The Efficacy and Safety of Brain-targeting Immune Cells (EGFRvIII-CAR T Cells) in Treating Patients With Leptomeningeal Disease From Glioblastoma. Administering Patients EGFRvIII -CAR T Cells May Help to Recognize and Destroy Brain Tumor Cells in Patients

Study Overview
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Brief Summary
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This phase I trial investigates the efficacy and safety of brain-targeting epidermal growth factor receptor chimeric antigen receptor immune cells (EGFRvIII-CAR T cells) in treating patients with leptomeningeal disease from glioblastoma. T cells are part of the immune system and help the body fight malignant tumours. Immune cells can be genetically modified to destroy brain tumor cells in the laboratory. EGFRvIII -CAR T cells are brain tumor specific and can enter and express its genes in immune cells. Administering patients EGFRvIII -CAR T cells may help to recognize and destroy brain tumor cells in patients with leptomeningeal disease from glioblastoma.

Detailed Description
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PRIMARY OBJECTIVES: Examine and describe the safety and feasibility of EGFRvIII-specific hinge-optimized CD3 ζ-stimulatory/41BB-co-stimulatory Chimeric Antigen Receptor autologous T-lymphocytes (EGFRvIII -CAR T cells) through intracerebroventricular (ICV) delivery as adjuvant therapy in participants with EGFRvIII+ leptomeningeal disease from glioblastoma. Determine the activity of EGFRvIII -CAR T cells based on survival rate at 12 months for both arms. SECONDARY OBJECTIVES: Describe persistence, expansion and phenotype of endogenous and EGFRvIII -CAR T cells in peripheral blood (PB), tumor cyst fluid (TCF) and cerebral spinal fluid (CSF) at applicable time points Describe cytokine levels in PB, TCF, and CSF at applicable time points Estimate the rate of disease response by Response Assessment in Neuro-Oncology Leptomeningeal Metastases (RANO LM) criteria Estimate rate of progression free survival at 6 months. Estimate rate of overall survival (OS) at 12 months by study arm. Estimate time to next treatment Evaluate EGFRvIII -CAR T cell persistence in the tumor tissue and the location of the EGFRvIII -CAR T cells with respect to the infusion site. Evaluate biomarkers and cytokine levels OUTLINE: Patients receive EGFRvIII -CAR T cells intracerebroventricular over 15 minutes on day 1. Patients may receive additional cycles based on the persistence of the cells. The patients are followed extensively according to the clinical pharmacology sampling plan; on days 1-30, months 2-12, and three times per year up to 10 years based on response

Official Title
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A Phase 1 Study to Evaluate EGFRvIII -Targeted Chimeric Antigen Receptor (CAR) T Cells for Adult Patients With Leptomeningeal Glioblastoma

Conditions
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Glioblastoma, Glioblastoma Multiforme, Glioma, Malignant

Intervention / Treatment
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* Biological: EGFRvIII-specific hinge-optimized CD3 ζ-stimulatory/41BB-co-stimulatory Chimeric Antigen Receptor autologous T-lymphocytes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has been treated for leptomeningeal metastases after intrathecal chemotherapy and/or radiation OR refuses to undergo additional radiation and/or intrathecal chemotherapy Participant must have a Karnofsky performance status (KPS) >= 60 Participant must have a life expectancy of >= 2 months Women of child-bearing potential must have negative serum pregnancy test and agree to use a reliable form of birth control prior to study entry and for at least two months following study treatment. Male research participants must agree to use a reliable form of birth control and not donate sperm during the study and for at least two months following study treatment Participant has a histologically confirmed EGFRvII+ (epidermal growth factor receptor) tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score >= 50) Participant or legal guardian must have the ability to understand and the willingness to sign a written informed consent Exclusion Criteria: Research participant requires supplemental oxygen to keep saturation greater than 95% Research participant requires dialysis Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy Failure of research participant or legal guardian to understand the basic elements of the protocol and/or the risks/benefits of participating in the study. Participant is unwilling to stop treatment with chemotherapy or endocrine therapy and/or radiation one week prior and during the first 4 cycles of the study Participant has ventriculoperitoneal shunt Participant has a coagulopathy or bleeding disorder Participant is HIV+ (human immunodeficiency virus) or has acute CMV (cytomegalovirus) infection Participant has any uncontrolled illness, including ongoing or active infection; participant has known active hepatitis B or C infection; participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections Participant has an autoimmune disease that requires constant treatment Participant has another active malignancy Participant is unable to undergo a brain magnetic resonance imaging (MRI) Participant is pregnant or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Patients receive EGFRvIII -CAR T cells intracerebroventricular over 15 minutes on day 1. Patients may receive additional cycles based on the persistence of the cells. | Biological: EGFRvIII-specific hinge-optimized CD3 ζ-stimulatory/41BB-co-stimulatory Chimeric Antigen Receptor autologous T-lymphocytes<br>* ICV administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | Up to 10 years | 
| Overall survival |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAR (chimeric antigen receptor) T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) | Measured by absolute number per ul by flow | Up to 6 cycles (3 months), at the end of each cycle 1 (each cycle is 14 days) | 
| Endogenous T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) | Measured by absolute number per ul by flow | Up to 6 cycles (3 months), at the end of each cycle 1 (each cycle is 14 days) | 
| Cell phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) | Measured by absolute number per ul by flow | Up to 6 cycles (3 months), at the end of each cycle 1 (each cycle is 14 days) | 
| Cytokine levels (Procartaplex panel) in PB, TCF and CSF |  | Up to 6 cycles (3 months), at the end of each cycle 1 (each cycle is 14 days) | 
| Disease response | Measured by Response Assessment in Neuro-Oncology Criteria (RANO LM). | Up to 10 years | 
| Time to progression | Progression defined by RANO LM criteria | Up to 10 years | 
| Overall survival |  | Up to 10 years | 
| CAR T and endogenous cells detected in tumor tissue | Detected in tumor tissue by immunohistochemistry (IHC) | Baseline and additional time points according to response (through study completion, up to 10 years by as needed basis) | 
| EGFRvII (epidermal growth factor receptor) antigen expression levels in tumor tissue. | Descriptive statistics will be provided | Baseline and additional time points according to response (through study completion, up to 10 years by as needed basis) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, CAR-T, EGFRvIII