Loc3CAR: Locoregional Delivery of B7-H3-CAR T Cells for Pediatric Patients With Primary CNS Tumors

Study Overview
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Brief Summary
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Loc3CAR is a Phase I clinical trial evaluating the use of autologous B7-H3-CAR T cells for participants ≤ 21 years old with primary CNS neoplasms. B7-H3-CAR T cells will be locoregionally administered via a CNS reservoir catheter. Study participants will be divided into two cohorts: cohort A with B7-H3-positive relapsed/refractory non-brainstem primary CNS tumors, and cohort B with brainstem high-grade neoplasms. Participants will receive six (6) B7-H3-CAR T cell infusions over an 8 week period. The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give patients with primary brain tumors.

Detailed Description
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Treatment on this study includes six (6) B7-H3-CAR T cell infusions over an 8 week period. B7-H3-CAR T cells will be locoregionally administered via a CNS reservoir catheter without lymphodepleting chemotherapy. The study will evaluate the safety and maximum tolerated dose (MTD) of B7-H3-CAR T cells using a 3+3 study design and an 8 week evaluation period. The total study duration will be 1 year, at which point patients will enroll on our existing institutional long-term follow up protocol.

Official Title
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Loc3CAR: Locoregional Delivery of B7-H3-specific Chimeric Antigen Receptor Autologous T Cells for Pediatric Patients With Primary CNS Tumors

Conditions
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Ependymoma, Central Nervous System Neoplasms, Atypical Teratoid/Rhabdoid Tumor, Diffuse Midline Glioma, H3 K27M-Mutant, High Grade Glioma, Glioblastoma, Medulloblastoma

Intervention / Treatment
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* Drug: B7-H3-CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening Eligibility Age ≤ 21 years of age Primary CNS tumor with measurable disease For Cohort A, must have evidence of relapsed or refractory non-brainstem CNS tumor For Cohort B, must meet one of the following criteria: Adequate tumor tissue from for central pathology review Brainstem high-grade neoplasm with available imaging for central review Life expectancy of > 12 weeks Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines Exclusion Criteria: Screening Eligibility All Participants 1. Clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with study procedure Inclusion Criteria: Procurement and T-cell Production Eligibility Age ≤ 21 years of age Primary CNS tumor with measurable disease and meets criteria for either Cohort A or B: Cohort A: relapsed/refractory non-brainstem CNS primary tumor AND tumor is B7-H3 positive Cohort B: brainstem high-grade neoplasm AND tumor is: B7-H3 positive OR H3K27-altered diffuse midline glioma OR radiographically-confirmed classic/typical DIPG Estimated life expectancy of >12 weeks Karnofsky or Lansky performance score ≥50 Participant of childbearing/child-fathering potential agrees to use contraception For females of childbearing age: Not pregnant with negative serum pregnancy test Not lactating with intent to breastfeed Chemotherapy/biologic therapy must be discontinued ≥ 7 days prior to enrollment The last dose of antibody therapy (including check point inhibitor) must be at least 3 half-lives or 30 days, whichever is shorter At least 30 days from most recent cell infusion prior to enrollment. All systemically administered corticosteroid therapy must be stable or decreasing for ≥1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m2/day Meets eligibility for apheresis, or has an apheresis product previously collected at a FACT-accredited program Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines Exclusion Criteria: Procurement and T-cell Production Eligibility Participant has a non-programmable ventricular shunt that could compromise study therapy Known primary immunodeficiency or acquired immunodeficiency. Known HIV positivity Severe intercurrent bacterial, viral or fungal infection Rapidly progressive disease Known underlying medical condition for which participation in this trial would not be in the best interest of the participant or that could prevent, limit or confound protocol assessments. Adult patient, Parent, or legal guardian is unwilling or unable to provide consent for participation in a 15 year long-term follow up study. Inclusion Criteria: Treatment Eligibility Cohort A Relapsed/refractory non-brainstem CNS primary tumor Tumor must be considered B7-H3 positive Cohort B Brainstem high-grade neoplasm. Must meet one of the following criteria Tumor is considered B7-H3 positive H3K27-altered diffuse midline glioma Radiographically-confirmed classic/typical DIPG Must complete standard radiation prior to Loc3CAR treatment and be a minimum of 6 weeks post-completion of radiation therapy All participants Age ≤ 21 years old Primary CNS tumor with measurable disease Available autologous T-cell product that has met GMP release criteria Participant has a CNS reservoir catheter (e.g., Ommaya) Participant is ≥ 5 days from CNS surgery, including catheter placement The following treatments must be discontinued for the specified duration prior to treatment enrollment: Radiation therapy: ≥ 6 weeks Bevacizumab: ≥ 28 days Cytotoxic chemotherapy: ≥ 21 days Biologic agents: ≥ 7 days Antibody therapy: ≥ 3 half-lives or 30 days (whichever is shorter) Cellular therapy: ≥ 30 days Investigational agent: ≥ 3 half-lives or 30 days (whichever is shorter) Corticosteroids: All systemically administered therapy must be stable or decreasing for ≥ 1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m2/day Estimated life expectancy of >8 weeks Karnofsky or Lansky performance score ≥ 50 Echocardiogram with a left ventricular ejection fraction > 50% Adequate organ function Adequate laboratory values Taking anti-seizure medication, or agrees to initiate anti-seizure medication Recovered from acute toxicities from prior therapy Male participants of child-fathering potential agree to use contraception Female participants of childbearing potential: Negative serum pregnancy test within 7 days prior to infusion Not lactating with intent to breastfeed If sexually active, agrees to use birth control until 3 months after T-cell infusion. Male partners should use a condom Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines Exclusion Criteria: Treatment Eligibility Participant has a non-programmable ventricular shunt that could compromise study therapy Known primary immunodeficiency or acquired immunodeficiency. Known HIV positivity Severe intercurrent bacterial, viral or fungal infection Myocardial infarction, unstable angina, New York Heart Association class III and IV congestive heart failure, myocarditis, or ventricular arrhythmias requiring medication within 6 months prior to study entry Receiving therapy outlined above during the 'wash-out' period Rapidly progressing disease Received any live vaccines within 30 days Known underlying medical condition for which participation in this trial would not be in the best interest of the participant or that could prevent, limit or confound protocol assessments Adult patient, Parent, or legal guardian is unwilling or unable to provide consent for participation in a 15 year long-term follow up study

Ages Eligible for Study
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Maximum Age: 21 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (relapsed/refractory CNS tumors)<br>Patients with B7-H3-positive relapsed/refractory non-brainstem primary CNS tumors. | Drug: B7-H3-CAR T cells<br>* Autologous T cells transduced with a lentiviral vector expressing a B7-H3-CAR with a CD28z signaling domain and 41BB ligand (B7-H3-CAR T cells). Six (6) infusions of B7-H3-CAR T cells will be locoregionally administered via CNS reservoir catheter.<br>|
| Experimental: Arm B (brainstem high-grade neoplasms)<br>Patients with high-grade neoplasms | Drug: B7-H3-CAR T cells<br>* Autologous T cells transduced with a lentiviral vector expressing a B7-H3-CAR with a CD28z signaling domain and 41BB ligand (B7-H3-CAR T cells). Six (6) infusions of B7-H3-CAR T cells will be locoregionally administered via CNS reservoir catheter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | To determine the maximum tolerated dose for the locoregional delivery of autologous B7-H3-CAR T cells in patients with recurrent/refractory B7-H3- positive primary CNS tumors (Cohort A) or high-grade brainstem neoplasms (Cohort B). | Eight (8) weeks after the first B7-H3-CAR T-cell infusion or 7 days after the sixth B7-H3-CAR T cell infusion, whichever is longer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained objective radiographic response | To assess the efficacy, defined as sustained objective response (a partial response (PR) or complete response (CR) sustained over 8 weeks) by iRANO criteria observed anytime on active treatment with B7-H3-CAR T cells in patients with relapsed/refractory B7-H3-positive primary CNS tumors (Cohort A) or high-grade brainstem neoplasms (Cohort B). | Eight (8) weeks post B7-H3-CAR T-cell infusion |