A Study of Intraventricular Liposomal Encapsulated Ara-C (DepoCyt) in Patients With Recurrent Glioblastoma

Despite significant improvements in diagnostic imaging and neurosurgical techniques, the
current treatment modalities for high-grade gliomas are inadequate. As such, the median
survival for most patients with GBM is on the order of months, even after cytoreductive
surgery, radiation and chemotherapy. Fewer than 3% of GBM patients are still alive at 5 years
after diagnosis. A rising incidence has been reported for GBM, and the survival rate for
patients with GBM has not shown improvement in the last two decades. For this reason
exploring novel therapies for the treatment of GBM is warranted.

Neuro-oncology is currently in the midst of a paradigm shift in terms of our accepted
understanding of the pathophysiology of gliomagenesis. Classic "dedifferentiation"
hypotheses, modeling the cellular origin of gliomas after neoplastic transformation of
differentiated glia, are currently being challenged by hypotheses suggesting dysregulated
glial progenitor cells are responsible for gliomagenesis. Growing evidence exists that glial
progenitor cells persisting in the adult mammalian brain, lining the lateral ventricles in
the subventricular zone (SVZ) and dentate gyrus, play a role in gliomagenesis. Gliomas
frequently occur in close proximity to the ventricular system and SVZ with high-grade lesions
like GBM "spreading" to midline structures and crossing the corpus callosum to the
contralateral hemisphere. Glial progenitor cells lining the lateral ventricles in the SVZ and
dentate gyrus may be the source of "tumor" cells "spreading" to midline structures such as
the corpus callosum as well as continuously replenishing the tumor bed resulting in local
recurrences.

The lack of significant clinical advances in treating GBM may be due to oversight of the SVZ
component of this disease. It is our hypothesis that successful treatment of GBM will require
suppression of the SVZ component in addition to the currently accepted modalities of
hemispheric tumor resection followed by radiation and chemotherapy. This understanding of
gliomagenesis has not yet been used clinically for the treatment of GBM. We hypothesize that
the SVZ is the incubator for future recurrences of GBM and propose targeting SVZ progenitor
cells with intraventricular liposomal encapsulated Ara-C (DepoCyt) in combination with
systemic metronomic dose temozolomide. Ara-C has been previously demonstrated to inhibit the
proliferation and migration of SVZ precursor cells in adult animals. Two patients treated
using this novel regimen have demonstrated significant responses warranting further study of
this treatment in the Phase I/II clinical trial proposed here. This has also been the basis
for successful application and granting of Orphan-Drug designation for cytarabine (Ara-C)
liposome injection (trade name: DepoCyt) for the treatment of gliomas (Designation # 06-2348)
on January 30, 2007.

Inclusion Criteria:

- Age Patients must be at least 18 years of age but no older than 85 years.

- Diagnosis Patients with the histological diagnosis of recurrent GBM made either by
biopsy or resection of recurrent disease. Cytological evidence of malignant cells in
CSF and/or clinical and radiographic evidence of leptomeningeal disease are irrelevant
in terms of inclusion or exclusion into this study. Bihemispheric extension
("butterfly GBM"), multi-focality, and/or subependymal spread are not
contraindications to enrollment.

- Prior therapy Patients must have had an initial diagnosis of "malignant glioma" (WHO
grade III or IV) and failed initial surgical resection followed by standard adjuvant
therapy including external beam radiotherapy to a 2cm margin of 60 Gy, and standard
temozolomide chemotherapy of 150 to 200 mg per square meter for 5 days during each
28-day cycle prior to "recurrence." Patients must not have received more than one
other systemic or ITV adjuvant chemotherapy regimen in addition to temozolomide prior
to enrollment, not including intracavitary Gliadel wafer placement. Prior Gliadel
wafer placement is not a contradiction to patient enrollment in this trial.

- Performance Status Patients must have Karnofsky performance status (KPS) of ≥ 60%.

- Recovery from Prior Therapy Patients must have recovered from the acute toxic effects
of all prior chemotherapy, immunotherapy, or radiotherapy, prior to entering this
study and must be without significant systemic illness (e.g. infection unresponsive to
treatment after 7 days). Such that they are healthy enough to safely undergo tumor
biopsy and Ommaya reservoir placement. Patients must not have received any systemic
therapy for recurrent disease within 3 weeks (6 weeks if a nitrosourea), or
irradiation within 8 weeks prior to treatment on this study.

- Hematologic Status Patients must have a platelet count > 75,000/mm3 and ANC > 1500/mm3
within 72 hours prior to ITV DepoCyt treatment.

- Hepatic and Renal Status Patients must have adequate liver function (total bilirubin <
2.0 mg%; ALT, and AST < 4 times normal); adequate renal function (serum creatinine
<1.6 mg, and BUN < 22); normal serum electrolytes (sodium, potassium, calcium,
magnesium, and phosphorus).

- Informed Consent (See Appendix) All patients or their legal guardians must sign a
document of informed consent indicating their awareness of the investigational nature
and the risks of this study.

Exclusion Criteria:

- Patients younger than 18 or older than 85 years of age.

- Patients with histological diagnoses other than recurrent GBM.

- Patients with a Karnofsky performance status (KPS) < 60%.

- Patients that have received more than one other systemic or ITV adjuvant chemotherapy
regimen in addition to temozolomide, not including intracavitary Gliadel wafer
placement.

- Patients concurrently receiving other therapies (either brachytherapy or systemic)
designed specifically to treat the recurrent GBM.

- Patients within 8 weeks of receiving stereotactic or external beam irradiation.

- Patients with a platelet count < 75,000/mm3 and ANC < 1500/mm3 within 72 hours prior
to ITV DepoCyt and/or oral temozolomide treatment.

- Patients with liver dysfunction (total bilirubin > 2.0 mg%; ALT, and AST > 4 times
normal).

- Patients with renal dysfunction (serum creatinine >1.6 mg, and BUN > 22).

- Patients with abnormal serum electrolytes (sodium, potassium, calcium, magnesium, and
phosphorus).

- Patients with contraindications to having placement of a ventricular access device
such as Ommaya reservoir.

- Patients with clinical and/or neuroradiographic evidence of hydrocephalus or increased
intracranial pressure.

- Patients with signs and symptoms of systemic infection precluding them from receiving
chemotherapy or prohibiting Ommaya reservoir placement.

- Pregnant and breast feeding women will be excluded. All other women of childbearing
years must have a negative serum pregnancy test.

- Patients with a ventricular-peritoneal or ventricular-atrial shunt.

- Prisoners will be excluded from this study.

- Patients or their legal guardians not willing or able to sign the informed consent
document.