GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma

Study Overview
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Brief Summary
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This is a first in human dose escalation trial to determine the safety of administering GPC2 CAR T cells in patients with advanced neuroblastoma.

Detailed Description
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Despite the use of intensive multimodal chemoradiotherapy, surgery, autologous stem cell transplant and disialoganglioside antigen (GD2)-targeted immunotherapy for the treatment of patients with high-risk neuroblastoma, approximately 60% of children still die from this disease and survivors suffer lifelong treatment related comorbidities. For patients who suffer a relapse after receiving therapy with standard of care multimodality treatment, there are no known curative options. Glypican 2 (GPC2) is highly expressed on the plasma membrane of most high-risk neuroblastomas, is further enriched in the tumor stem cell compartment, but is not expressed at significant levels on normal tissues, making it an ideal target for immune directed therapies. To therapeutically leverage GPC2's differential expression, a GPC2-directed CAR T cell therapy that potently inhibits the growth of neuroblastoma patient-derived xenografts has been developed. This investigation will be a single institution, open-label first in human, dose escalation and expansion study designed to assess the safety, tolerability, and manufacturing feasibility of GPC2 CAR T cells.

Official Title
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Phase 1 Trial of GPC2-Directed Chimeric Antigen Receptor Autologous T Cells (GPC2 CAR T) for Relapsed or Refractory Neuroblastoma

Conditions
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Refractory Neuroblastoma, Relapsed Neuroblastoma, High-risk Neuroblastoma

Intervention / Treatment
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* Biological: GPC2 CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form ≥ 1 year of age Disease status Patients must have high-risk neuroblastoma according to Children's Oncology Group risk classification at the time of study enrollment. Histologically confirmed diagnosis of neuroblastoma that is recurrent/relapsed/persistent according to International Neuroblastoma Response Criteria Patients must have evaluable or measurable disease at enrollment Adequate organ function Adequate performance status defined as Lanksy or Karnofsky performance score ≥60. Subjects of reproductive potential must agree to use acceptable birth control methods. Exclusion Criteria: Patients with active hepatitis B or active hepatitis C. Patients with HIV infection. Patients with uncontrolled active infection Patients with primary or acquired immunodeficiency disorder. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well. Patients with actively progressing Central Nervous System metastases, including parenchymal or leptomeningeal involvement. Active medical disorder that, in the opinion of the investigator, would substantially increase. the risk of uncontrollable Cytokine Release Syndrome and/or neurotoxicity. Patients with congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), unstable angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6 months prior to study entry or a history of myocarditis. Patients who have received any live vaccines within 30 days prior to enrollment. Pregnant or nursing (lactating) women.

Ages Eligible for Study
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Minimum Age: 1 Year

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Arm<br>The dose escalation arm will determine the maximum tolerated dose of GPC2 CAR T cells using a standard 3+3 trial design. | Biological: GPC2 CAR T cells<br>* The GPC2 CAR T investigational product is comprised of autologous human T cells that have been genetically modified to express a GPC2-targeting chimeric antigen receptor (CAR) transgene.<br>|
| Experimental: Dose Expansion Arm<br>If at least one dose from the dose expansion arm is determined to be safe, additional patients will be enrolled to the dose expansion arm to preliminarily evaluate the rate of response to GPC2 CAR T cells and further characterize the safety profile of GPC2 CAR T cells. | Biological: GPC2 CAR T cells<br>* The GPC2 CAR T investigational product is comprised of autologous human T cells that have been genetically modified to express a GPC2-targeting chimeric antigen receptor (CAR) transgene.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the Maximum Tolerated Dose of GPC2 CAR T cells | The Maximum Tolerated Dose of GPC2 CAR T cells will be determined by measuring the incidence of dose limiting toxicities following administration of the product. | 5 years | 
| Frequency of Adverse Events Following GPC2 CAR T cell administration | Assess the frequency and severity of treatment related adverse events following administration of GPC2 CAR T cells. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Manufacturing Feasibility of GPC2 CAR T cells | Manufacturing Feasibility will be evaluated as the Percentage of patients with GPC2 CAR T cell products that meet release criteria | 5 years | 
| Persistence of GPC2 CAR T cells | Persistence of GPC2 CAR T cells will be measured by Polymerase Chain Reaction (or flow cytometry) analysis of whole blood to detect and quantify survival of GPC2 CAR T cells over time. | 5 years | 
| Preliminarily define the clinical activity of GPC2 CAR T in patients with relapsed or refractory neuroblastoma | Overall Response Rate will be determined based on international Neuroblastoma Response Criteria | 5 years | 
| Severity of Adverse Events Following GPC2 CAR T cell administration. | The safety of GPC2 CAR T cell therapy reinfusions will be measured by the monitoring the frequency and severity of adverse events after multipleGPC2 CAR T cells infusions. | 5 years |