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

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and best dose of carboxylesterase-expressing allogeneic neural stem cells when given together with irinotecan hydrochloride in treating patients with high-grade gliomas that have come back. Placing genetically modified neural stem cells into brain tumor cells may make the tumor more sensitive to irinotecan hydrochloride. Irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving carboxylesterase-expressing allogeneic neural stem cells and irinotecan hydrochloride may be a better treatment for high-grade gliomas.

Detailed Description
-----------------
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 liposomal 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.

Official Title
-----------------
A Phase I Study of Intracranially Administered Carboxylesterase-Expressing Neural Stem Cells in Combination With Intravenous Irinotecan in Patients With Recurrent High-Grade Gliomas

Conditions
-----------------
Recurrent Anaplastic Astrocytoma, Recurrent Anaplastic Oligoastrocytoma, Recurrent Anaplastic Oligodendroglioma, Recurrent Glioblastoma, Recurrent Gliosarcoma, Recurrent Malignant Glioma, Recurrent WHO Grade III Glioma

Intervention / Treatment
-----------------
* Biological: Carboxylesterase-expressing Allogeneic Neural Stem Cells
* Drug: Irinotecan
* Drug: Irinotecan Hydrochloride
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (hCE1m6-NSCs and irinotecan hydrochloride)<br>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. | Biological: Carboxylesterase-expressing Allogeneic Neural Stem Cells<br>* Given intracranially<br>* Other names: hCE1m6-NSC;Drug: Irinotecan<br>* Given IV<br>Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: Irinotecan Monohydrochloride Trihydrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | Tables will be created to summarize all toxicities and side effects by dose, course, organ severity (by NCI CTCAE version 4.0), and attribution. Rates and associated 95% Clopper Pearson confidence limits will be estimated for DLTs. | 28 days | 
| Incidence of all attributable toxicities graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | Tables will be created to summarize all toxicities and side effects by dose, course, organ severity (by NCI CTCAE version 4.0), and attribution. | Up to 30 days after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameters, including maximum concentration and area under the curve of irinotecan and SN-38 in dialysate and plasma | Pharmacokinetic data from patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods. The biologic activity of the carboxylesterase-expressing allogeneic neural stem cells (hCE1m6-NSCs) will be assessed using a one-sided two-sample t test. Regression analysis will be used to assess the relationship between hCE1m6-NSC dose and liposomal SN-38 concentrations in brain interstitium using microdialysis data from the patients treated with the initial neural stem cells (NSC) dose and from the patients in the expansion cohort treated with the highest NSC dose. | Pre-dose, at 90 minutes (just prior to the end of the infusion), and then at 30 minutes, 1, 2, 4, 8, 24, and 48 hours after the end of the infusion | 
| Development of neural stem cells (NSC) immunogenicity after first and repeat exposures | Will be summarized using descriptive statistics and graphical methods. | Up to 15 years | 
| Clinical benefit, defined by tumor response based on magnetic resonance imaging (MRI) results | Rates and associated 95% Clopper Pearson confidence limits will be estimated for clinical benefit at the recommended phase II dose. | Up to 15 years | 
| Fate of the neural stem cells (NSCs), defined by NSC persistence | Will be summarized using descriptive statistics and graphical methods. | Up to 15 years |