Clinical Trial Finder

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 tacrolimus; 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)

PRIMARY OBJECTIVE:

• I. To define the recommended phase II doses (RP2D) of intracranially administered carboxylesterase-expressing allogeneic neural stem cells (hCE1m6-NSCs) 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 (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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 3 and 6 months, and then annually thereafter for a minimum of 15 years.

Arms

Experimental: Treatment (hCE1m6-NSCs and irinotecan hydrochloride)

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 IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions

Biological: - Carboxylesterase-expressing Allogeneic Neural Stem Cells

Given intracranially

Drug: - Irinotecan

Given IV

Drug: - Irinotecan Hydrochloride

Given IV

Other: - Laboratory Biomarker Analysis

Correlative studies

Other: - Pharmacological Study

Correlative studies