Carboxylesterase-Expressing Allogeneic Neural Stem Cells and Irinotecan Hydrochloride in Treating Patients With Recurrent High-Grade Gliomas

PRIMARY OBJECTIVES:

I. To define the recommended phase II doses (RP2D) of intracranially administered hCE1m6-NSCs
(carboxylesterase-expressing allogeneic neural stem cells) in combination with intravenous
irinotecan in patients with recurrent high grade glioma.

SECONDARY OBJECTIVES:

I. To describe the relationship between hCE1m6-NSC dose and SN-38 (liposomal SN-38)
concentrations in brain interstitium.

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

III. To investigate the biologic activity of hCE1m6 NSCs by comparing SN-38 concentrations in
the brain after treatment with hCE1m6-NSCs and irinotecan versus irinotecan alone.

IV. To assess for possible development of adenovirally transduced neural stem cell (NSC)
immunogenicity after first exposure and with repeat doses of NSCs.

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 intracranially over
1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan
hydrochloride intravenously (IV) over 90 minutes on days 3 and 17. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 and 6 months and then
annually thereafter for 15 years.

Inclusion Criteria:

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

- Participant must be willing to comply with study and/or follow-up procedures

- Karnofsky performance status >= 70%

- Life expectancy of >= 3 months

- 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 tumor(s); if a patient is going to be
enrolled to dose level two or higher, the patient must have a component of
supratentorial disease (so as to enable placement of a Rickham reservoir/catheter)
that is amenable to resection or biopsy

- High-grade glioma has recurred or progressed after prior treatment with brain
radiation and temozolomide

- Participant 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 judgment, there is no anticipated physical connection
between the post-resection tumor cavity and the cerebral ventricles

- Neurosurgeon finds the prospective participant is able to undergo neurosurgery

- Any number of prior therapies is permitted; from the start of study treatment, the
following time periods must have elapsed: 6 weeks from nitrosourea-containing
chemotherapy, 4 weeks from non-nitrosourea-containing cytotoxic chemotherapy (except
23 days from last daily dose of temozolomide taken in a 5 of 28 day regimen), and 2
weeks from last dose of a targeted agent (except 4 weeks for bevacizumab); there is no
time period requirement for prior radiation therapy

- Any clinically significant toxicity from prior therapy must have improved to grade 0
or grade 1

- Absolute neutrophil count (ANC) >= 1,500 cells/ul

- Platelets > 100,000 cells/ul

- Total bilirubin =< 2.0 mg/dl

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

- Serum creatinine =< 1.5 x the institutional upper limit of normal

- Homozygous negative for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT
1A1)*28 allele

- Absence anti-human leukocyte antigen (HLA) antibodies specific for HLA class I
antigens expressed by the coagulation factor III (thromboplastin, tissue factor)
(F3).cytosine deaminase (CD).carboxylesterase (CE) NSCs

- Negative serum pregnancy test (women of childbearing potential only)

- Agreement by females of childbearing potential and sexually active males 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

Exclusion Criteria:

- Prior therapy with neural stem cells

- Use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers
including hepatic enzyme-inducing anticonvulsants (phenytoin, fosphenytoin,
carbamazepine, phenobarbital, primidone, oxcarbazepine) within 2 weeks prior to start
of study treatment

- Use of moderate to strong CYP3A4 inhibitors within 2 weeks prior to start of study
treatment

- Use of drugs known to inhibit UGT1A1, such as atazanir, gemfibrozil, indinavir, or
ketoconazole, within 2 weeks prior to start of study treatment

- Co-medication that may interfere with study results; e.g. immuno-suppressive agents
other than corticosteroids, such as systemic cyclosporine and tacrilomus; consult
principal investigator for questions, including necessary washout period for the
specific drug

- Flucytosine within 2 weeks prior to start of study treatment

- Use of herbal medications

- Current use (or planned use during the treatment period) of other investigational
agents, or biological, chemotherapy, radiation or other anti-tumor therapy

- Patient has known human immunodeficiency virus (HIV) or hepatitis C infection;
baseline testing for HIV or hepatitis C is not required

- Prospective participant is unable to undergo a magnetic resonance imaging (MRI) with
contrast agent

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

- Clinically significant uncontrolled illness

- Active infection requiring antibiotics

- Diagnosis of Gilbert's disease

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

- Known sensitivity to any of the products to be administered during dosing

- Any other active malignancy

- Pregnant women and women who are lactating

- 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

- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)