Repeated Super-Selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Newly Diagnosed GBM

Study Overview
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Brief Summary
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The high-grade malignant brain tumors, glioblastoma multiforme (GBM), 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 of only 9-12 months. 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). We have shown in a previous phase I trial that a single Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM. Therefore, this phase I/II clinical research trial is an extension of that trial in that we seek to test the hypothesis that repeated dosing of intra-arterial Bevacizumab is safe and effective in the treatment of newly diagnosed malignant glioma. By achieving the aims of this study we will also determine if repeated intra-arterial Bevacizumab improves progression free and overall survival in newly diagnosed patients. We expect that this project will provide important information regarding the utility of repeated SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to our patients in the near future.

Detailed Description
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The experimental aspects of this experimental plan will include: Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 20%; delivered IA, 12.5 mL over 2 minutes) in order to disrupt the blood brain barrier. This technique has been used in several thousand subjects in previous studies for the IA delivery of chemotherapy for malignant glioma. Subjects will then be treated with repeated intraarterial delivery (SIACI) of Bevacizumab. Each subject will receive one dose of IA Bevacizumab on day 30, followed by chemoradiation. SIACI of Bevacizumab will be repeated every three months for a total of 3 infusions.

Official Title
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Phase I/II Trial of Repeated Super-Selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Newly Diagnosed Glioblastoma Multiforme

Conditions
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Glioblastoma Multiforme, Brain Tumor

Intervention / Treatment
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* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Criteria for Inclusion: Male or female patients of ≥18 years of age. Patients with documented histologic diagnosis of glioblastoma multiforme (newly diagnosed) Patients must have at least one confirmed and evaluable tumor site.∗ *A confirmed tumor site is one which is biopsy-proven. NOTE: Radiographic procedures (e.g., Gd-enhanced MRI or CT scans) documenting existing lesions must have been performed within three weeks of treatment on this research study. Patients must have a Karnofsky performance status ≥70% (or the equivalent ECOG level of 0-2) and an expected survival of ≥ three months. 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. Criteria for Exclusion: Previous treatment with Bevacizumab. Women who are pregnant or lactating. Women of childbearing potential and fertile men who decline to 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIACI of Bevacizumab<br>Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab | Drug: Bevacizumab<br> <br> * Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite overall response rate (CORR) | Composite overall response rate (CORR) through the Response Assessment in Neuro-Oncology (RANO) | 6 month | 
| Progression-free survival (PFS) and Overall survival (OS) | OS will be measured from the date of the first dose of SIACI Bevacizumab to the date of death. A two-year follow-up time is expected to determine the safety of repeated superselective intracranial intraarterial infusions of Bevacizumab at a dose of 15 mg/kg IA. | 6-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities | The descriptive frequency of subjects experiencing toxicities will be tabulated. | 1 month ongoing |