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.

Eligibility

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