UCD19 CarT in Treatment of Pediatric B-ALL and B-NHL

Study Overview
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Brief Summary
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This phase I/II trial will investigate a new CD19 directed CAR-T therapy manufactured locally with the goals to expedite infusion to wider patient inclusion that includes those who were previously excluded, such as pediatric patients with B-cell NHL and patients in primary relapse.

Detailed Description
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Pediatric patients with refractory or multiply relapsed leukemia and lymphoma do very poorly with traditional chemotherapy and have overall survival rates of well under 20%. There has been much excitement over the development of Car T cell therapy for these types of leukemia/lymphoma, but many patients may not fit the standard criteria to receive them or they cannot tolerate the extended wait and ongoing therapy that is needed for manufacture of these cells at the commercial level. With this study, the investigators will investigate a new CD19 directed CAR-T therapy that will be manufactured locally with a goal of wider patient inclusion and less delay to CAR-T infusion. The investigators hypothesize that CD19 directed CAR-T cells manufactured using the Prodigy ClinicMACS system developed by Miltenyi (UCD19 CAR-T) will be safe and tolerable and show preliminary efficacy in pediatric patients with relapsed and/or refractory B-ALL or B- NHL.

Official Title
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Phase 1/2 Dose Escalation and Preliminary Efficacy of CD19 Directed Car T Cells Generated Using The Miltenyi Clinimacs Prodigy System (UCD19 CarT) in Pediatric Patients With Relapsed and/or Refractory B-Cell Acute Lymphoblastic Leukemia (B-ALL) and B-Cell Non-Hodgkins Lymphoma(B-NHL)

Conditions
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B-cell Acute Lymphoblastic Leukemia, B-cell Non Hodgkin Lymphoma

Intervention / Treatment
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* Drug: CD19CAR-CD3Zeta-4-1BB-Expressing Autologous T-Lymphocyte Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets criteria for potential leukapheresis collection or has leukapheresis product previously collected and stored per recommended guidelines; Provision of signed and dated consent form from parent or guardian (patients <18), the patient themselves (>18), or legally authorized representative (patient >18 who lack decision-making capacity); Willingness to participate in long-term follow-up study; Stated willingness to comply with all study procedures and be available for the duration of the study; Males OR non-pregnant, non-lactating females; Aged 31 days to 30 years (inclusive) at time of consent and enrollment; Acute Lymphoblastic Leukemia (ALL) OR Non-Hodgkin Lymphoma (NHL) of B-cell origin that: Has confirmed expression of CD19 by flow cytometry, immunohistochemistry (IHC), or both ; Meets any one of the following conditions: Relapsed two or more times Relapsed at any time after allogeneic BMT Refractory to standard therapy as determined by the treating physician Meets criteria for BMT but is ineligible as determined by the treating physician Patient and/or parents declining BMT options and would prefer CAR-T Therapy. Non-Hodgkin Lymphoma includes all of the following: Diffuse large B-cell lymphoma (DLBCL) Burkitt Lymphoma Intermediate lymphoma between Burkitt and DLBCL Primary Mediastinal B-cell Lymphoma (PMBL) Follicular lymphoma High-grade B cell lymphoma Transformed lymphoma Performance score (Lansky or Karnofsky) of 50% or better; Unable to receive commercially available CD19 CAR-T Therapy. Exclusion Criteria: Active, uncontrolled CNS leukemia or lymphoma, as clinically indicated, at eligibility, prior to lymphodepleting chemotherapy (LD chemo), and pre-cell infusion; Active Graft-versus-Host Disease (GvHD); Active, uncontrolled, life threatening infection that at the determination of the treating physician would preclude safe leukapheresis or tolerance of lymphodepleting chemotherapy, cell infusion, or cytokine release syndrome; Evidence of severe organ dysfunction that at the determination of the treating physician would preclude safe leukapheresis or tolerance of lymphodepleting chemotherapy, cell infusion, or cytokine release syndrome including any of the following: Myocardial dysfunction (based on age standards) Baseline oxygen saturation of < 90% on room air Diffusion capacity of the lungs for carbon monoxide (DLCO) < 40%, as determined within 45 days before cell infusion Transaminases > 10x upper limit of normal (ULN) or bilirubin >2x the ULN, unless thought to be related to primary disease Estimated Cr clearance <60 mL/min/1.73 m2 (if nuclear medicine GFR or other more specific testing exceeds this level than it can supersede the estimated clearance) Post-pubertal females that are pregnant, planning to become pregnant, or unwilling to use birth control (includes abstinence) for the study duration; Known HIV infection, or active Hepatitis B or active Hepatitis C infection; Prior gene therapy, including prior CAR-T cell.

Ages Eligible for Study
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Minimum Age: 31 Days
Maximum Age: 30 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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I: Dose Escalation<br>First 3-21 subjects enrolled. Treated with escalating doses of therapy until the RP2D is determined. | Drug: CD19CAR-CD3Zeta-4-1BB-Expressing Autologous T-Lymphocyte Cells<br>* The CD19 CAR used in this study consists of three main components: the variable regions of the anti-CD19 monoclonal antibody FMC63 71, linked to the TNFRSF19-derived transmembrane domain, the 4-1BB costimulatory molecule, and the signaling domain of the CD3-zeta molecule. The DNA encoding this receptor was cloned into a lentiviral vector (LV) backbone.<br>|
| Experimental: II: Dose Expansion<br>22-40 additional subjects treated at the RP2D, including those treated within the phase 1 portion of the trial. | Drug: CD19CAR-CD3Zeta-4-1BB-Expressing Autologous T-Lymphocyte Cells<br>* The CD19 CAR used in this study consists of three main components: the variable regions of the anti-CD19 monoclonal antibody FMC63 71, linked to the TNFRSF19-derived transmembrane domain, the 4-1BB costimulatory molecule, and the signaling domain of the CD3-zeta molecule. The DNA encoding this receptor was cloned into a lentiviral vector (LV) backbone.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities | Adverse events (toxicity assessments) will be done by medical staff at different time points | Up to 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The subject will be followed throughout the study and up to 5 years after the study for overall survival. | 5 years | 
| Time to Transplant | The subject will be followed throughout the study and up to 5 years after the study for time to transplant. | 5 years | 
| Relapse | The subject will be followed throughout the study and up to 15 years after the study for relapse. | 5 years | 
| Non-Relapse Mortality | The subject will be followed throughout the study and up to 15 years after the study for non-relapse mortality | 5 years |