Abstract
BackgroundThis study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).MethodsProspective, 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).ResultsThe 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.ConclusionsThe 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 registrationClinicalTrials.gov NCT01570790.
Highlights
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)
5 patients had active choroidal neovascularization (CNV) at baseline, one patient had history of CNV resolved with disciform scarring and light-perception vision, and two patients had no history of CNV
None of our patients was naïve to treatment at baseline with all of them receiving at least 2 sessions of photodynamic therapy (PDT) prior to the study (Table 1)
Summary
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). Because of its reversible effects and the short half-life of about 10-27 min, as demonstrated in animal studies, CA4P does not display the side effects typical of tubulin binding inhibitors [1]. It is a vascular targeted agent, its specific mechanism of action and side effect profile differ from those of vascular endothelial growth factor (VEGF) inhibitors [2]. Multiple human studies have demonstrated significant decrease in tumor blood flow within a few hours of CA4P administration, whether examined with dynamic contrast enhanced (DCE), MRI, PET scan or perfusion CT scan. Consistent with its vascular activity, the most typical adverse effects in descending order are nausea, headache, tumor pain, fatigue, vomiting, sinus tachycardia and bradycardia, paresthesia, diarrhea, sweating, and transient hypertension and QTc prolongation [4]
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