Genetically Modified Neural Stem Cells, Flucytosine, and Leucovorin for Treating Patients With Recurrent High-Grade Gliomas

PRIMARY OBJECTIVES:

I. To define the phase II recommended dose of intracerebrally administered cytosine deaminase
(CD)-expressing neural stem cells (NSCs) in combination with oral 5-fluorocytosine (FC)
(flucytosine) and leucovorin.

II. To determine the feasibility of treating study patients with more than 1 dose of NSCs
followed by 7-day courses of 5-FC and leucovorin.

SECONDARY OBJECTIVES:

I. To assess for possible development of NSC immunogenicity (anti-NSC T cell and/or antibody
response) with repeat doses of NSCs.

II. To characterize the relationship between intracerebral and systemic concentrations of
5-FC and 5-FU at the maximum tolerated dose/maximum feasible dose level.

III. To describe the clinical benefit (defined as stable disease, partial response, or
complete response) of this treatment regimen.

IV. To determine, at time of autopsy, the fate of the NSCs.

OUTLINE: This is dose-escalation study of CD-expressing genetically modified neural stem
cells and flucytosine.

Patients receive CD-expressing neural stem cells intracranially (IC) on days 1 and 15 and
flucytosine orally (PO) every 6 hours on days 4-10 and 18-24. Depending on when a subject
enters the study, s/he may also be given leucovorin orally every 6 hours on days 4-10 and
18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed at 30 days, 3 months, 6 months, 1
year, and then annually thereafter.

Inclusion Criteria:

- Patient has had a prior, histologically-confirmed, diagnosis of a grade III or IV
glioma (including glioblastoma, anaplastic oligodendroglioma, or anaplastic
astrocytoma, gliosarcoma, anaplastic oligodendroglioma, or anaplastic
oligoastrocytoma), or has a prior, histologically-confirmed, diagnosis of a grade II
glioma and now has radiographic findings consistent with a high-grade glioma (grade
III or IV)

- Imaging studies show evidence of recurrent, supratentorial tumor(s). The presence of
infratentorial tumor is allowed as long as the patient also has supratentorial disease
that is amenable to resection or biopsy.

- Patient's high-grade glioma has recurred or progressed after prior treatment with
brain radiation and temozolomide

- Patient has a Karnofsky performance status of >= 70%

- Patient has a life expectancy of >= 3 months

- Female patients of childbearing potential and sexually-active male patients must agree
to use an effective method of contraception while participating in this study; women
of childbearing potential must have a negative pregnancy test =< 2 weeks prior to
registration

- The patient must be in need of a craniotomy for tumor resection or a stereotactic
brain biopsy for the purpose of diagnosis or differentiating between tumor progression
versus treatment-induced effects following radiation therapy +/- chemotherapy

- Based on the neurosurgeon's judgement, there is no anticipated physical connection
between the post-resection tumor cavity and the cerebral ventricles

- Absolute neutrophil count (ANC) >= 1500 cells/mm^3

- Platelet count >= 100,000 cells/mm^3

- Total bilirubin =< 2.0 mg/dl

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4
times the institutional upper limit of normal

- Serum creatinine =< the institutional upper limit of normal

- There is no limit to the number of prior therapies

- All subjects must have the ability to understand and the willingness to sign a written
informed consent

Exclusion Criteria:

- Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens
expressed by the NSCs

- Patient has not recovered from any toxicity of prior therapies; an interval of

- At least 6 weeks must have elapsed since taking a nitrosourea-containing
chemotherapy regimen

- At least 4 weeks since completing a non-nitrosourea-containing cytotoxic
chemotherapy regimen (except temozolomide: only an interval of 23 days is
required from the last dose administered when patient has been recently treated
with the standard temozolomide regimen of daily for 5 days, repeated every 28
days)

- At least 2 weeks from taking the last dose of targeted agent

- At least 4 weeks from the last dose of bevacizumab

- Patient is unable to undergo a magnetic resonance imaging (MRI)

- Patient is allergic to 5-FC, leucovorin, or 5-FU

- Patient has chronic or active viral infections of the central nervous system (CNS)

- Patient has a coagulopathy or bleeding disorder

- Patient has an uncontrolled illness including ongoing or active infection

- Patient is receiving any other investigational agents, or concurrent biological,
chemotherapy, or radiation therapy

- Patient has had prior therapy with neural stem cells

- Patient is pregnant or breast feeding; pregnant women are excluded from this study;
breastfeeding should be discontinued if the mother is participating in this study

- Patient has another active malignancy

- Non-compliance; a patient has a serious medical or psychiatric illness that could, in
the investigator's opinion, potentially interfere with the safety monitoring
requirements and completion of treatment according to this protocol