CD45RA-depleted CD19-CAR T Cell Consolidation After TCRαβ+/CD19 B Cell-depleted Haploidentical Hematopoietic Cell Transplantation for Relapsed/Refractory CD19+ ALL and Lymphoma

Overview

The purpose of this study is to learn more about newer methods of transplanting blood cells donated by a partially matched family member to children with high-risk CD19 positive leukemia ALL. Primary Objective: \- To assess the safety and feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies. Secondary Objectives: * To estimate 1-year post-transplant overall survival, event-free survival, and GVHD-free relapse-free survival (GRFS). * To estimate cumulative incidence of engraftment, acute and chronic GVHD, and immune-related adverse events, including CRS and ICANS.

Detailed description

This is a Phase I study evaluating the addback of CD19-CAR(Mem) T cells after TCRαβ+/CD19 B cell depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.

Donors that meet eligibility criteria will be consented to undergo two separate collections: 1) G-CSF mobilized stem cell graft via apheresis for progenitor cell infusion and 2) Non-mobilized peripheral blood mononuclear cells (PBMC) via apheresis for subsequent CAR T-cell manufacturing and DLI if needed.

Patients that meet eligibility criteria to receive therapy will be consented to proceed on study. Treatment will include a conditioning chemotherapy preparative regimen followed by infusion of TCRαβ/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product, as well as collection of correlative samples.

Interventions

• Drug Anti-Thymocyte Globulin (Rabbit)
  Days -10, -11, -12.
• Drug Cyclophosphamide
  60 mg/kg intravenous once daily on day -9.
• Drug Fludarabine
  30 mg/m2 intravenous once daily for \>10 kg, 1 mg/kg intravenous once daily for ≤10 kg on days -4, -5, -6, -7, -8.
• Drug Thiotepa
  5 mg/kg intravenous twice daily on day -3.
• Drug Mesna
  Mesna is planned to be administered at 15 mg/kg/dose prior to cyclophosphamide and at approximately 3, 6, and 9 hours after the cyclophosphamide infusion, to give a 1:1 ratio of mesna:cyclophosphamide.
• Drug Melphalan
  70 mg/m2 intravenous once daily for \>10 kg, 2.3 mg/kg intravenous once daily for ≤10 kg on days -1, and -2.
• Drug Filgrastim
  G-CSF\* 10 mcg/kg/day SC days 0, -1, -2, -3, -4, -5.
• Device 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.

Primary outcome measures

• To assess the safety of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies. [Time frame: This will be assessed 100 days post-HCT]
• To assess the feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies. [Time frame: This will be assessed in the first 60 days post-HCT]

Secondary outcome measures (6)

• To assess the feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies. [Time frame: This will be assessed in the first 60 days post-HCT]
• Estimate 1-year post-transplant relapse free survival [Time frame: This will be assessed in the first 3 years post-HCT]
• Estimate cumulative incidence of neutrophil engraftment [Time frame: This will be assessed in the first 30 days post-HCT]
• Estimate cumulative incidence of platelet engraftment [Time frame: This will be assessed in the first 100 days post-HCT]
• Estimate cumulative incidence of acute and chronic GVHD [Time frame: This will be assessed in the first 3 years post-HCT]
• Estimate cumulative incidence of immune-related adverse events [Time frame: This will be assessed in the first 1 years post-HCT]

Eligibility criteria

Inclusion criteria

Recipient

• Age less than or equal to 21 years
• High risk hematologic malignancy where allogeneic transplantation is the current standard of care. This includes (but is not limited to):

• High risk CD19+ B cell ALL in CR1 or CR2
• Any CD19+ B-cell ALL in CR3 or subsequent
• If prior CNS leukemia, it must be treated and in CNS CR
• Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%
• Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2
• Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
• Karnofsky or Lansky (age dependent) performance score ≥ 50 (See APPENDIX A)
• Bilirubin ≤ 3 times the upper limit of normal for age
• Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age

Donor

• At least single haplotype matched (≥ 4 of 8) family member
• At least 18 years of age
• HIV negative
• If sexually active, agreement to use birth control until 2 weeks after completion of the mobilization and apheresis procedure
• Regarding donation eligibility, is identified as either:

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

Exclusion criteria

Recipient

• Has a suitable HLA-identical sibling or suitable 12/12 (HLA-A, B, C, DRB1, DQB1, and DPB1) HLA-matched unrelated donor available in an appropriate time frame
• Any other active malignancy other than the one for which this HCT is indicated
• Received a prior allogeneic HCT at any time
• Pregnant, if female is of childbearing potential, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment
• If sexually active, agreement to use birth control until 6 months after T cell infusion
• Breast feeding
• Any severe current uncontrolled bacterial, fungal or viral infection

Donor

• Pregnant, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment if female
• If female, breast feeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• St. Jude Children's Research Hospital — Memphis

Identifiers

NCT: NCT07257419 · HAPALL · NCI-2025-08364

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗