Genetically Modified Stem Cells and Irinotecan Hydrochloride in Treating Patients With Recurrent High-Grade Gliomas

PRIMARY OBJECTIVES:

I. To define the recommend phase II doses of intracranially administered active modified
human form of carboxylesterase (hCE1m6)- neuronal stem cells (NSCs)
(carboxylesterase-expressing allogeneic neural stem cells) in combination with intravenous
irinotecan (irinotecan hydrochloride).

II. To determine the biologic activity of the hCE1m6-NSCs by comparing SN-38 concentrations
in the brain after treatment with hCE1m6-NSCs and irinotecan compared to irinotecan alone.

SECONDARY OBJECTIVES:

I. To investigate the relationship between hCE1m6-NSC dose and SN-38 concentrations in brain
interstitium.

II. To characterize the relationship between intracerebral and systemic concentrations of
irinotecan and SN-38.

III. To assess for possible development of NSC immunogenicity after first exposure and with
repeat doses of NSCs.

IV. To evaluate the intracerebral distribution of NSCs by using iron-labeling as a cellular
tracker.

V. To describe the clinical benefit (defined as stable disease, partial response, or
complete response) in patients who receive treatment with repeat cycles of NSCs and
irinotecan.

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

OUTLINE: This is a dose-escalation study of carboxylesterase-expressing allogeneic neural
stem cells.

Patients receive carboxylesterase-expressing allogeneic neural stem cells via intracerebral
catheter on day 1 of week 1; weeks 1 and 3, weeks 1, 2, and 3; or weeks 1, 2, 3, and 4.
Patients also receive irinotecan hydrochloride intravenously (IV) over 90 minutes on day 3
of week 1; weeks 1 and 3, weeks 1, 2, and 3; or weeks 1, 2, 3, and 4. Courses repeat every 6
weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 15 years.

Inclusion Criteria:

- Patient has a prior, histologically-confirmed, diagnosis of a grade III or IV glioma
(including glioblastoma, 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)

- 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

- PROTOCOL-SPECIFIC CRITERIA

- 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

- Patients who will undergo tumor resection must have residual enhancing tumor (i.e. a
gross total resection is not anticipated)

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

- Absolute neutrophil count (ANC) of >= 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

- Patient must be able to understand and be willing to sign a written informed consent
document

- INCLUSION CRITERIA FOR MTD COHORT 2

- Patient has a prior, histopathologically-confirmed diagnosis of glioblastoma

- Patient has not received any therapy for recurrent disease

- INCLUSION CRITERIA FOR PROCEEDING TO TREATMENT WITH IRINOTECAN DURING CYCLE 1

- A patient's daily total dose of dexamethasone must be =< 16 mg by day 3

Exclusion Criteria:

- Patient is homozygous or heterozygous for the UDP glycosyltransferase 1 family,
polypeptide A1*28 allele (UGT 1A1*28) allele and/or has Gilbert's disease

- Patient must not be taking any cytochrome P450 3A4 (CYP3A4) hepatic enzyme-inducing
anticonvulsants (phenytoin, fosphenytoin [Cerebyx], carbamazepine, phenobarbital,
primidone, oxcarbazepine) or other moderate to strong CYP3A4 inhibitors or inducers
for at least 2 weeks prior to start of study treatment

- Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens
expressed by the F3.CD.CE 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, and at least 2 weeks from taking the last dose of a targeted
agent and the start of study treatment, with the exception of bevacizumab, where a
wash out period of at least 4 weeks is required before starting study treatment

- Patient is taking flucytosine

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

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

- Patient may not be receiving any other investigational agents, or concurrent
biological, chemotherapy, or radiation therapy

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to irinotecan

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is participating in this study

- A patient with another active malignancy is ineligible for this study

- Non-compliance