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About
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.
Full description
PRIMARY OBJECTIVES:
I. Assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded autologous memory-enriched T cells (Arms 1, 2, 3, or 4 = Tcm or Arm 5 = Tn/mem) that are genetically modified using a self-inactivating (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13Ra2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated CD19 (CD19t) for participants with recurrent/refractory malignant glioma in one of the following ways: (1) directly into the tumor (intratumoral), (2) into the tumor cavity (intracavitary), (3) into the lateral ventricles (intraventricular), or (4) into both the tumor/tumor cavity (intratumoral) and into the lateral ventricles (intraventricular) (dual delivery).
II. Determine maximum tolerated dose schedule (MTD)/maximum feasible dose schedule (MFD) and a recommended phase II dosing plan (RP2D) for each arm based on dose limiting toxicities (DLTs) and the full toxicity profile.
SECONDARY OBJECTIVES:
I. In research participants who receive the full schedule of three CAR+ T cell doses:
II. Describe cytokine levels (tumor cavity fluid, CSF, peripheral blood) over the study period.
III. Describe CAR T cell and endogenous immune populations (CSF, tumor cavity fluid, peripheral blood) over the study period; and IV. Identify tumor and tumor micro-environment markers associated with response to CAR T cells.
EXPLORATORY OBJECTIVES:
I. Assess the timing and extent of brain inflammation following CAR T cell administration; II. Evaluate CAR T cell product characteristics; and
III. For research participants who undergo a second resection or autopsy:
OUTLINE: This is a dose-escalation study. Research subjects will receive an initial low dose (cycle 1) followed by 2 additional infusions at a higher cell dose (cycles 2 and 3) of autologous IL13Ra2-CAR/CD19t+ Tcm or Tn/mem, potentially followed by additional cycles at up to the highest tolerated cell dose (cycles 4+). CAR T cells will be administered in one of four ways:
ARM 1: (Intratumoral delivery a/f biopsy): Patients receive IL13Ra2-CAR/CD19t+ Tcm directly into the tumor via intratumoral (ICTb) catheter. Patients who progress on intratumoral administration may move to intraventricular catheter for the optional infusions.
ARM 2: (Intratumoral delivery a/f biopsy/Intracavitary a/f resection): Patients receive IL13Ra2-CAR/CD19t+ Tcm directly into the tumor via intratumoral (ICTb) catheter, or into the tumor resection cavity via intracavitary (ICTr) catheter. Patients who progress on intratumoral/intracavitary administration may move to intraventricular catheter for the optional infusions.
ARM 3: (Intraventricular delivery): Patients receive IL13Ra2-CAR/CD19t+ Tcm via intraventricular (ICV) catheter.
ARM 4: (Dual delivery): Patients receive IL13Ra2-CAR/CD19t+ Tcm via ICTb/r catheter and ICV catheter. 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).
ARM 5: (Dual delivery): Patients receive IL13Ra2-CAR/CD19t+ Tn/mem via ICTb/r catheter and ICV catheter. 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).
CAR T cells will be administered at one of three dose schedules:
After completion of the study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10, and 12 months, and then yearly for 15 years.
Enrollment
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Inclusion criteria
SCREENING INCLUSION CRITERIA
Participant has a prior histologically-confirmed diagnosis of a grade III or IV glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now has radiographic progression consistent with a grade III or IV malignant glioma (MG) after completing standard therapy
Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of the initial radiation therapy
Karnofsky performance status (KPS) >= 60%
Life expectancy > 4 weeks
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
City of Hope (COH) Clinical Pathology confirms IL13R alpha 2+ tumor expression by immunohistochemistry (>= 20%, 1+)
All research participants must have the ability to understand and the willingness to sign a written informed consent
ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION
Research participant must not require more than 2 mg three times daily (TID) of dexamethasone on the day of PBMC collection.
Research participant must have appropriate venous access
At least 2 weeks must have elapsed since the research participant received his/her last dose of prior chemotherapy or radiation
ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT
Creatinine < 1.6 mg/dL
White blood cell (WBC) > 2,000/dl or
Absolute neutrophil count (ANC) > 1,000
Platelets >= 100,000/dl
International normalized ratio (INR) < 1.3
Bilirubin < 1.5 mg/dL
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limits of normal
An interval of at least 12 weeks must have elapsed since the completion of initial radiation therapy
Wash-out requirements (standard or investigational):
ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION
Research participant has a released cryopreserved T cell product
Research participant does not require supplemental oxygen to keep saturation greater than 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are progressive
Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias
Research participant does not have a fever exceeding 38.5° Celsius (C); there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren't any indications of meningitis
Research participant serum total bilirubin does not exceed 2 x normal limit
Research participant transaminases does not exceed 2 x normal limit
Research participant serum creatinine =< 1.8 mg/dL
Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell dose
Research participant platelet count must be >= 100,000; however, if platelet level is between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is >= 100,000
Research participants must not require more than 2 mg TID of dexamethasone during T cell therapy
Exclusion criteria
Primary purpose
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65 participants in 5 patient groups
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Data sourced from clinicaltrials.gov
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