Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab (Bevacizumab) For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma.

• Composite overall response rate: The composite overall response rate (CORR) will be examined. The overall response proportion along with a 95% confidence interval will be estimated via binomial proportions. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  
• Six-month progression-free survival PFS will be measured from the date of the first dose of SIACI Bevacizumab to the date of progression. OS will be measured from the date of the first dose of SIACI Bevacizumab to the date of death. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  

• The safety of repeated SIACI of mannitol and Bevacizumab at 15mg/kg. The descriptive frequency of subjects experiencing toxicities will also be tabulated. [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]
  

1. Non-technical research plan: The current standard of care for recurring GBM is for patients to receive Bevacizumab (Bevacizumab) intravenously (IV) at 10mg/kg with CPT-11 (Irinotecan) every two weeks until their tumor grows more than 25%. At that point, these patients are deemed treatment failures and are given another 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. The investigators have recently completed a Phase I clinical trial that has shown that SIACI of Bevacizumab is safe and effective up to a dose of 10mg/kg in patients with recurrent malignant glioma. This two arm open-label, randomized trial is a follow up study to that trial and will ask two simple questions: Is it safe to deliver repeated doses (every three months) of Bevacizumab intra-arterially using these super selective intra-arterial delivery techniques? Is it necessary to combine this IA regimen of treatment with biweekly IV Bevacizumab in order to improve progression free survival (PFS) and overall survival (OS)? Information from this trial will yield important answers to the durability and efficacy of this delivery technique and may radically change the way chemotherapy is given to the patients with brain tumors.

Current Standard of Care:

Day 0: Intravenous Bevacizumab (10mg/kg) and CPT-11 Day 14, 28 (and every two weeks thereafter): Intravenous Bevacizumab and CPT-11

Experimental portion of this proposal: This trial will have two experimental arms that will be open labeled and non-randomized:

ARM 1:

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) after Mannitol to open the blood brain barrier Day 28 Intravenous Bevacizumab (10mg/kg) every two weeks thereafter until disease progression on MRI scan.

If progression occurs, repeat Intraarterial Bevacizumab single dose (15mg/kg) to area of progression and wait 28 days and then restart Intravenous Bevacizumab (10mg/kg) every two weeks thereafter until progression on MRI scan.

Repeat Cycle

ARM 2:

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) after Mannitol to open the blood brain barrier Day 28 No IV Bevacizumab treatment If MRI shows progression then repeat Intraarterial Bevacizumab single dose (15mg/kg) to area of progression Repeat Cycle

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. The investigators have used this without complication in the 15 patients from the Phase I protocol as well.
2. To treat patients with one of two arms with repeated intraarterial delivery (SIACI) of Bevacizumab for patients with recurring or relapsing high grade glioma. Each arm gets IA delivery with one arm getting IV Bevacizumab biweekly as well and the other arm not getting intervening IV therapy. In each arm, IA therapy is repeated when MRI shows progression. Persistent progression after three intra-arterial chemotherapies would remove the patient from the trial Inclusion criteria: Males or females, 18 years of age, with documented histologic diagnosis of relapsed or refractory glioblastoma multiforme (GBM), anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma (AOA). The lesion must be <3.5cm in greatest diameter and circumscribed to fall within an area targetable by IA therapy. The patient's KPS > 70 and the patient must have a life expectancy greater than 12 weeks.

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 serial history, neurological and physical examinations together with MRI will be performed every cycle or approximately once a month. The following subjects will be taken off protocol: those with progressive disease after three cycles of IA therapy; those who experience dose-limiting toxicity (DLT). DLT will be defined as Grade III or worse non-hematologic and hematologic toxicity or Grade II or worse CNS hemorrhage. Follow-up will continue until disease progression or death. Survival will be measured from the time of the first dose of IA Bevacizumab® (given at the start of each treatment cycle).

This treatment may be harmful to a fetus if you were pregnant. If you are a female of childbearing age, you will be asked to practice birth control methods while participating in this research study and for 3 months following your 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