An Open Label, Pilot (Phase I/II), Dose-Escalation Safety and Tolerability Study of Combretastatin A4 Phosphate in Patients With Neovascular Age-Related Macular Degeneration.

Date de début de l'étude : 1 mai 2003

Inclusion Criteria: 1. Age 50 years or older; 2. 12-lead electrocardiogram (ECG) performed at least 2 weeks but less than 4 weeks prior to entry into the study showing a QTc \<440 with no evidence of current or prior myocardial ischemia, infarction or significant arrhythmia as determined by review and signature of the cardiologist. 3. Adequate bone marrow function: Absolute granulocyte count ≥1500 cells/mm3; Platelet count ≥100,000 cells/mm3; Hemoglobin ≥9.0gm/ dL; 4. PT/PTT within the institution upper limit of normal (ULN) or INR \<1.1 ; 5. Adequate hepatic function: Total bilirubin within the institution ULN; Alanine and aspartate aminotransferase (ALT/AST) \<3 times the institutional ULN; 6. Adequate renal function: serum creatinine ≤2.0 mg/dL; 7. Ophthalmic criteria: 1. Best corrected visual acuity in the study eye of ≤20/40 and ≥20/800 in the fellow eye. 2. Subfoveal choroidal neovascularization (as illustrated by fluorescein angiography) secondary to age-related macular degeneration, with a total lesion size of ≤12 total disc areas, of which at least 50% must be active CNV. 3. Subretinal hemorrhage ≤50% of total lesion size; 4. For patients with minimally classic and purely occult CNV, there must be documented evidence of ≥2 lines of vision loss (ETDRS) during the previous 12 weeks; 5. Clear ocular media and adequate papillary dilatation to permit good quality stereoscopic fundus photography; 8. Male fertile patients must abstain from sexual intercourse or use effective birth control; 9. Women must be post-menopausal for at least 12 months prior to study entry, or surgically sterile, or must be using two forms of effective contraception. 10. Able to return for all study visits within required visit windows; 11. Be able to give written informed consent. Exclusion Criteria: 1. Previous subfoveal thermal laser therapy; 2. Any subfoveal scarring or atrophy, or \>25% of the total lesion size is made up of scarring or atrophy; 3. Significant media opacities, including cataract, which can interfere with visual acuity, assessment of toxicity, or fundus photography; 4. Presence of other causes of choroidal neovascularization, including pathologic myopia (spherical equivalent of ≥-8.0 diopters, or axial length of ≥25mm), ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis and other uveitic entities; 5. Any condition that might interfere with assessment of the progression of CNV; 6. Any intraocular surgery in the study eye within 12 weeks of screening for the study; 7. Other treatment for AMD of the study eye within 12 weeks prior to screening; 8. Known allergy to fluorescein; 9. Any current or history of significant gastrointestinal, oral, or nasal bleeding; 10. Serious intercurrent infections or other nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy; 11. Grade 2 (CTC v.3.0) or greater pre-existing peripheral neuropathy; 12. Psychiatric disorders or other conditions rendering patients incapable of complying with the requirements of the protocol; 13. Pregnant or breast-feeding women; 14. History of angina, myocardial infarction, CHF, non-controlled atrial arrhythmias or clinically significant arrhythmias including conduction abnormality, nodal junctional arrhythmias and dysrhythmias, sinus bradycardia or tachycardia, supraventricular arrhythmias, atrial fibrillation or flutter, syncope or vasovagal episodes; 15. Abnormal cardiac stress test; 16. Uncontrolled hypertension (consistently \>150/100mmHg irrespective of medication); 17. Uncontrolled hypokalemia and/or hypomagnesemia; 18. ECG with evidence of prior myocardial infarction, QTc \> 450 msec or other clinically significant abnormalities; 19. Drug(s) known to prolong the QTc interval; 20. Patients with conditions associated with QTc prolongation; 21. Any investigational drug or device within 4 weeks prior to screening; 22. Decreased ejection fraction ≤50% or prior myocardial infarction.