Bevacizumab Therapy for Brain Arteriovenous Malformation

Brain AVMs are relatively rare, though their potential for ICH along with the existence of
effective treatments makes their diagnosis and management essential to the community. The
2-4% annual incidence of such secondary ICH creates controversy regarding treatment for
asymptomatic patients. Brain AVMs thus require multidisciplinary evaluation for optimal
management especially for surgical grades III - V lesions that often require some combination
of embolization, microsurgery, and/or radiosurgical treatment. Currently there is no
designated medical therapy for bAVM, though there is growing animal and human evidence
supporting a role for bevacizumab to reduce the size of AVMs in the brain and liver,
respectively. This proposal is a pilot study to assess the efficacy and safety of bevacizumab
in humans with bAVMs.

Inclusion Criteria:

- bAVM deemed unsuitable for invasive treatment OR patient has elected to defer invasive
treatment OR failed conventional therapy

- Age greater than 18 years at time of first study drug administration

- Spetzler-Martin grade III - V

- Progressive or disabling signs and symptoms as determined by the study investigators.
In the case of sporadic bAVM, these would be referable to the lesion, e.g.,
progressive neurological deficits, refractory headaches and seizures; for HHT
patients, bAVM may be asymptomatic, but patient must have one progressively
symptomatic manifestation of HHT that is referable to a vascular lesion, e.g.,
epistaxis, GI bleeding; or another solid organ AVM

- Patients must have adequate bone marrow function (WBC > 3,000/μl, ANC > 1,500/mm3,
platelet count of > 100,000/mm3, and hemoglobin > 10 mg/dl), adequate liver function
(SGOT and bilirubin < 1.5 times ULN), and adequate renal function (creatinine < 1.5
mg/dL) within 14 days before starting therapy

- Negative pregnancy test within 14 days of starting therapy

- Patients must not have proteinuria at screening as demonstrated by either 1) urine
protein: creatinine (UPC) ratio > 1.0 at screening, OR 2) urine dipstick for
proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis
at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of
protein in 24 hours to be eligible)

- Patients must not have inadequately controlled hypertension (defined as systolic blood
pressure >150 and/or diastolic blood pressure > 100 mmHg) on antihypertensive
medications

- Patients must not have any prior history of hypertensive crisis or hypertensive
encephalopathy

- Patients must not have New York Heart Association Grade II or greater congestive heart
failure

- Patients must not have history of myocardial infarction or unstable angina within 12
months prior to study enrollment

- Patients must not have symptomatic peripheral vascular disease

- Patients must not have significant vascular disease (e.g., aortic aneurysm, aortic
dissection)

- Patients must not have major surgical procedure, open biopsy, or significant traumatic
injury within 4 weeks of beginning Avastin or the anticipation of need for major
surgical procedure during the course of the study

- Patients must not have core biopsy or other minor surgical procedure, excluding
placement of a vascular access device, within 7 days prior to bevacizumab

- Patients must not have a history of abdominal fistula, gastrointestinal perforation,
or intra-abdominal abscess within 6 months prior to study enrollment

- Patients must not have serious, non-healing wound, ulcer, or bone fracture

- Patients must not be pregnant or breast-feeding. Women of childbearing potential are
required to obtain a negative pregnancy test within 14 days of starting treatment.
Effective contraception (men and women) must be used in subjects of child-bearing
potential

- Patients must not be on any other experimental agents/clinical trials

- Signed informed consent

Exclusion Criteria:

- Diffuse lesion that cannot be assessed in terms of volume by cross-sectional imaging
on MRI

- Inability to undergo MRI scans

- Coagulation disorders, e.g., thrombocytopenia, coagulopathy or anticoagulant therapy
(Plavix and ASA is not excluded)

- Low probability to adhere to study protocol or functional impairment that could
compromise safety monitoring

- Unstable medical or psychiatric illness

- Ovarian dysfunction (criteria waived if potential future to have children (e.g. post
menopausal or s/p tubal ligation) limited biologically.

- Clinically significant thrombotic episode within the last 24 weeks

- Atrial fibrillation