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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2026

Detailed Description

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. .

Interventions

  • Biological: CD19-CAR(Mem) T-cells
    • Allogeneic CD19-CAR.CD45RA-negative T-cells Intravenous infusion
  • Drug: Cyclophosphamide
    • 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.
  • Drug: Fludarabine
    • 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.
  • Drug: Mesna
    • 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.
  • Device: CliniMACS
    • A CliniMACS device is used to select donor T-cells for manufacturing of the memory CAR T-cell product.
  • Procedure: Leukapheresis
    • 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.

Arms, Groups and Cohorts

  • Experimental: Group A
    • Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
  • Experimental: Group B
    • Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.

Clinical Trial Outcome Measures

Primary Measures

  • Maximum tolerated dose of allogeneic, CD19-CAR.CD45RA-negative cells
    • Time Frame: 4 weeks after CAR T-cell infusion
    • 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.

Participating in This Clinical Trial

Inclusion Criteria Eligibility Criteria for Donors: Apheresis and Manufacturing

  • Age ≥ 18 years old – At least single haplotype matched (≥ 3/6) family member – HIV negative – For females of child bearing age: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment AND Not lactating with intent to breastfeed – Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance For Cohort A only, identified recipient with relapsed and/or refractory CD19-positive leukemia For Cohort B only, iIdentified recipient with relapsed and/or refractory CD19-positive leukemia who is not suitable to receive autologous CD19-CAR T-cell therapy as defined by the following: – Relapsed and/or refractory disease despite prior treatment with autologous CD19- CAR T-cell therapy – History of prior autologous leukapheresis failure – History of prior autologous CAR T-cell manufacturing failure – Unable to undergo autologous leukapheresis in the opinion of the study PI(s): examples may include – patient small size/low weight, inadequate T-cell counts, rapidly progressive leukemia, clinical status not amenable to apheresis Eligibility Criteria for Patients: Treatment – Age ≤ 21 years old – Relapsed and/or refractory CD19-positive leukemia*: – Refractory disease (defined as any of the following): – Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission – Refractory disease despite salvage therapy – Relapsed disease (defined as any of the following): – 2nd or greater relapse – Any relapse after allogeneic hematopoietic cell transplantation (HCT) – 1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT CD19-positivity confirmed within 2 months and after receipt of any CD19-directed therapy – Patient cohorts: – Cohort A: patient has previously received a HCT from the selected CAR T-cell donor – Cohort B – patient has NOT previously received a HCT from the selected CAR T-cell donor. – For Cohort B only, not suitable to receive autologous CD19-CAR T-cell therapy as defined above in Criteria: Eligibility Criteria for Donors: Apheresis and Manufacturing – Detectable medullary CD19-positive leukemia – Estimated life expectancy of ≥ 8 weeks – Karnofsky or Lansky performance score ≥ 50 – No CNS-3 disease or any level of detectable leukemia in CNS with associated neurologic symptoms – If history of allogeneic HCT (regardless of donor type), prior to planned CAR T-cell infusion, must meet the following criteria: – ≥ 3 months from HCT – have recovered from prior HCT therapy – have no evidence of active GVHD within prior 2 months – have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned CAR T-cell infusion – Adequate cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25% (function may be supported by pharmacologic therapy) – EKG without evidence of clinically significant arrhythmia – Adequate renal function: creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if < 2 years of age) – Adequate pulmonary function: forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing – Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome – Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age – No history of HIV infection – No evidence of severe, uncontrolled bacterial, viral or fungal infection – Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy – For females of child bearing age: – Not pregnant with negative serum or urine pregnancy test ≤ 7 days prior to enrollment AND Not lactating with intent to breastfeed – If sexually active, agreement to use birth control until 6 months after CAR T-cell infusion – No history of hypersensitivity reactions to murine protein-containing products – Not receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone ≤ 7 days prior to CAR T-cell infusion – Not receiving systemic therapy ≤ 14 days prior to CAR T-cell infusion, which will interfere with the activity of the CAR T-cell product in vivo (in the opinion of the study PI(s)) – Not receiving intrathecal chemotherapy ≤ 7 days prior to CAR T-cell infusion Exclusion Criteria:

NA

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 21 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • St. Jude Children’s Research Hospital
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Aimee C. Talleur, MD, Principal Investigator, St. Jude Children’s Research Hospital
    • Stephen Gottschalk, MD, Principal Investigator, St. Jude Children’s Research Hospital
  • Overall Contact(s)
    • Aimee C. Talleur, MD, 866-278-5833, referralinfo@stjude.org

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