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Intraarterial Mannitol 25% 3-10 ml to open the blood brain barrier followed by Intraarterial Cetuximab single dose (starting at 100mg/m2 and escalating up to 500mg/m2)

Superselective Intraarterial Cerebral Infusion of Cetuximab

John Boockvar, MD

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. Initial therapy consists of either surgical resection, external beam radiation or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). Superselective Intraarterial Cerebral Infusion (SIACI) is a technique that can effectively increase the concentration of drug delivered to the brain while sparing the body of systemic side effects. One currently used drug called, Cetuximab (Erbitux) has been shown to be active in human brain tumors but its actual CNS penetration is unknown. This phase I clinical research trial will test the hypothesis that Cetuximab can be safely used by direct intracranial superselective intraarterial infusion up to a dose of 500mg/m2 to ultimately enhance survival of patients with relapsed/refractory GBM/AA. By achieving the aims of this study the investigators will determine the the toxicity profile and maximum tolerated dose (MTD) of SIACI Cetuximab. The investigators expect that this study will provide important information regarding the utility of SIACI Cetuximab therapy for malignant glioma, and may alter the way these drugs are delivered to the investigators patients in the near future.

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.

Super-Selective Intraarterial Cerebral Infusion of Cetuximab (Erbitux) for Treatment of Relapsed/Refractory GBM and AA

Phase I Trial of Super-Selective Intraarterial Cerebral Infusion of Cetuximab (Erbitux) for Treatment of Relapsed/Refractory Glioblastoma Multiforme and Anaplastic Astrocytoma

Northwell Health

Director of Neurosurgery

Symptoms and General Pathology

Recurrence

Amino Acids

Erlotinib Hydrochloride

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Tarceva®: Will be given at a starting dose of 150mg QD dose for the first cycle which is 28 days. This will be followed by 14 days of 100mg PO on a bid schedule and 150mg PO on a bid schedule for the final 14 days of the second cycle. Assuming no dose limiting toxicity, 150 mg PO tid will be continued for up to 10 more cycles. This is an outpatient regimen, in which the drug is admininistered orally. Tumor response will be assessed after every 2nd treatment cycle. Patients may receive a maximum of 12 cycles of treatment under this research protocol.

Erlotinib

John A Boockvar, M.D.

This study will offer a safe treatment for patients with relapsing recurring glioblastoma (GBM) or anaplastic astrocytoma (AA). The trial will test the hypothesis that Erlotinib (Tarceva, OSI-774) can be safely used up to a dose of 150 mg two times a day for 12 months to ultimately enhance survival of patients with relapsed/refractory GBM/AA. Correlation of response to Tarceva with particular genetic alterations including epidermal growth factor receptor variant type III (EGFRvIII) amplification and phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN) loss will be studied.

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA, from initial diagnosis, despite multimodal treatment approaches. Initial therapy consists of either surgical resection, external beam radiation or both. The role of adjuvant or concomitant chemotherapy in the initial therapy of GBM and AA has not, as yet, been clearly defined. Since most of these patients experience a recurrence after first-line therapy, improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. In August 2003, the U.S. Food and Drug Administration (FDA) granted orphan drug status for Erlotinib in patients with malignant glioma. Erlotinib (OSI-774) has been shown to be active in a range of tumors including GBM, AA and non small cell lung cancer. Because of the promising results in preliminary studies of Erlotinib and because of significant experience with the safety of the dosages proposed in this study, this study will offer a safe adjuvant treatment for patients with relapsing recurring glioblastoma or anaplastic astrocytoma. Therefore, this phase I/II clinical research trial will test the hypothesis that Erlotinib can be safely used up to a dose of 150 mg bid for 12 cycles to ultimately enhance survival of patients with relapsed/refractory GBM/AA with particular genetic alterations including EGFRvIII amplification and PTEN loss.

Oral Tarceva Study for Recurrent/Residual Glioblastoma Multiforme and Anaplastic Astrocytoma

Phase I/II Trial of Oral Erlotinib (Tarceva, OSI-774) for Treatment of Relapsed/Refractory Glioblastoma Multiforme and Anaplastic Astrocytoma

Greater than or equal to Grade 2 Adverse Event

Genentech, Inc.

Professor

Erlotinib: Tarceva®: Will be given at a starting dose of 150mg QD dose for the first cycle which is 28 days. This will be followed by 14 days of 100mg PO on a bid schedule and 150mg PO on a bid schedule for the final 14 days of the second cycle. Assuming no dose limiting toxicity, 150 mg PO tid will be continued for up to 10 more cycles. This is an outpatient regimen, in which the drug is admininistered orally. Tumor response will be assessed after every 2nd treatment cycle. Patients may receive a maximum of 12 cycles of treatment under this research protocol.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Super-Selective Intraarterial Cerebral Infusion of Cetuximab (Erbitux) for Treatment of Relapsed/Refractory GBM and AA	NCT01238237	Glioblastoma Mu... ANAPLASTIC ASTR... GBM Anaplastic Astr...	Superselective ...	18 Years -	Northwell Health
Oral Tarceva Study for Recurrent/Residual Glioblastoma Multiforme and Anaplastic Astrocytoma	NCT00301418	Glioblastoma Mu... Anaplastic Astr...	Erlotinib	18 Years -	Northwell Health

Spots Global Cancer Trial Database for high grade glial neoplasms