This phase I trial tests the safety, side effects and best dose of TGFβR2KO/IL13Rα2 chimeric antigen receptor (CAR) T-cells given within the skull (intracranial) in treating patients with glioblastoma or IDH-mutant grade 3 or 4 astrocytoma that has come back after a period of improvement (recurrent) or that is growing, spreading, or getting worse (progressive). CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. When the cells are taken from the patient's own blood, it is known as autologous. Then the gene for special receptors that bind to a certain proteins on the patient's tumor cells are added to the T cells in the laboratory. The special receptors are called CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain tumors. Giving TGFβR2KO/IL13Rα2 CAR T cells may be safe, tolerable, and/or effective in treating patients with recurrent or progressive glioblastoma or grade 3 or 4 IDH-mutant astrocytoma.
PRIMARY OBJECTIVE: I. Assess the safety and determine the maximum tolerated dose (MTD) of intracranial (IC) administration of TGFβR2KO/IL13Rα2-CAR T cell therapy. SECONDARY OBJECTIVES: I. In participants who receive at least 50% of the assigned cell dose for each of the four cycles and at least 70% of the total cumulative dose for all cycles (1-4): Ia. Estimate overall response rates (ORR) and complete response (CR) rate at 3, 6, 9-months; and Ib. Estimate overall survival (OS) at 9-months. II. Determine feasibility of IC administered TGFβR2KO/IL13Rα2-CAR T cell therapy as assessed by leukapheresis and manufacturing processes, including ability to meet the TGFβR2KO/IL13Rα2-CAR T cell dose and product release requirements; III. Determine the maximum feasible dose (MFD), as assessed by leukapheresis, manufacturing, toxicity, and response data. EXPLORATORY OBJECTIVES: I. Descriptively compare CAR T persistence in the cerebrospinal fluid (CSF) and the blood, cytokine dynamics, and response among patients treated on institutional review boards (IRBs) 24717 and 13384. II. Profile cytokine levels and graphically evaluate cytokine levels over time and changes in the presence of cytokine release syndrome (CRS) toxicity (CSF, tumor cavity fluid \[TCF\], peripheral blood \[PB\]). III. Describe CAR T cell and endogenous immune cell populations (CSF, TCF, PB). IV. Describe tumor and tumor micro-environment markers and their relationship to treatment outcomes. V. For participants who undergo secondary resection(s) or autopsy on study: Va. Evaluate CAR T cell persistence in the tumor micro-environment, location of the CAR T cells with respect to the injection site; and Vb. Evaluate changes in IL13Rα2 antigen expression levels pre and post CAR T cell therapy. VI. Through the use of biomathematical modeling techniques, characterize tumor growth and its relationship to treatment outcomes. OUTLINE: This is a dose-escalation study. Patients undergo leukapheresis and standard of care surgical resection with or without placement of Rickham catheter. Starting on day 0, patients receive autologous TGFβR2KO/IL13Rα2-CAR T cells intracranially over approximately 5 minutes once weekly (QW). Cycles repeat weekly for up to 4 cycles (28 days) in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles if they continue to meet infusion criteria and have doses available for infusion. Patients also undergo CSF and blood sample collection and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) and MRI throughout the study. Additionally, patients may undergo echocardiography at screening. After completion of study treatment, patients are followed up on day 30, months 3, 6, 9 and 12, then yearly for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Undergo CSF and blood sample collection
Given autologous TGF-betaR2KO/IL13R-alpha2-CAR T cells intracranially
Undergo echocardiography
Undergo FDG-PET
Undergo placement of Rickham catheter
Undergo leukapheresis
Undergo MRI
Undergo FDG-PET
Undergo surgical resection
City of Hope Medical Center
Duarte, California, United States
RECRUITINGDose-limiting toxicities (DLTs)
Will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants experiencing DLTs at the maximum tolerated dose schedule
Time frame: Up to 28 days
Incidence of grade 3+ adverse events (AEs)
Will be assessed using the CTCAE v 5.0. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm. In study participants who received the full schedule of 4 cycles.
Time frame: Up to 30 days after last dose of study drug
Incidence of cytokine release syndrome
Will be graded using American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Criteria. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm. In study participants who received the full schedule of 4 cycles.
Time frame: Up to 30 days after last dose of study drug
Incidence of all other AEs
Will be assessed using the CTCAE v 5.0. Neurotoxicity will be graded using ASTCT Consensus Criteria, Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome grading system, and tumor inflammation-associated neurotoxicity grading system. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm.
Time frame: Up to 30 days after last dose of study drug
Overall response rate
Evaluated using Response Assessment in Neuro-Oncology (RANO) criteria. Will estimate the rates (90% CI) of disease response.
Time frame: At 3, 6, and 9 months
Complete response rate
Evaluated using RANO criteria. Will estimate the rates (90% CI) of disease response.
Time frame: At 3, 6, and 9 months
Overall survival (OS)
Will estimate the rates (90% CI) of OS. Kaplan Meier methods will be used to estimate median OS and graph the results.
Time frame: From cycle 1 to last contact or death from any cause, assessed at 9 months
Ability to meet the TGFβR2KO/IL13Rα2-CAR T cell dose requirements (product feasibility)
Time frame: Up to 1 year
Ability to meet product release requirements (product feasibility)
Time frame: Up to 1 year
Maximum feasible dose (MFD)
The MFD will be determined based on observed toxicities/DLTs, including toxicities experienced in later cycles (5+), leukapheresis, manufacturing, and response data.
Time frame: Up to 1 year
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