Reduction of Plasma Free VEGF-A Using Low-dose Bevacizumab in Hemodialysis Patients

It has been found that hemodialysis arteriovenous fistula failure is partly mediated through
a VEGF pathway. The administration of bevacizumab (a VEGF-A monoclonal antibody) in
arteriovenous fistula (AVF) murine models at a dose of 5mg/kg (a standard chemotherapeutic
dose) has shown a significant reduction in stenosis formation and an overall improvement in
vascular remolding. However, previous pharmacokinetic human studies have shown that
bevacizumab administered at a low dose of 1.25mg intravitreally (ocular neovascularization
patients) is sufficient enough to suppress circulating VEGF-A levels up to 30 days post
administration. A chart review on 14 hemodialysis patients receiving an arteriovenous access
and intravitreal bevacizumab has demonstrated a significant improvement in patency (HR:
0.45, p-value: 0.037) when compared to controls. Prior to a phase 1 trial, it is essential
to determine if intravenous administration of bevacizumab demonstrates the same
pharmacokinetics and bio-response profile as intravitreal administration, and to determine
the optimal dose and frequency. This phase 0 study will be conducted in 10 existing
hemodialysis patients at a dose of 1.25mg with a potential dose escalation to 2.5mg if
optimal results are not seen. The findings from this study can have a substantial clinical
impact not only in ESRD patients but also in patients receiving other vascular or
endovascular procedures.

Inclusion Criteria

- Patients between 18 and 85 years old, inclusive

- Patients with end stage renal disease (ESRD) who are currently undergoing
hemodialysis treatment through an upper extremity fistula

- Hemoglobin ≥8g/dL and platelet count ≥100,000/mm3 prior to Day 1

- Adequate liver function, defined as serum bilirubin ≤1.5 mg/dL;
gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine
transaminase (ALT), and alkaline phosphatase ≤2x upper limit of normal or
international normalized ratio (INR) ≤ 1.5 prior to Day 0 or INR ≤ 2 if on
anticoagulant therapy.

- Ability to communicate meaningfully with investigative staff, competence to give
written informed consent, and ability to comply with entire study procedures

- If female and of childbearing years, must have a negative serum pregnancy test at the
screening visit (Visit 1). Both female patients of childbearing potential and male
patients with childbearing potential partners must be willing to use contraception
from the time of screening to completion of the study

- Life expectancy of at least 1 year

Exclusion Criteria

- Known sensitivity to bevacizumab or prior treatment with any medication known to
target VEGF

- Current use of medications that are known to interact with the safety and efficacy of
bevacizumab (most commonly: Antineoplastics (Anthracyclines), Belimumab,
Bisphosphonate Derivatives, Clozapine, Dipyrone, Irinotecan, Sorafenib, and Sutent)

- History or evidence of severe cardiac disease (NYHA Functional Class III or IV),
myocardial infarction within six months of study entry (Day 1), ventricular
tachyarrhythmias requiring continuing treatment, or unstable angina

- Significant uncontrolled hypertension (systolic blood pressure above 160 mm Hg and/or
diastolic blood pressure above 100 mm Hg);

- Stroke within six (6) months of study entry (Day 1)

- Treatment with any investigational drug/ device within 60 days prior to study entry
(Day1)

- Treatment with vitamin K-antagonists or direct thrombin inhibitors with an INR ≥2

- All patients (including both female patients of childbearing potential and male
patients with childbearing potential partners) who do not use a highly effective
method of birth control (failure rate less than 1% per year when used consistently
and correctly), e.g. implants, injectables, combined oral contraceptives in
combination with a barrier method, some intrauterine contraceptive devices, sexual
abstinence, or a vasectomized partner

- Malignancy or treatment for malignancy within the previous 6 months

- Immunodeficiency including AIDS / HIV or Active autoimmune disease

- Documented hypercoagulable state or history of 2 or more deep vein thromboses (DVTs)
or other spontaneous intravascular thrombotic events

- Bleeding diathesis or Anemia with a hematocrit level of less than 30%

- A prothrombin time or a partial thromboplastin time more than 1.2 times the upper
limit of normal, or absolute platelet counts below the lower limit of normal; an
absolute neutrophil count below 1,500/mm3

- Active local or systemic infection (WBC > 15,000/mm3)

- Gastrointestinal ulcer or bleeding, or wound dehiscence

- Scheduled elective surgery within 2 months of start date

- Known serious allergy to aspirin or penicillin

- Any other condition which in the judgment of the investigator would preclude adequate
evaluation of the safety and efficacy of bevacizumab

- Employees of the sponsor or patients who are employees or relatives of the
investigator