Trials / Active Not Recruiting

Active Not RecruitingNCT03849651

TCRαβ-depleted Progenitor Cell Graft With Additional Memory T-cell DLI, Plus Selected Use of Blinatumomab, in Naive T-cell Depleted Haploidentical Donor Hematopoietc Cell Transplantation for Hematologic Malignancies

Status: Active Not Recruiting
Phase: Phase 2
Study type: Interventional
Enrollment: 69 (actual)

Sponsor: St. Jude Children's Research Hospital · Academic / Other
Sex: All
Age: 21 Years
Healthy volunteers: Not accepted

Summary

Patients less than or equal to 21 years old with high-risk hematologic malignancies who would likely benefit from allogeneic hematopoietic cell transplantation (HCT). Patients with a suitable HLA matched sibling or unrelated donor identified will be eligible for participation ONLY if the donor is not available in the necessary time. The purpose of the study is to learn more about the effects (good and bad) of transplanting blood cells donated by a family member, and that have been modified in a laboratory to remove the type of T cells known to cause graft-vs.-host disease, to children and young adults with a high risk cancer that is in remission but is at high risk of relapse. This study will give donor cells that have been TCRαβ-depleted. The TCR (T-cell receptor) is a molecule that is found only on T cells. These T-cell receptors are made up of two proteins that are linked together. About 95% of all T-cells have a TCR that is composed of an alpha protein linked to a beta protein, and these will be removed. This leaves only the T cells that have a TCR made up of a gamma protein linked to a delta protein. This donor cell infusion will be followed by an additional infusion of donor memory cells (CD45RA-depleted) after donor cell engraftment. This study will be testing the safety and effects of the chemotherapy and the donor blood cell infusions on the transplant recipient's disease and overall survival.

Detailed description

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who lack an available suitable human leukocyte antigen (HLA) matched related/sibling donor (MSD) or matched unrelated donor (MUD), will receive a TCRαβ-depleted haploidentical donor HCT with additional memory cell DLI. One course of blinatumomab will be empirically added for patients with CD19+ malignancy. Primary Objectives * Determine the maximum effective dose for prophylactic CD45RA-depleted DLI when given in the early post-engraftment period. * Assess the efficacy of TCRαβ-depleted progenitor cell graft with additional memory T-cell DLI, plus selected use of blinatumomab, in haploidentical donor hematopoietic cell transplantation for hematologic malignancies as measured by 1 year EFS (events = relapse, death) Secondary Objectives * Assess the safety and feasibility of the addition of blinatumomab in the early post- engraftment period in patients with CD19+ malignancy * Estimate the incidence of neutrophil and platelet engraftment, malignant relapse,event-free survival per disease subgroups (e.g. ALL vs AML), and overall survival at one-year post-transplantation. * Estimate incidence and severity of acute and chronic (GVHD). * Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation. * To measure and describe the pharmacokinetics of rabbit ATG in HCT recipients on this study. Exploratory Objectives * Record immune reconstitution parameters, including chimerism analysis, quantitative lymphocyte subsets, T cell receptor excision circle (TREC) analysis, V-beta spectratyping, and lymphocyte phenotype and function. * Describe the use of additional CD45RA-depleted DLI for recipients who have severe viral infections, disease recurrence or progression, or poor immune reconstitution. Assess and record efficacy of CD45RA-depleted DLI for these conditions, and all adverse events that are related to CD45RA-depleted DLI. Blinatumomab will be given to patients with a history of CD19+ malignancy as determined by St. Jude hematopathologist review of current and historical specimens and reports. Blinatumomab dosing will begin no sooner than 1 week after CD45RA-depleted DLI and no later than Day +90. There must be no acute GVHD or it must be quiescent. ALT must be less than 5x ULN, bili less than or equal to 1.5x ULN, and creatinine less than or equal to 1.5x ULN. If more than one family member donor is suitable, then donor selection will be based on several factors including: degree of KIR mismatching, donor-recipient matching of CMV serology, donor-recipient red blood cell compatibility, degree of HLA matching, size of the potential donor, previous use as a donor, presence of donor-specific antibody, and overall health and availability of the potential donor. A G-CSF mobilized peripheral blood progenitor cell product (identified as HPC,A) is the preferred progenitor cell graft source. Our desired target goal will be 5 x 10\^6 CD34+ cells/kg. This number of cells will be necessary to provide an adequate graft, following the various ex vivo manipulations, for prompt reconstitution. More than one collection may be needed to achieve this goal. Donors will undergo a standard hematopoietic progenitor cell mobilization regimen consisting of 5 days of GSF given subcutaneously at 10 micrograms/kilogram. The graft will be collected by leukapheresis on day 5 (and 6 if needed) of G-CSF. The HPC product will typically be collected and infused fresh, however there may be patients or logistical situations that require the HPC product to be collected early, processed, and stored frozen.

Conditions

Interventions

Type	Name	Description
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. intravenously (IV) once daily (QD) on day -9
BIOLOGICAL	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. fludarabine phosphate IV QD on days -8 to -4
DRUG	Thiotepa	Thiotepa is a cell-cycle nonspecific polyfunctional alkylating agent.
DRUG	Melphalan	Melphalan, a derivative of nitrogen mustard, is a bifunctional alkylating agent. Melphalan is active against tumor cells that are actively dividing or at rest. melphalan IV QD on days -2 to -1
BIOLOGICAL	G-csf	G-csf (granulocytic colony stimulating factor), is a biosynthetic hematopoietic agent that is made using recombinant DNA technology in cultures of Escherichia coli. G-CSF stimulates production, maturation and activation of neutrophils. In addition, endogenous G-CSF enhances certain functions of mature neutrophils, including phagocytosis, chemotaxis and antibody--dependent cellular cytotoxicity.
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. Following glomerular filtration, mesna disulfide is rapidly reduced in the renal tubules back to mesna, the active form of the drug.
DEVICE	CliniMACS	Cells for infusion are prepared using the CliniMACS
BIOLOGICAL	ATG (rabbit)	Anti-thymocyte globulin is a purified, pasteurized, gamma immune globulin, obtained by immunization of rabbits with human thymocytes. rabbit anti-thymocyte globulin IV daily over 6 hours on days -5 to -3,
DRUG	Blinatumomab	Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that mediates formation of a synapse between T cells and the CD19+ target cell, resulting in lysis of that CD19+ cell.Blinatumomab will be given to patients with a history of CD19+ malignancy as determined by St. Jude hematopathologist review of current and historical specimens and reports. blinatumomab IV for 28 days beginning at least 1 week post-DLI
BIOLOGICAL	TCRα/β+	IV on day 0 and may receive an additional dose on day 1
BIOLOGICAL	CD19+	IV on day 0 and may receive an additional dose on day 1
BIOLOGICAL	CD45RA-depleted DLI	infusion IV

Timeline

Start date: 2019-01-31
Primary completion: 2024-08-07
Completion: 2026-06-07
First posted: 2019-02-21
Last updated: 2026-04-13
Results posted: 2026-03-04

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study
FDA-regulated device study

Source: ClinicalTrials.gov record NCT03849651. Inclusion in this directory is not an endorsement.