Chronic Convection Enhanced Delivery of Topotecan

Malignant gliomas are among the most pernicious of human tumors - locally invasive and
universally recurrent, with recurrence usually occurring within two centimeters of the
original resection cavity. Although numerous chemotherapeutic drugs demonstrate significant
anti-tumor activity in preclinical studies, the efficacy in clinical trials has been dismal
because systemic delivery fails to achieve therapeutic drug levels in tumor cells due to
various factors including limited blood-brain barrier permeability and systemic toxicity.

Convection-enhanced delivery (CED) is a method of regional drug delivery that circumvents
this problem. Phase 1 clinical trial has shown that a potent topoisomerase inhibitor,
topotecan (TPT), can be safely and effectively delivered by CED into patients with recurrent
malignant gliomas. This study will expand on these clinical results to address two current
limitations to the clinical application of CED: 1) A reliable method for non-invasively
monitoring drug distribution throughout the tumor and brain does not exist; and 2) Duration
of CED therapy has been limited to short-term infusions secondary to the use of externalized
infusion pumps.

The hypothesis is that extended chronic local-regional delivery of TPT is safe, effective and
feasible in patients with recurrent gliomas. TPT will be directly and chronically delivered
into the tumor and surrounding brain by CED through subcutaneously implanted pumps while
innovating a methodology for monitoring the drug distribution through non-invasive imaging.
This strategy will overcome the limitations of chemotherapy as currently used in the
treatment of gliomas, and may be applicable to other central nervous system (CNS) diseases
currently limited by drug delivery barriers.

Inclusion Criteria:

- Patients must have a recurrent malignant glioma (World Health Organization (WHO) grade
III-IV), including recurrent glioblastoma, anaplastic astrocytoma, anaplastic
oligodendroglioma, anaplastic oligoastrocytoma, and anaplastic ependymoma.
Stereotactic biopsies will be performed to confirm this diagnosis prior to initiating
the treatment.

- Patients with tumors of the brain must have been previously treated with surgical
resection, external beam radiation, and temozolomide chemotherapy.

- An magnetic resonance (MR) scan must be obtained within 30 days of enrollment and must
demonstrate an enhancing mass without significant mass effect. Tumors must be less
than 32 cc in total volume. The lesion must be stereotactically accessible.

- Patients must have demonstrated evidence of increasing contrast enhancement on MR or
computed tomography (CT) imaging while on stable or increasing dose of steroid.

- Karnofsky performance score of greater than or equal to 60.

- Men and women of childbearing potential must practice birth control. Women of child
bearing potential must have a urine pregnancy test within 7 days of study entry.

- Patients must possess the ability to give Informed Consent.

- Patients must be willing to and medically capable of undergoing the surgical
operation.

- There is no upper age limit. Patients at extreme upper end of the age spectrum will
not be automatically excluded, but will be carefully scrutinized to determine their
suitability for this procedure.

- Patients must be at least 18 years old.

- Patients must have normal organ and marrow function as defined below:

- Leukocytes: ≥3,000/ cells per microliter of blood (mcL)

- Absolute neutrophil count: ≥1,500/mcL

- Platelets: ≥100,000/mcL

- Total bilirubin: within normal institutional limits

- aspartate aminotransferase (AST) (SGOT)/alanine aminotransferase (ALT) (SGPT):
≤2.5 × institutional upper limit of normal

- Creatinine: within normal institutional limits OR

- Creatinine clearance: ≥60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal.

Exclusion Criteria:

- Patients with diffuse subependymal or cerebral spinal fluid (CSF) disease.

- Patients with tumors involving the cerebellum or both cerebral hemispheres.

- Patients with an active infection requiring treatment or having an unexplained febrile
illness.

- Patients who are known HIV, Hepatitis B or Hepatitis C positive. HIV-positive patients
on combination antiretroviral therapy are ineligible because of the potential for
pharmacokinetic interactions with topotecan. In addition, these patients are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.

- Patients with systemic diseases which may be associated with unacceptable
anesthetic/operative risk.

- Patients who have previously received systemic topotecan for their tumor

- Patients who are not able to receive an MRI scan.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to topotecan, other topoisomerase inhibitors or gadolinium compounds.