong

AU - Shah, Syed Mahmood

AU - Hafiz, Gulnar

AU - Quinlan, Edward

AU - Sung, Jennifer

AU - Chu, Karen

AU - Cedarbaum, Jesse M.

AU - Campochiaro, Peter A.

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N2 - Objectives: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). Design: Randomized, multicenter, placebo-controlled clinical trial. Participants: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. Methods: Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap-a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. Main Outcome Measures: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. Results: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12%, -10%, -66%, and -60%, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P<0.02 by analysis of covariance [ANCOVA]) and -5.6%, +47.1%, and -63.3% for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P<0.02, ANCOVA). A significant change in VA was not noted in this small study. Conclusions: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60% of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.

AB - Objectives: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). Design: Randomized, multicenter, placebo-controlled clinical trial. Participants: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. Methods: Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap-a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. Main Outcome Measures: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. Results: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12%, -10%, -66%, and -60%, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P<0.02 by analysis of covariance [ANCOVA]) and -5.6%, +47.1%, and -63.3% for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P<0.02, ANCOVA). A significant change in VA was not noted in this small study. Conclusions: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60% of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.

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