Vascular disrupting agent for neovascular age related macular degeneration: A pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate

Mohamed A. Ibrahim, Diana V. Do, Yasir J. Sepah, Syed M. Shah, Elizabeth Van Anden, Gulnar Hafiz, J. Kevin Donahue, Richard Rivers, Jai Balkissoon, James T. Handa, Peter A. Campochiaro, Quan Dong Nguyen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).Methods: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).Results: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.Conclusions: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.Trial registration: ClinicalTrials.gov NCT01570790.

Original languageEnglish (US)
Article number7
JournalBMC Pharmacology and Toxicology
Volume14
DOIs
StatePublished - Jan 14 2013

Fingerprint

Macular Degeneration
Blood Vessels
Phosphates
Safety
Intravenous Infusions
Visual Acuity
Vital Signs
Fluorescein Angiography
Photochemotherapy
Optical Coherence Tomography
Therapeutics
Standard of Care
Nausea
Physical Examination
Headache
Electrocardiography
Clinical Trials
Blood Pressure
Injections
Temperature

Keywords

  • Angiogenesis
  • CA4P
  • Combretastatin A-4 Phosphate
  • Neovascularization
  • Ocular pharmacology
  • Retinal degeneration
  • VDA
  • Vascular disrupting agents

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Vascular disrupting agent for neovascular age related macular degeneration : A pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate. / Ibrahim, Mohamed A.; Do, Diana V.; Sepah, Yasir J.; Shah, Syed M.; Van Anden, Elizabeth; Hafiz, Gulnar; Donahue, J. Kevin; Rivers, Richard; Balkissoon, Jai; Handa, James T.; Campochiaro, Peter A.; Nguyen, Quan Dong.

In: BMC Pharmacology and Toxicology, Vol. 14, 7, 14.01.2013.

Research output: Contribution to journalArticle

Ibrahim, MA, Do, DV, Sepah, YJ, Shah, SM, Van Anden, E, Hafiz, G, Donahue, JK, Rivers, R, Balkissoon, J, Handa, JT, Campochiaro, PA & Nguyen, QD 2013, 'Vascular disrupting agent for neovascular age related macular degeneration: A pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate', BMC Pharmacology and Toxicology, vol. 14, 7. https://doi.org/10.1186/2050-6511-14-7
Ibrahim, Mohamed A. ; Do, Diana V. ; Sepah, Yasir J. ; Shah, Syed M. ; Van Anden, Elizabeth ; Hafiz, Gulnar ; Donahue, J. Kevin ; Rivers, Richard ; Balkissoon, Jai ; Handa, James T. ; Campochiaro, Peter A. ; Nguyen, Quan Dong. / Vascular disrupting agent for neovascular age related macular degeneration : A pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate. In: BMC Pharmacology and Toxicology. 2013 ; Vol. 14.
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abstract = "Background: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).Methods: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).Results: The most common adverse events were elevated blood pressure (46.7{\%}), QTc prolongation (23.3{\%}), elevated temperature (13.3{\%}), and headache (10{\%}), followed by nausea and eye injection (6.7{\%}). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15{\%} at end of treatment period and by 43.75{\%} at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.Conclusions: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.Trial registration: ClinicalTrials.gov NCT01570790.",
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T2 - A pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate

AU - Ibrahim, Mohamed A.

AU - Do, Diana V.

AU - Sepah, Yasir J.

AU - Shah, Syed M.

AU - Van Anden, Elizabeth

AU - Hafiz, Gulnar

AU - Donahue, J. Kevin

AU - Rivers, Richard

AU - Balkissoon, Jai

AU - Handa, James T.

AU - Campochiaro, Peter A.

AU - Nguyen, Quan Dong

PY - 2013/1/14

Y1 - 2013/1/14

N2 - Background: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).Methods: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).Results: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.Conclusions: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.Trial registration: ClinicalTrials.gov NCT01570790.

AB - Background: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).Methods: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).Results: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.Conclusions: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.Trial registration: ClinicalTrials.gov NCT01570790.

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KW - CA4P

KW - Combretastatin A-4 Phosphate

KW - Neovascularization

KW - Ocular pharmacology

KW - Retinal degeneration

KW - VDA

KW - Vascular disrupting agents

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