Trial Information

Phase I Trial Of Super-Selective Intraarterial Cerebral Infusion Of Avastin (Bevacizumab) 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).