Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells
|Leukemia, Acute Chronic Myelogenous Leukemia (CML) Myelodysplastic Syndrome (MDS) Non-Hodgkin Lymphoma (NHL) Chronic Lymphocytic Leukemia (CLL) Acute Myelogenous Leukemia (AML) Acute Lymphoblastic Leukemia (ALL)||Drug: Regulatory T-cells Drug: Conventional T-cells Drug: Melphalan Drug: Thiotepa Device: Fludarabine Drug: Anti-thymocyte globulin, rabbit Drug: CliniMACS CD34 Reagent System||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Feasibility Trial of Post-Transplant Infusion of Allogeneic Regulatory T Cells and Allogeneic Conventional T Cells in Patients With Hematologic Malignancies Undergoing Allogeneic Myeloablative Hematopoietic Cell Transplantation From Haploidentical-Related Donors|
- Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells [ Time Frame: 30 days after HSCT infusion ]The maximum-tolerated dose (MTD) was to be determined based on the safety and feasibility observed for a pre-determined set of cellular dose level combinations of regulatory T-cells (T-reg) and conventional T-cells (T-con).
- Acute Graft-versus-Host-Disease (aGvHD) [ Time Frame: 1 year ]The primary outcome was incidence of grade 3 or 4 acute graft-vs-host-disease (aGvHD), reported as the number of participants developing grade 3 or 4 aGvHD.
- Overall Survival (OS), 1 Year [ Time Frame: 1 year ]Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause)
- Median Overall Survival (OS) [ Time Frame: 25 months ]Reported as the median overall survival (OS) in months from infusion of the hematopoietic stem cells (HSCT)
- To Measure the Incidence and Severity of Acute and Chronic GvHD [ Time Frame: 1 year ]Population of participants that received HSCT and T-reg plus T-con, and developed actue, chronic, or any graft vs host disease (GvHD)
- Serious Infections [ Time Frame: 1 year ]Serious infections are reported as the number of participants experienced serious infections.
|Study Start Date:||June 2009|
|Study Completion Date:||June 2014|
|Primary Completion Date:||August 2012 (Final data collection date for primary outcome measure)|
|Experimental: T-reg Cell Infusion after Allogeneic Stem Cell Transplant||
Drug: Regulatory T-cells
To ameliorate the impaired immune recovery and address the significant relapse incidence in the haploidentical setting. Cells will be selected by a tandem selection process and infused on day +14. These are the enriched but naturally-occurring regulatory T cells. Possible dose cohorts and levels are:
Other Name: T-reg cellsDrug: Conventional T-cells
These are conventional (unselected) donor T-cells. Cell dosage of the infusion will be based on the CD3+ cell content and infused on day +16.
Other Name: T-con cellsDrug: Melphalan
Anti-cancer chemotherapy drug administered IV at 140 mg/m² on Day -8 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)
Other Names:Drug: Thiotepa
Anti-cancer chemotherapy drug administered IV at 10 mg/kg on Day -7 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)
Other Names:Device: Fludarabine
Anti-cancer chemotherapy drug administered IV at 160mg/m² on Days -6; -5; -4; and -3 prior to HSCT (a component of the conditioning regiment prior to infusion of cells
Other Names:Drug: Anti-thymocyte globulin, rabbit
Rabbit-derived antibodies against human T-cells used as transplant rejection prophylaxis. Administered at 6 mg/kg IV on Days -6; -5; -4; and -3 prior to HSCT
Other Names:Drug: CliniMACS CD34 Reagent System
An in vitro medical device system that uses antibodies conjugated to magnetic beads to select and enrich for CD34+ blood stem cells from the allogeneic donor apheresis product prior to HSCT, while removing other cells that can cause GvHD. CD34+ cell dosage will be based on the participant's body weight.
This is dose-escalation study intended to evaluate the use of classification determinant 15-positive (CD15+), CD4+, CD127dim, and FoxP3+ regulatory T-cells (T-reg cells) supplemented by conventional T-cells (T-con cells), to enhance the efficacy of allogeneic (CliniMACS CD34+ selected) hematopoietic stem cell transplantation (allo-HSCT), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (MDS). This study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical HSCT setting.
Pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (rATG).
Stem cell rescue will be with CD34+ selected cells. The rescue infusion will be supplemented with infusions of regulatory T-cells (T-reg) and conventional T-cells (T-con) from the same donor collection, on Treatment Days 14 and 16 respectively. CD34+ cell infusion day is Treatment Day 0.
T-reg cells are those cells enriched by immunomagnetic selection of CD25+ cells, and further purified by flow cytometric cell sorting for the CD15+, CD4+, CD127dim, FoxP3+ cell population. These cells are an enriched but naturally-occurring T-cell population.
T-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure.
Post-transplant follow-up is for 5 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01050764
|United States, California|
|Stanford University School of Medicine|
|Stanford, California, United States, 94305|
|Principal Investigator:||Everett H Meyer, MD, PhD||Stanford University|