Super-Selective Intraarterial Cerebral Infusion Of Temozolomide (Temodar) For Treatment Of Newly Diagnosed GBM And AA
Super-Selective Intraarterial Cerebral Infusion Of Temozolomide (Temodar) For Treatment Of Newly Diagnosed GBM And AA
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. Initial therapy has consisted of
 surgical resection, external beam radiation or both. More recently, a Phase 3 clinical
 published by Stupp et al in 2005 showed a benefit for using radiotherapy plus concomitant and
 adjuvant Temozolomide. Still, 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 Intra-arterial 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 Temozolomide (Temodar) has been shown to be active in human brain tumors but its
 actual central nervous system (CNS) penetration is unknown. This phase I clinical research
 trial will test the hypothesis that following the standard 42 day Temozolomide/radiotherapy
 regimen, Temozolomide can be safely used by direct intracranial superselective intra-arterial
 cerebral infusion (SIACI) up to a dose of 250mg/m2, followed by the standard maintenance
 cycle of temozolomide to ultimately enhance survival of patients with newly diagnosed GBM/AA.
 The investigators will determine the toxicity profile and maximum tolerated dose (MTD) of
 SIACI Temozolomide. The investigators expect that this project will provide important
 information regarding the utility of SIACI Temozolomide therapy for malignant gliomas, and
 may alter the way these drugs are delivered to our patients in the near future.
The current standard of care for newly diagnosed GBM is radiation therapy plus concomitant
 oral Temozolomide of doses of 75mg/m2 up to 150mg/m2. Because of the blood brain barrier
 (BBB) where drugs do not penetrate the blood vessel walls well to get into the brain, no one
 knows for sure if these oral drugs actually get into the brain after infusion. Previous
 studies have shown that intra-carotid artery (intra-arterial) delivery is superior to
 standard intravenous or oral delivery for increasing the penetration of drug to the brain.
 Previous techniques using intra arterial (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 into the arterial tree where
 chemotherapies can be delivered without the risk of adverse affects such as blindness.
 Therefore, this trial will ask one simple question: Is it safe to deliver a dose of
 Temozolomide intraarterially using these super selective delivery techniques in addition to
 the standard oral route of administration? This should not only increase the amount of drug
 that gets to the tumor but also spare the patient many of the adverse effects from a less
 selective delivery. Prior to this single dose of intra-arterial Temozolomide, the patient
 will also receive a dose of mannitol that will increase the permeability of the blood brain
 barrier to improve delivery of the agent to the brain. After this single dose of mannitol and
 Temozolomide, the patient will be evaluated for 4 weeks to assess for toxicity. If there is
 no toxicity at this point, then the patient will proceed with oral maintenance Temozolomide
 chemotherapy. In summary, this is a Phase I trial that is designed to test the safety of a
 single dose of intra-arterial delivery of Temozolomide immediately following 42 days of
 radiotherapy/oral temozolomide and prior to starting oral maintenance Temozolomide.

 To summarize:

 Current Standard of Care Therapy:

 Days 1-42: Adjuvant dose of Temozolomide 75mg/m2 for 42 days concomitant with focal
 radiotherapy Day 42: 4 week rest period Day 70: Maintenance dose of Temozolomide 150mg/m2
 once daily for Days 1-5 of a 28 day cycle for 6 cycles

 Experimental portion of this proposal:

 Days 1-42: Adjuvant dose of Temozolomide 75mg/m2 for 42 days concomitant with focal
 radiotherapy Day 42: Single Intra-arterial Mannitol to increase the permeability of the blood
 brain barrier followed by Intra-arterial Temozolomide single dose (starting at 75mg/m2 and up
 to 250mg/m2) followed by 4 week rest period Day 70: Maintenance dose of Temozolomide 150mg/m2
 once daily for Days 1-5 of a 28 day cycle for 6 cycles

 Therefore the experimental aspects of this treatment plan will include:

 1. On day 42, subjects will first be treated with Mannitol prior to chemotherapy infusion
 (Mannitol 25%; 3-10 mLs for 30seconds) in order to disrupt the blood brain barrier. This
 technique has been used in several thousand patients in previous studies for the
 intraarterial (IA) delivery of chemotherapy for malignant glioma.

 2. Following the addition of mannitol, the investigators will deliver a single SIACI dose
 of Temozolomide for patients with high-grade glioma. After a one-cycle observation
 period to assess for toxicity from the IA infusion, the subject will receive the
 standard oral maintenance regimen of Temozolomide chemotherapy. The Intra-Arterial
 Infusion Procedure will be done under general anesthesia and standard monitoring will
 occur.

 The dose escalation algorithm is as follows: The investigators will use a single intracranial
 superselective intra-arterial infusion of Temozolomide, starting at a dose of 75mg/m2 in the
 first three patients. Assuming no dose limiting toxicity during the next 28 days after the
 infusion, the patient will then begin standard maintenance oral Temozolomide chemotherapy
 regimen. The doses will be escalated from 75 to 100, to 150, 200, and finally 250mg/m2 in
 this Phase I trial.

 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. However, the investigators
 will evaluate response to the one time IA Temozolomide therapy with a MRI with the injection
 of contrast approximately 4 weeks after infusion. Follow-up of all patients in the trial
 after the IA Temozolomide therapy will continue until disease progression or death. Survival
 will be measured from the time of the dose of IA Temozolomide®. The investigators expect
 patients in the trial to be monitored for 12 months.
Criteria for Inclusion:

 -  Male or female patients of ≥18 years of age.

 -  Patients with a documented histologic diagnosis of newly diagnosed or glioblastoma
 multiforme (GBM), anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma
 (AOA).

 -  Patients must have at least one confirmed and evaluable tumor site.∗

 *A confirmed tumor site is one in which is biopsy-proven. NOTE: Radiographic
 procedures (e.g., Gad-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 ≥60% (or the equivalent ECOG level
 of 0-2) and an expected survival of ≥ three months.

 -  No other chemotherapy for two weeks prior to treatment under this research protocol

 -  Patients must have adequate hematologic reserve with WBC≥3000mm3, absolute neutrophils
 ≥1500mm3 and platelets ≥100,000 mm3. Patients who are on Coumadin must have a platelet
 count of ≥150,000 mm3

 -  Pre-enrollment chemistry parameters must show: bilirubin<1.5X the institutional upper
 limit of normal (IUNL); AST or ALT<2.5X IUNL and creatinine<1.5X IUNL.

 -  Pre-enrollment coagulation parameters (PT and PTT) must be ≤1.5X the IUNL.

 -  Concomitant Medications:

 -  Growth factor(s): Must not have received within 1 week of entry onto this study.

 -  Steroids: Systemic corticosteroid therapy is permissible in patients with CNS tumors
 for treatment of increased intracranial pressure or symptomatic tumor edema. Patients
 with CNS tumors who are receiving dexamethasone must be on a stable or decreasing dose
 for at least 1 week prior to study entry.

 -  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.

 -  Patients on steroids must receive prophylaxis for PCP pneumonia with Bactrim, unless
 they have a history of allergy to sulfa drugs.

 -  Patients must be able to understand and give written informed consent. Informed
 consent must be obtained at the time of patient screening.

 Exclusion Criteria:

 -  Women who are pregnant or lactating.

 -  Subjects who decline birth control. Women of childbearing potential and fertile men
 will be informed as to the potential risk of procreation while participating in this
 research trial and will be advised that they must 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.