This phase I trial tests the safety, side effects, and best dose of intracerebroventricularly (ICV) administered CD19-chimeric antigen receptor (CAR) T cells in treating patients with central nervous system (CNS) lymphoma. 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 cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein, CD19, on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. ICV is an injection technique that delivers the CD19-CAR T cells directly into the cerebrospinal fluid (which flows in and around the hollow spaces of the brain and spinal cord, and the thin layers of tissue that cover and protect the brain and spinal cord) in the brain, through a surgically placed catheter. Giving CD19-CAR T cells ICV may be more effective at treating patients with CNS lymphoma than giving them via other methods.
PRIMARY OBJECTIVES: I. Examine and describe the safety and feasibility of ICV delivery of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem T-lymphocytes (CD19-CAR T cells) and determine the recommended phase 2 dose (RP2D) in participants with primary CNS lymphoma, or secondary lymphoma with CNS only relapse. II. Determine the activity of ICV-delivered CD19-CAR T cells based on disease response at the maximum tolerated dose (MTD). SECONDAY OBJECTIVES: I. Describe persistence, expansion and phenotype of endogenous and CD19-CAR T cells in peripheral blood (PB), and cerebral spinal fluid (CSF), when available. II. Describe cytokine levels (PB, CSF) over study period. III. Quantify B-cell aplasia over the treatment period as a surrogate for targeted cytotoxicity in the periphery. IV. Assess prolonged cytopenia based on prolonged grade 4 continuous or intermittent anemia, neutropenia, thrombocytopenia, and hypogammaglobulinemia \> 60 days or deemed medically significant. V. Estimate rates of disease response. VI Estimate rate of 6-month progression free survival (PFS6mon). VII. Estimate median overall survival (OS). EXPLORATORY OBJECTIVES: I. Characterize changes in potential molecular and gene-analysis based indicators of neurotoxicity in CSF and PB. II. Describe the tumor phenotype pre- and post-therapy. III. Characterize functional and phenotypic metabolic profile of CAR T cells pre- and post-infusion. IV. Assess the presence and magnitude of human anti-mouse antibody (HAMA). OUTLINE: This is a dose-escalation study followed by a dose-expansion study. Patients may undergo catheterization, undergo leukapheresis, may receive fludarabine intravenously (IV) and cyclophosphamide IV, and receive CD19-CAR T cells ICV on study. Patients also undergo magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), collection of blood samples, and CSF aspiration throughout the trial, and lumbar puncture as clinically indicated.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Undergo CSF aspiration
Undergo blood sample collection
Undergo catheterization
Given ICV
Undergo CT
Given IV
Given IV
Undergo leukapheresis
Undergo lumbar puncture
Undergo MRI
Undergo PET
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of adverse events
Will be assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0, particularly dose-limiting toxicities (DLTs), cytokine release syndrome (CRS) based on the revised CRS grading system by American Society for Transplantation and Cellular Therapy Consensus Criteria, and all other toxicities. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for participants experiencing DLTs, each type of cytopenia, disease response and progression free survival (PFS) at 6 months. All toxicities and side effects will be summarized in tables by period, organ, severity and attribution.
Time frame: Up to 15 years
Disease response
Will be assessed per International Primary Central Nervous System Lymphoma Collaborative Group criteria.
Time frame: Up to 15 years
Chimeric antigen receptor (CAR) T and endogenous T cell levels and phenotype
Detected in peripheral blood (PB) and cerebral spinal fluid (CSF) when available, (absolute number per uL by flow). CAR T cell level and cytokines will be interrogated if CRS or neurotoxicity attributed at the probable level to CAR T cells are observed. Statistical and graphical longitudinal methods will be used to describe the profile of the CAR T cells, and endogenous immune cell populations including B cells through one-year post T cell infusion. Regression analysis will be used to assess the relationship between CAR T cell levels and B cells levels.
Time frame: Through 1 year post T cell infusion
Cytokine levels
Measured in PB, and CSF, when available. CAR T cell level and cytokines will be interrogated if CRS or neurotoxicity attributed at the probable level to CAR T cells are observed. Cytokine levels (PB and CSF) will be described using longitudinal statistical and graphical methods over the study period.
Time frame: Up to 15 years
B cell level
Measured in PB. CAR T cell level and cytokines will be interrogated if CRS or neurotoxicity attributed at the probable level to CAR T cells are observed. Statistical and graphical longitudinal methods will be used to describe the profile of the CAR T cells, and endogenous immune cell populations including B cells through one-year post T cell infusion. Regression analysis will be used to assess the relationship between CAR T cell levels and B cells levels.
Time frame: Through 1 year post T cell infusion
Anemia, neutropenia, thrombocytopenia, and hypogammaglobulinemia lasting longer than 60 days or deemed medically significant
Measured in PB. Rates and associated 90% Clopper and Pearson Binomial confidence limits will be estimated for each type of cytopenia.
Time frame: Up to 15 years
PFS time
Patients are considered a failure for this endpoint if they die (regardless of cause) or experience disease relapse.
Time frame: At 6 months
Overall survival (OS) time
Kaplan Meier methods will be used to estimate median OS and graph the results.
Time frame: Up to 15 years
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