Bevicizumab (Avastin) Infusion for Choroidal Neovascularization (CNV) Not Associated With Age-Related Macular Degeneration (AMD)

Phase 1

Completed

• Conditions: Choroidal Neovascularization; Degenerative Myopia; Pathological Myopia

• Registration Number: NCT00407719
• Lead Sponsor: Johns Hopkins University

Brief Summary

The purpose of this study is to see if the drug bevacizumab is safe and effective to use for people with choroidal neovascularization (CNV). CNV is an eye condition where abnormal blood vessels grow in the part of the eye responsible for central (straight ahead) vision. The drug is produced using recombinant DNA technology and has been approved by the FDA for use in colon cancer. Although not yet approved for people with CNV, the FDA has given permission to use this drug in this study.

Detailed Description

Bevacizumab is a recombinant humanized monoclonal antibody against VEGF. It has been approved by the FDA for the treatment of metastatic colon cancer 18. We hypothesize that VEGF also plays a role in the development of CNV in pathologic myopia. Therefore, employing a mode of therapy that would decrease the risks posed to eyes with attenuated sclera, we have treated, through special approval by the Pharmacy and Therapeutic Committee of the Johns Hopkins University School of Medicine, two patients with persistent myopic CNV with intravenous bevacizumab 19. Despite multiple treatments with PDT, the CNV remained active and vision continued to decline in these two index patients. After four infusions of bevacizumab, the CNV became inactive. Six months after the last infusion in each patient, the CNV showed no evidence of activity or leakage on fluorescein angiography. Vision also improved in the diseased eyes of both patients. The two patients tolerated the infusions well, with no adverse events detected. In particular, blood pressure remained stable and no proteinuria was noted on serial analyses of 24-hour urine collections. The Bascom Palmer Eye Institute at the University of Miami has also recently reported favorable outcomes of bevacizumab administered in repeated doses to 14 patients (age \> 65 years) with CNV secondary to AMD that has been refractory to other therapies.

We propose a non-randomized, open-label pilot study to evaluate the effect of bevacizumab in patients with CNV due to any cause other than AMD. This design will allow us to closely monitor safety and tolerability of bevacizumab while we evaluate 3 bioactivity outcomes. Based upon dramatic responses in two patients with CNV due to myopic degeneration, we hypothesize that treatment with bevacizumab may have major advantages over current standard of care.

Study Timeline

• Study Start: 2005-06
• Study First Submitted: 2006-12-01
• Study First Submitted QC: 2006-12-01
• Study First Posted: 2006-12-05
• Primary Completion: 2007-04
• Study Completion: 2008-05
• Status Verified: 2009-01
• Last Update Submitted: 2009-02-02
• Last Update Posted: 2009-02-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

) Subfoveal CNV in study eye due to cause other than AMD. Best corrected visual acuity of 20/30 or less in study eye. Evidence of retinal thickening or subretinal fluid by OCT in study eye. Must be fluorescein leakage due to CNV in the study eye. If the CNV is a complication of another disease (i.e. uveitis), the disease must be under stabilization for at least 3 months prior to enrollment.

(ECG)at least 28 days prior to entry into the study must show no evidence of current or prior myocardial ischemia, infarction, or significant arrhythmia.

Adequate bone marrow function:

Absolute granulocyte count (neutrophils and bands) > 1500 cells/mm3;

1. Platelet count > 100,000 cells/mm3;
2. 9.0 g/dL; 9) PT/PTT within the institution upper limit of Hemoglobin, normal (ULN) or INR <1.1. 10) Adequate renal function: serum creatinine ≤ 2.0 mg/dL. 11)Patients of child bearing potential must abstain from sexual intercourse or use effective birth control. Negative serum pregnancy test result confirmation prior to treatment.

Patients must be able to return for all study visits within required visit windows.

Patients must provide written informed consent

Exclusion Criteria

1. Previous subfoveal thermal laser therapy.
2. Significant scarring or atrophy in the fovea that indicates substantial irreversible vision loss.
3. Significant media opacities, including cataract, which can interfere with visual acuity, assessment of toxicity, or fundus photography.
4. Any intraocular surgery in the study eye within 12 weeks of entry.
5. If the CNV in the study eye has been treated with photodynamic therapy (PDT), the treatment must be at least 12 weeks prior to study entry, unless it is judged by the investigator that the ocular disease has deteriorated within the 12-week period
6. Any treatment for CNV in the study eye with anti-vascular endothelial growth factor (anti-VEGF) therapy, intraocularly or intravenously, must be at least 6 weeks prior to study entry, unless it is judged that the ocular disease has deteriorated within the 6-week period
7. Uncontrolled hypertension defined as blood pressure consistently (at 3 or more consecutive visits) greater than 150/100 irrespective or medication.
8. Any history, physical signs, or EKG findings suggesting significant heart disease.
9. History of thromboembolism or stroke.
10. History, physical signs, or laboratory of bleeding diathesis or coagulopathy. Any history (within 3 years) of significant gastrointestinal, oral (gum), or nasal bleeding..
11. History or physical signs of peripheral vascular disease.
12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to entry.
13. Anticipation of need for major surgical procedure during the course of the study.
14. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to entry.
15. Women who are pregnant (positive pregnancy test) or breastfeeding.
16. Protein concentration in a 24-hour urine specimen more than 1.3 x ULN.
17. History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 6 months prior to entry.
18. Serious, non-healing wound, ulcer, or bone fracture.
19. Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, cavitation, or history of hemoptysis.
20. Inability to comply with study and/or follow-up procedures.
21. Any patient who is on standard anticoagulant therapy [INR targeted at 2.0 to 3.0] or treatment for deep vein thrombosis, or grade 3 or 4 venous thrombosis (Table 1), is not eligible to enroll in the study. Patients who are on stable, low-dose heparin or warfarin therapy may be eligible for the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Visual acuity: In this pilot study, the sample size is not powered for clinical response. However, preliminary data on visual acuity will aid in the design of future randomized control trial.	each visit for study duration up to 24 mos

Secondary Outcome Measures

Name	Time	Method
Retinal thickness assessed by OCT	each visit
CNV leakage assessed by Digital Fluorescein Angiography	per protocol