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
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|ClinicalTrials.gov Identifier: NCT03849651|
Recruitment Status : Recruiting
First Posted : February 21, 2019
Last Update Posted : May 1, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Acute Lymphoblastic Leukemia (ALL) Acute Myeloid Leukemia (AML) Myelodysplastic Syndromes (MDS) NK-Cell Leukemia Hodgkin Lymphoma Non Hodgkin Lymphoma (NHL) Juvenile Myelomonocytic Leukemia (JMML) Chronic Myeloid Leukemia (CML)||Drug: Cyclophosphamide Biological: Fludarabine Drug: Thiotepa Drug: Melphalan Biological: G-csf Drug: Mesna Device: CliniMACS Biological: ATG (rabbit) Drug: Blinatumomab Biological: TCRα/β+ Biological: CD19+ Biological: CD45RA-depleted DLI||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||140 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||January 31, 2019|
|Estimated Primary Completion Date :||July 1, 2024|
|Estimated Study Completion Date :||July 1, 2025|
Experimental: 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 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
Other Name: Cytoxan
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
Other Name: Fludara
Thiotepa is a cell-cycle nonspecific polyfunctional alkylating agent.
Other Name: Thioplex
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
Other Name: Alkeran
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 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.
Other Name: Mesnex
Cells for infusion are prepared using the CliniMACS
Other Name: CliniMACS Prodigy
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,
Other Name: Thymoglobulin
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
Other Name: Blincyto
IV on day 0 and may receive an additional dose on day 1
IV on day 0 and may receive an additional dose on day 1
Biological: CD45RA-depleted DLI
- Maximum effective dose for prophylactic CD45RA-depleted DLI [ Time Frame: 90 days after the transplant date of the last enrolled patient. ]Description: A maximum effective dose of CD45RA-depleted DLI is defined as the maximum value of doses that satisfy the proportion of patients with their memory T cell count measured at week 4 post-DLI more than 300/uL is more than 50% and the toxicity of grade 3-4 aGVHD is less than 20%.
- One-year Event Free Survival (EFS) after completion of the protocol [ Time Frame: One year after the transplant date of the last enrolled patient ]Proportion of patients who are alive and relapse free one year after the date of transplant. (Events=relapse, death)
- The number of patients experiencing Blinatumomab permanent discontinuation due to toxicity [ Time Frame: 120 days after transplant date of the last enrolled patient ]If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued
- The estimate of cumulative incidence of relapse [ Time Frame: One year after the transplant date of the last enrolled patient ]The cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The Kaplan-Meier estimates of Overall Survival (OS) and Event Free Survival (EFS) along with their standard errors will be calculated. OS is defined as time from transplantation to death or last follow-up, whichever comes first. EFS is defined as time from transplantation to events including relapse, graft failure, death due to any cause and last follow-up, whichever comes first. The participants are alive at the time of analysis without events will be censored.
- The cumulative incidence of acute and chronic Graft-Versus-Host Disease (GVHD) [ Time Frame: One year after the transplant date of the last enrolled patient ]The cumulative incidence of acute and chronic (GVHD) will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GVHD and chronic GVHD will be described.
- The cumulative incidence of transplant related mortality [ Time Frame: 100 days after the transplant date of the last enrolled patient ]The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Death before day 100 of other reasons are the competing risk events.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03849651
|Contact: Brandon Triplett, MDemail@example.com|
|United States, Tennessee|
|St. Jude Children's Research Hospital||Recruiting|
|Memphis, Tennessee, United States, 38105|
|Contact: Brandon Triplett, MD 866-278-5833|
|Contact: Brandon Triplett, MD|
|Principal Investigator:||Brandon Triplett, MD||St. Jude Children's Research Hospital|