Combretastatin A4 Phosphate 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.

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.