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Antineoplastic Agents, Alkylating

Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.

Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.

Allogeneic CD19-CAR.CD45RA-negative T-cells Intravenous infusion

CD19-CAR(Mem) T-cells

Cyclophosphamide is a nitrogen mustard derivative. It acts as an alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids and other intracellular structures, thus interfering with the normal function of DNA.

Fludarabine phosphate is a synthetic purine nucleoside analog. It acts by inhibiting DNA polymerase, ribonucleotide reductase and DNA primase by competing with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis.

Mesna is a synthetic sulfhydryl (thiol) compound. Mesna contains free sulfhydryl groups that interact chemically with urotoxic metabolites of oxaza-phosphorine derivatives such as cyclophosphamide and ifosfamide.

A CliniMACS device is used to select donor T-cells for manufacturing of the memory CAR T-cell product.

CliniMACS

Leukapheresis is performed to collect the T cells that are needed to generate the CD19-CAR.CD45RA-negative T-cells product for the clinic study.

Leukapheresis

Aimee C. Talleur, MD

Stephen Gottschalk, MD

This is a Phase I clinical study evaluating the safety and maximum tolerated dose of a novel CAR T-cell product: allogeneic memory (CD45RA- negative) T-cells expressing a CD19-specific CAR 41BBz (CD19-CAR.CD45RA- negative T-cells) for the treatment of patients ≤ 21 years old with relapsed and/ or refractory CD19-positive leukemia.

Primary Objective

To determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with allogeneic CD19-CAR.CD45RA-negative T-cells in pediatric, adolescent and young adult patients ≤ 21 years of age, with relapsed and/or refractory CD19-positive leukemia.

Secondary Objectives

* To evaluate the anti-leukemic activity of allogeneic CD19-CAR.CD45RA-negative T-cells.
* To determine rates and severity of graft-versus-host-disease (GVHD) after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells.

Exploratory Objectives

* To study the expansion, persistence and phenotype of allogeneic CD19-CAR.CD45RA-negative T-cells.
* To characterize the cytokine profile in the peripheral blood and CSF after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells.
* To assess whether allogeneic CD19-CAR.CD45RA-negative T-cells acquire functional versus exhaustion-associated epigenetic programs.
* To determine immune reconstitution post treatment, and the clonal structure and endogenous repertoire of allogeneic CD19-CAR.CD45RA-negative T-cells and relate inferred specificity to CAR response profiles.
* To characterize incidence and mechanisms of relapse post-therapy with allogeneic CD19-CAR.CD45RA-negative T-cells.

This is a Phase I dose escalation study using a 3+3 study design. Two groups of patients will be evaluated in this study: group A - patients have received a prior stem cell transplant from their CAR T-cell donor; group B - patients have not received a prior stem cell transplant from their CAR T-cell donor. There will be up to 30 participants per group and a donor/ family member for each patient.

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Study of CD19-directed Allogeneic Memory T-cell Therapy for Relapsed/Refractory CD19+ Leukemia

A Phase I Study Evaluating Allogeneic Memory T Cells Engineered to Express Chimeric Antigen Receptors Specific for CD19 for the Treatment of Pediatric and Young Adult Patients ≤ 21 Years of Age With Relapsed or Refractory CD19-Positive Leukemia

This phase I study includes dose escalation/de-escalation based on dose limiting toxicity (DLT) assessment to determine the maximum tolerated dose (MTD) of allogeneic, CD19-CAR.CD45RA-negative cells.

St. Jude Children's Research Hospital

Leukemia, B-Cell

Patients in both the Phase I and Phase II portion of the study will receive lymphodepleting chemotherapy (unless determined by PI that lymphodepletion is not necessary), followed by a single infusion of the patient-derived SJCAR19 cellular product. The most commonly used lymphodepleting chemotherapy regimen will consist of the agents: Fludarabine and Cyclophosphamide. They will also receive Mesna. Dosing of SJCAR19 on the Phase I study will follow a dose escalation schema, with dose changes based on dose-limiting toxicities. In the Phase II study, SJCAR19 dosing with follow the maximum tolerated dose, as determined in the Phase I portion.

Cells for infusion are prepared using the CliniMACS System.

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest.

CD19- specific CAR engineered autologous T-cells (SJCAR19 product)

SJCAR19 is a research study seeking to evaluate the use of chimeric antigen receptor (CAR) T cell therapy, a type of cellular therapy, for the treatment of pediatric, adolescent and young adult patients with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL). CAR therapy combines two of the body's basic disease fighters: antibodies and T Cells. For this type of therapy, peripheral (circulating) immune cells are collected and then undergo a manufacturing process to engineer them to more effectively kill cancer cells. The SJCAR19 product will be manufactured at the St. Jude Children's Research Hospital's Good Manufacturing Practice (GMP) facility.

The main purpose of this study is to determine:

1. The largest dose of SJCAR19 that is safe to give,
2. How long SJCAR19 cells last in the body,
3. The side effects of SJCAR19, and
4. Whether or not treatment with SJCAR19 is effective in treating people with refractory or relapsed ALL.

SJCAR19 is a Phase I/II clinical trial evaluating the use of SJCAR19 (CD19- specific CAR engineered autologous T-cells) in pediatric, adolescent and young adult patients with relapsed/ refractory CD19+ ALL. Treatment will include a single treatment course, with most patients receiving a lymphodepleting chemotherapy preparative regimen of fludarabine/ cyclophosphamide, followed by a single infusion of SJCAR19.

This protocol contains a 3-part consent process: 1) to proceed with autologous apheresis, 2) to proceed with manufacturing of the SJCAR19 product, and 3) to receive treatment with the SJCAR19 product (initially as Phase I, then proceeding to Phase II). The Phase I portion will evaluate the safety and maximum tolerated dose (MTD) of SJCAR19.

The Phase II portion will evaluate the efficacy, and provide further safety evaluation, of SJCAR19 in an expansion cohort at the MTD determined in the Phase I portion of the study. Additionally, for both the Phase I/II portions of the study there are correlative studies evaluating the biology of this treatment as well assessments into patient/caregiver experiences with undergoing this treatment.

Evaluation of CD19-Specific CAR Engineered Autologous T-Cells for Treatment of Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia

SJCAR19: A Phase I/II Study Evaluating SJCAR19 (CD19-Specific CAR Engineered Autologous T-Cells) in Pediatric and Young Adult Patients ≤ 21 Years of Age With Relapsed or Refractory CD19+ Acute Lymphoblastic Leukemia

The primary objectives for the Phase I study portion are to determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with SJCAR19 in pediatric and young adult patient's ≤ 21 years of age, with relapsed or refractory CD19+ ALL.

The primary objective for the Phase II study portion is to evaluate the complete response (CR) rates of SJCAR19 in pediatric and young adult patient's ≤ 21 years of age, with relapsed or refractory CD19+ ALL.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of CD19-directed Allogeneic Memory T-cell Therapy for Relapsed/Refractory CD19+ Leukemia	NCT04881240	Acute Lymphobla... Acute Lymphobla... Pediatric ALL	CD19-CAR(Mem) T... Cyclophosphamid... Fludarabine Mesna CliniMACS Leukapheresis	- 21 Years	St. Jude Children's Research Hospital
Evaluation of CD19-Specific CAR Engineered Autologous T-Cells for Treatment of Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia	NCT03573700	Acute Lymphobla... Acute Lymphobla...	Cyclophosphamid... Fludarabine Mesna CliniMACS CD19- specific ...	- 21 Years	St. Jude Children's Research Hospital
Study of CD19-directed Allogeneic Memory T-cell Therapy for Relapsed/Refractory CD19+ Leukemia	NCT04881240	Acute Lymphobla... Acute Lymphobla... Pediatric ALL	CD19-CAR(Mem) T... Cyclophosphamid... Fludarabine Mesna CliniMACS Leukapheresis	- 21 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for acute lymphoblastic leukemia, refractory