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

• Status: Recruiting
• Trial end date: 2026-01-01
• Target enrollment: 0
• Participant gender: All

Summary

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 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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: St. Jude Children's Research Hospital
• Treatments: Cyclophosphamide; Fludarabine

Criteria

Inclusion Criteria: Donors: Apheresis and Manufacturing

• Age ≥ 18 years old

• At least single haplotype matched (≥ 3/6) family member

• HIV negative

• For females of childbearing 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

Regarding donation eligibility, is identified as either:

1. Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR

2. Does not meet 21 CFR 1271 eligibility requirements but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271.

Identified 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:

1. Relapsed and/or refractory disease despite prior treatment with autologous CD19-CAR T-cell therapy

2. History of prior autologous leukapheresis failure

3. History of prior autologous CAR T-cell manufacturing failure

4. 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 Inclusion Criteria: Treatment

• Age ≤ 21 years old

• Not suitable to receive autologous CD19-CAR T-cell therapy as defined in section 3.1.6

• Relapsed and/or refractory CD19-positive leukemia*: *CD19-positivity confirmed within 2 months and after receipt of any CD19-directed therapy

Refractory disease (defined as any of the following):

1. Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission 2. Refractory disease despite salvage therapy

Relapsed disease (defined as any of the following):

1. 2nd or greater relapse

2. Any relapse after allogeneic hematopoietic cell transplantation (HCT)

3. 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

Inclusion Criteria: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.

• Detectable medullary CD19-positive leukemia

• Estimated life expectancy of ≥ 8 weeks

• Karnofsky or Lansky performance score ≥ 50 (Appendix A)

• 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:

1. ≥ 3 months from HCT

2. have recovered from prior HCT therapy

3. have no evidence of active GVHD within prior 2 months

4. 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%

• 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 childbearing age:

1. 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

• Agreement to participate in long-term follow-up on protocol NCT00695279

Exclusion Criteria:

• NA