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CLOSED TO ACCRUAL 03/02/2018.

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

Patients receive IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

Given via intratumoral or intraventricular catheter

IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells

Given via intratumoral, intracavitary, or intraventricular catheter

IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes

Laboratory Biomarker Analysis

Magnetic Resonance Imaging

Magnetic Resonance Spectroscopic Imaging

Quality-of-Life Assessment

Behnam Badie

This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells.

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded autologous memory-enriched T cells that are genetically modified using a self-inactivating (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13R alpha 2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated human cluster of differentiation 19 (CD19) for participants with recurrent/refractory malignant glioma in one of the following ways: stratum 1 (intratumoral delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ central memory T cells \[Tcm\]) (IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes), stratum 2 (intracavitary delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tcm, stratum 3 (intraventricular delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tcm), stratum 4 (dual delivery \[both intratumoral and intraventricular\] of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tcm), or stratum 5 (dual delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ naive and memory T cells \[Tn/mem\]).

II. To determine maximum tolerated dose schedule (MTD) and a recommended phase II dosing plan (RP2D) for each stratum based on dose limiting toxicities (DLTs) and the full toxicity profile.

SECONDARY OBJECTIVES:

I. To assess the timing and extent of brain inflammation, as assessed by magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS), following T cell administration.

II. To describe cytokine levels (cyst fluid, peripheral blood) over the study period.

III. In research participants who receive the full schedule of three CAR+ T cell doses IIIa. Estimate the six month progression free survival rate. IIIb. Estimate disease response rates. IIIc. Estimate median overall survival.

IV. In research participants who receive intraventricular infusions after progressing following intratumoral/intracranial infusions (stratum 1 or 2):

IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations, as well as cytokine and microenvironment profiles (cerebral spinal fluid \[CSF\], cyst fluid, peripheral blood) considering post progression therapy(ies), if applicable.

V. In research participants who receive at least one dose of CAR+ T cells estimate the mean change from baseline in quality of life using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ brain neoplasm (BN)-20 survey scale, domain and item scores during and post treatment.

VI. For research participants who undergo a second resection or autopsy:

VIa. To evaluate CAR T cell persistence in the tumor micro-environment and the location of the CAR T cells with respect to the injection.

VII. To evaluate IL13R alpha 2 antigen expression levels pre and post CAR T cell therapy.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 5 strata.

STRATUM I (Intratumoral delivery) CLOSED TO ACCRUAL 03/02/2018: Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.

STRATUM II (Intracavitary delivery): Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.

STRATUM III (Intraventricular delivery): Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.

STRATUM IV (Dual delivery): Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

STRATUM V (Dual delivery): Patients receive IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10, and 12 months, and then yearly for 15 years.

Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma

Phase I Study of Cellular ImmunoTx Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Pts With Rec/Ref MaligGlioma

Will be graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0, the revised cytokine release syndrome grading system as well as the modified neurological grading system.

Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants' experiencing DLTs at the recommended phase II dosing plan schedule.

Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and strata.

Descriptive statistics will be provided for brain inflammation (largest length of tumor) pre and post treatment.

Statistical and graphical methods will be used to describe the cytokine levels (cyst fluid, peripheral blood) over the study period.

Statistical and graphical methods will be used to describe the CAR T cell levels (cyst fluid, peripheral blood) over the study period.

Kaplan Meier methods will be used to estimate median PFS and graph the results.

Will be detected peripheral blood and cerebral spinal fluid.

Kaplan Meier methods will be used to estimate median overall survival and graph the results. OS will also be examined for all patients, as well as, separately for those that received initial treatment only and those that received intraventricular infusion following progression.

Estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and the domain scale and items scores from the QLQ-brain neoplasm20.

In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.

Spots Global Cancer Trial Database for refractory who grade iii glioma