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
NCT ID: NCT03849651
Last Updated: 2025-02-25
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE2
140 participants
INTERVENTIONAL
2019-01-31
2025-08-07
Brief Summary
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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.
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Detailed Description
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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
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Transplant participants
Participants receive a conditioning regimen of ATG (rabbit),Cyclophosphamide 60 mg/kg intravenous once daily, mesna, fludarabine, thiotepa, melphalan, followed by HPC,A Infusion(TCRα/β+ and CD19+ depleted),HPC, A infusion (if needed to achieve goal CD34+ cell dose.CD45RA-depleted DLI will be given at least two weeks after engraftment. Blinatumomab will be given at least one week post-DLI, and only to patients with CD19+ malignancies. G-csf 5mcg/kg subcutaneous or intravenous daily until ANC \>2000 for 2 consecutive days.
Cells for infusion are prepared using the CliniMACS system.
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
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
Thiotepa
Thiotepa is a cell-cycle nonspecific polyfunctional alkylating agent.
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
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.
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.
CliniMACS
Cells for infusion are prepared using the CliniMACS
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,
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
TCRα/β+
IV on day 0 and may receive an additional dose on day 1
CD19+
IV on day 0 and may receive an additional dose on day 1
CD45RA-depleted DLI
infusion IV
Interventions
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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
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
Thiotepa
Thiotepa is a cell-cycle nonspecific polyfunctional alkylating agent.
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
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.
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.
CliniMACS
Cells for infusion are prepared using the CliniMACS
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,
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
TCRα/β+
IV on day 0 and may receive an additional dose on day 1
CD19+
IV on day 0 and may receive an additional dose on day 1
CD45RA-depleted DLI
infusion IV
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Does not have a suitable HLA-matched sibling donor (MSD) or volunteer 10/10 HLA-matched unrelated donor (MUD) available in the necessary time for progenitor cell donation.
* Has a suitable single haplotype matched (≥ 3 of 6) family member donor.
High risk hematologic malignancy. High risk ALL in CR1. Examples include, but not limited to: t(9;22) with persistent or recurrent transcript, hypodiploid cytogenetics, MRD \>1% at the end of induction, M2 or greater marrow at the end of induction, recurrent or rising MRD after induction, Infants with MLL fusion or t(4;11), relapse after prior CART therapy.
ALL in High risk CR2. Examples include, but not limited to t(9;22), BM relapse \<36 mo CR1 or \<6mo after completion of therapy, any T-ALL, very early (\< 6mo CR1) isolated CNS relapse, late BM relapse with poor response to standard reinduction therapy(e.g. MRD positive or recurrence after two blocks), relapse after prior CART therapy.
ALL in CR3 or subsequent.
AML in high risk CR1 (diagnosis of AML includes myeloid sarcoma). Examples include but not limited to: preceding MDS or MDS-related AML, FAB M0, FAB M6, FAB M7 with high risk genetics such as ML not t(1;22), MRD \> 0.1% after two cycles of induction, MRD \> 1% after one cycle of induction, FLT3-ITD in combination with NUP98-NSD1 fusion or WT1 mutation, any high risk cytogenetics such as: DEK-NUP214 \[t(6;9)\], KAT6A-CREBBP \[t(8;16)\], RUNX1-CBFA2T3 \[t(16;21)\], -7, -5, 5q-, KMT2A-MLLT10 \[t(6;11)\], KMT2A-MLLT4 \[t(10;11)\], inv(3)(q21q26.2), CBFA2T3-GLIS2 \[inv(16)(p13.3q24.3)\], NUP98-KDM5A \[t(11;12)(p15;p13)\], ETV6-HLXB \[t(7;12)(q36;p13)\], NUP98-HOXA9 \[t(7;11)(p15.4;p15)\], NUP98-NSD1.
AML in CR2 or subsequent.
* Therapy related AML, with prior malignancy in CR \> 12mo
* MDS, primary or secondary
* NK cell, biphenotypic, or undifferentiated leukemia in CR1 or subsequent.
* CML in accelerated phase, or in chronic phase with persistent molecular positivity or intolerance to tyrosine kinase inhibitor.
* Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable to mobilize progenitor cells for autologous HCT.
* Non-Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable to mobilize progenitor cells for autologous HCT.
* JMML
* If prior CNS leukemia, it must be treated and in CNS CR
* Does not have any other active malignancy other than the one for which this HCT is indicated.
* No prior allogeneic HCT, and no autologous HCT within the previous 12 months.
Patient must fulfill pre-transplant organ function criteria:
* 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.
* Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment.
* Not breast feeding
* Does not have current uncontrolled bacterial, fungal, or viral infection.
* At least single haplotype matched (≥ 3 of 6) family member
* At least 18 years of age.
* HIV negative.
* Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
* Not breast feeding.
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
21 Years
ALL
No
Sponsors
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St. Jude Children's Research Hospital
OTHER
Responsible Party
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Principal Investigators
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Brandon Triplett, MD
Role: PRINCIPAL_INVESTIGATOR
St. Jude Children's Research Hospital
Locations
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St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Countries
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Related Links
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St. Jude Children's Research Hospital
Clinical Trials Open at St. Jude
Other Identifiers
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NCI-2019-00338
Identifier Type: REGISTRY
Identifier Source: secondary_id
HAP2HCT
Identifier Type: -
Identifier Source: org_study_id
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