Super-Selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Vestibular Schwannoma

Newer techniques in interventional neuroradiology have allowed for a more selective delivery
of catheters higher up into the arterial tree where agents such as chemotherapies, can be
delivered without the risk of adverse affects such as blindness. In fact, studies here at
Cornell have developed very new and exciting super selective intraarterial delivery treatment
for Retinoblastoma and Malignant Glioma brain tumors with little toxicity. Therefore, this
trial will ask one simple question: Is it safe to deliver a first dose of Avastin
intraarterially using these super selective delivery techniques instead of the standard
intravenous route of administration? This should not only increase the amount of drug that
gets to the VS but also spare them of any adverse effects from a less selective delivery.
During that single dose of intraarterial Avastin, they will also receive a dose of mannitol
that opens up the blood brain barrier to improve delivery of the agent to the tumor. After
that single dose of Mannitol and Avastin intraarterially, the patient will be evaluated for 4
weeks to assess for toxicity. If no toxicity, then the will go on and get MRI of the brain
every two months to assess for response up to 12 months. After this, the subject is done with
the "experimental" aspects of the protocol. This is a Phase I trial that is designed to test
the safety of the single dose intraarterial delivery of Avastin and Mannitol,.

To summarize:

Current Standard of Care: Surgery or radiosurgery: IV Avastin

Experimental portion of this proposal:

Day 0: Intraarterial Avastin single dose (starting at 2mg/kg and up to 10mg/kg) after
Mannitol to open the blood brain barrier Day 28 (and every two months thereafter): MRI brain
with contrast

Therefore the experimental aspects of this treatment plan will include:

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol
25%; 3-10 mL/s for 30seconds) in order to disrupt the blood brain barrier. This
technique has been used in several thousand patients in previous studies for the IA
delivery of chemotherapy for malignant glioma.

2. To add a single intraarterial delivery (SIACI) of the Avastin with VS.

3. The dose escalation algorithm is as follows: We will use a single intracranial
superselective intraarterial infusion of Avastin, starting at a dose of 2mg/kg in the
first three patients. Assuming no dose limiting toxicity during the first 28 days after
IA infusion, an MRI of the brain will be performed. The doses will be escalated to 4,6,8
and finally 10mg/kg in this Phase I trial.

Inclusion criteria Include: Males or females, >=18 years of age, with documented Radiologic
or histologic diagnosis of VS

Both hematologic and non-hematologic toxicity will be determined and scored according to the
NCI Common Toxicity Criteria (version 3.0). Monitoring will be conducted by post procedure
history, neurological and physical examinations together with serial blood counts,
prothrombin time (PT), partial thromboplastin time (PTT) and chemistries.

Response will be evaluated after 4 weeks via a MRI with the injection of contrast. The
following will be evaluated every cycle, and then during follow-up: neurological examination,
physical examination, performance status, laboratory parameters and review of adverse
reactions. Contrast enhanced MRI (MRI with gadolinium is the preferable imaging study. The
following subjects will be taken off protocol: those with progressive disease; those who
experience dose-limiting toxicity (DLT). Follow-up will continue until disease progression or
death. Survival will be measured from the time of the first dose of IA Avastin® (given at the
start of each treatment cycle).

Inclusion Criteria:

- Male or female patients of >= 18 years of age.

- Patients with a documented diagnosis of unilateral or bilateral VS based on MRI and
who have evidence of progressive vestibular schwannomas, and are considered poor
candidates for surgery and radiation therapy or declined these treatments.

- Patients must have a Karnofsky performance status >=60% (or the equivalent ECOG level
of 0-2) (see Appendix A; Performance Status Evaluation) and an expected survival of >=
three months.

- No chemotherapy for two weeks prior to treatment under this research protocol and no
external beam radiation for two weeks prior to treatment under this research protocol.

- Patients must have adequate hematologic reserve with WBC>=3000/mm3, absolute
neutrophils >=1500/mm3 and platelets >=100,000/ mm3. Patients who are on Coumadin must
have a platelet count of >=150,000/ mm3.

- Pre-enrollment chemistry parameters must show: bilirubin< 1.5X the institutional upper
limit of normal (IUNL); AST or ALT< 2.5X IUNL and creatinine < 1.5X IUNL.

- Pre-enrollment coagulation parameters (PT and PTT) must be <1.5X the IUNL.

- Patients must agree to use a medically effective method of contraception during and
for a period of three months after the treatment period. A pregnancy test will be
performed on each premenopausal female of childbearing potential immediately prior to
entry into the research study.

Exclusion Criteria:

- Previous treatment with Avastin®.

- Women who are pregnant or lactating.

- Women of childbearing potential and fertile men will be informed as to the potential
risk of procreation while participating in this research trial and will be advised
that they must use effective contraception during and for a period of three months
after the treatment period.

- Patients with significant intercurrent medical or psychiatric conditions that would
place them at increased risk or affect their ability to receive or comply with
treatment or post-treatment clinical monitoring including MRI with gadolinium.

- Surgery (including open biopsy), significant traumatic injury within 28 days prior to
randomization, or anticipation of the need for major surgery during study treatment.

- Current or recent (within 10 days of Avastin) use of aspirin (> 325 mg/day), full dose
(i.e., therapeutic dose) of oral or parenteral anticoagulants or thrombolytic agents
for therapeutic purposes. Prophylactic use of anticoagulants is allowed (e.g.,
warfarin (1 mg qd) for catheter prophylaxis, and prophylactic low molecular-weight
heparin (i.e., enoxaparin [(40mg QD0]).

- History or evidence of inherited bleeding diathesis or coagulopathy with a risk of
bleeding.

- Inadequately controlled hypertension (blood pressure: systolic > 150 mmHg and/or
diastolic > 100 mmHg).

- Patients with baseline urine dipstick for proteinuria > 2+ must undergo a 24-hours
urine collection and must demonstrate ≤ 1 g of protein in 24 hours.

- Clinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular
accident or myocardial infarction within 6 months prior to randomization),unstable
angina, congestive heart failure (NYHA Class ≥ II), or serious cardiac arrhythmia that
is uncontrolled by medication or may interfere with administration of study treatment.

- Serious non-healing sound, active peptic ulcer, or untreated bone fracture.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months of enrollment.

- Known hypersensitivity to Avastin or any of its excipients.