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.