Trial Information

PHASE I TRIAL OF SUPER-SELECTIVE INTRAARTERIAL CEREBRAL INFUSION OF CETUXIMAB (ERBITUX) FOR TREATMENT OF RELAPSED/REFRACTORY GLIOBLASTOMA MULTIFORME AND ANAPLASTIC ASTROCYTOMA.

There is no current standard of care for recurring GBM after patients receive Bevacizumab
(Avastin) intravenously (IV) at 10mg/kg with CPT-11 (Irinotecan). At that point, these
patients are deemed treatment failures and are given another experimental treatment.
Because of the blood brain barrier (BBB) where IV drugs do not penetrate the blood vessel
walls well to get into the brain, no one knows for sure if these IV drugs actually get into
the brain after infusion. Previous studies have shown that if you want to increase your
penetration of drug to the brain, that intra-carotid artery (intraarterial) delivery is
superior to standard intravenous delivery. Previous techniques using intraarterial
(intracarotid) infusion still were non-selective as drug delivery still went to all blood
vessels in the brain, so patients still had significant adverse events, such as blindness.
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
treatments for Retinoblastoma, eye tumors with little toxicity and a clinical trial of
intraarterial delivery of Avastin is currently underway for GBM. Therefore, this trial will
ask one simple question: Is it safe to deliver a dose of Cetuximab 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 tumor but
also spare the patient any adverse effects from a less selective delivery. Prior to that
single dose of intraarterial Cetuximab, the patient will also receive a dose of mannitol
that opens up the blood brain barrier to improve delivery of the agent to the brain. After
that single dose of Mannitol and Cetuximab intraarterially, the patient will be evaluated
for 4 weeks to assess for toxicity. After this point, the patient is done with the
"experimental" aspects of the protocol. If no toxicity at this point, then the patient will
go on and get their chosen chemotherapy as determined by their treating oncologist. In
summary, this is a Phase I trial that is designed to test the safety of a single dose of
intraarterial delivery of Mannitol and Cetuximab , prior to starting the patients next round
of chosen chemotherapy

To summarize:

Current Standard of Care Therapy : None

Experimental portion of this proposal:

Day 0: Intraarterial Mannitol to open the blood brain barrier followed by Intraarterial
Cetuximab single dose (starting at 100mg/m2 and up to 500mg/m2)

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 Cetuximab for patients with
recurring or relapsing high grade glioma. After a one cycle observation period to
assess for toxicity from the IA infusion, the subject will receive a regimen of
chemotherapy to be decided by their treating oncologist The dose escalation algorithm
is as follows: We will use a single intracranial superselective intraarterial infusion
of Cetuximab, starting at a dose of 100mg/m2 in the first three patients. Assuming no
dose limiting toxicity during the next 28 days after the infusion, the patient will
then begin their standard chemotherapy regimen which is to be determined by their
treating oncologist. The doses will be escalated from 100, to 200, 300, 400 and
finally 500mg/m2 in this Phase I trial.

Both hematologic and non-hematologic toxicity from the IA infusion of Cetuximab will be
determined and scored according to the NCI Common Toxicity Criteria (version 3.0).
Monitoring will also include an MRI of the brain at 4 weeks post infusion.

Most patients with GBM are also monitored every two months with serial history, neurological
and physical examinations together with serial blood counts, prothrombin time (PT), partial
thromboplastin time (PTT) and chemistries. In addition, most patients with GBM have an MRI
performed every two cycles or approximately every two months to assess for tumor
progression. .

Since this is a Phase I trial, response is not a primary endpoint of the trial. However, we
will evaluate response to the one time IA Cetuximab therapy with a a MRI with the injection
of contrast about 4 weeks after infusion. Follow-up of all patients in the trial regardless
of the chemotherapy regimen they try after the IA Cetuximab therapy will continue until
disease progression or death. Survival will be measured from the time of the dose of IA
Cetuximab®. We expect patients in the trial to monitored for 12 months.

This treatment may be harmful to a fetus . female subjects of childbearing age, will be
asked to practice birth control methods while participating in this research study and for 3
months following her treatment. These methods include oral contraceptives, contraceptive
shots, and barrier methods, such as condom use, sponges, and diaphragms. Fertile males are
required to use these barrier methods.

The patient may be responsible for any additional costs associated with enrollment in the
trial. All costs of the IA delivery and the cost of the drug will be submitted to the
patient's insurance provider.