The purpose of the study is assess safety, bioactivity, and maximal tolerated dose of repeated weekly intravenous infusion of combretastatin A-4 phosphate (CA4P) in patients with neovascular age-related macular degeneration
The study is designed as a single escalating dose with cohorts of five subjects. Escalation to the next cohort was based on the presence of no more than one subject with a dose limiting toxicity (DLT). The first cohort is to receive 27 mg/m2 intravenous infusion of of CA4P, 36mg/m2 to the second cohort, and 45mg/m2 to the third cohort. CA4P will be infused at baseline and every week for a total of 4 doses. Follow up visits will be scheduled at week 8 and 12. Safety data will be collected during the 12-week duration of the study and will be assessed using the common terminology criteria of adverse events (CTCAE v3.0). Bioactivity data will be assessed by measuring change in best corrected visual acuity, changes in central retinal thickness as measured by Optical coherence tomography, and changes in the amount of leakage on fluorescein angiography. DLTs were defined as specific events that are considered to be probably or definitely related to CA4P. Major DLTs included QTc interval ≥ 500 msec (based on measurements provided by the core laboratory for ECG analysis), Grade-2 or greater ventricular arrhythmia, unexplained syncope, Grade-3 or greater toxicity, delayed recovery postponing re-treatment by \>14 days, and ocular toxicity such as keratopathy, uveitis, optic neuropathy, and retinopathy, at the discretion of the investigator.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
8
27 mg/m2 CA4P IV infusion at baseline and every week for 4 doses
36 mg/m2 CA4P IV infusion at baseline and every week for 4 doses
45 mg/m2 CA4P IV infusion at baseline and every week for 4 doses
Wilmer Eye Institute
Baltimore, Maryland, United States
Safety and Tolerability
To report frequency and severity of adverse events, as defined by the common terminology criteria of adverse events (CTCAE v.3.0; National Cancer Institute), and to determine the degree of relationship of adverse events to the study drug (CA4P).
Time frame: 12 weeks after the first infusion of the Study Drug
Dose Limiting Toxicities (DLT)
DLT is defined as any of the following adverse events if ≥Grade-2 in severity: ventricular arrhythmia, second or third degree AV block, severe sinus bradycardia \< 45 bpm, tachycardia \>120 bpm, supraventricular arrhythmia \> 24 hours, ventricular tachycardia (\>9 beats in a row), any length of torsades de pointes, unexplained recurrent syncope, QTc prolongation ≥500 msec on \> 2 consecutive ECGs, Grade-2 or greater myocardial infarction, or ocular toxicities deemed by the investigator not acceptable for the patients to receive further treatments.
Time frame: 12 weeks after the first infusion of the study drug
Maximum Tolerated Dose
Maximum Tolerated Dose (MTD) of intravenous infusion of combretastatin A-4 phosphate in patients with neovascular age related macular degeneration. The MTD is defined as the maximum dose level of CA4P administered at which, DLT is observed in fewer than 2 patients at a given cohort.
Time frame: 12 weeks after the first infusion of the study drug
Change in Best Corrected Visual Acuity
Difference change from baseline in Best corrected visual acuity, as measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, at week 4 and week 12.
Time frame: 4 and 12 weeks after first infusion of the study drug
Change in Central Retinal Thickness
Difference change from baseline in central retinal thickness as measured by Optical Coherence Tomography at week 4 and week 12.
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Time frame: 4 and 12 weeks following the first infusion of CA4P