Unrelated Cord Blood Transplant Plus a Haplo-Identical (Half-Matched), T-Cell Depleted Stem Transplant From a Related Donor for Subjects With High Risk Malignancies
|Hematologic Malignancy Myelodysplastic Syndrome (MDS) Aplastic Anemia||Biological: haplo/cord transplant||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Prospective, Phase I/II Trial Determining the Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation Using Banked Unrelated Umbilical Cord Blood Supplemented With Related, Haplo-Identical T-Cell Depleted Stem Cells in Subjects With High Risk Malignancies|
- The Number of Participants Reaching Primary Endpoint of Absolute Neutrophil Count (ANC) of 500/uL (Engraftment). [ Time Frame: By day 100 ]
- 180 Day Survival [ Time Frame: 180 days ]Number of participants alive at 180 days post transplant
- Non-Relapse Mortality at 180 Days Post Transplant [ Time Frame: 180 days ]
- Platelet Engraftment (Untransfused and Platelet Count > 50,000) [ Time Frame: Approximately 1 year ]Participants platelet engrafted.
- Incidence of Primary and Secondary Graft Failure [ Time Frame: 100 days post transplant ]Number of participants experiencing graft failure.
- Number of Participants With Acute or Chronic Graft-versus-host Disease (GVHD) [ Time Frame: two years ]Acute and chronic GVHD
- Rates of Leukemic Relapse [ Time Frame: Up to 2 years post transplant ]Number of participants relapsed
- Number of Participants With Donor Cells at 100 Days Post-transplant [ Time Frame: Post transplant ]
|Study Start Date:||August 2007|
|Study Completion Date:||April 2012|
|Primary Completion Date:||April 2012 (Final data collection date for primary outcome measure)|
Biological: haplo/cord transplant
T-cell depleted haplo-matched cells from related donor and unrelated umbilical cord blood
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Over the past decade, umbilical cord blood transplantation has been shown to be a viable alternative donor stem cell source for hematopoietic cell transplantation in subjects with catastrophic diseases treatable with transplantation therapy. UCB cells can cross partially mismatched HLA barriers without intolerable acute or chronic Graft-versus-Host Disease(GVHD). Thus, many subjects lacking a sufficiently matched, living related or unrelated bone marrow or adult stem cell donor, can use partially HLA-matched UCB cells for stem cell rescue after myeloablative irradiation and/or chemotherapy. UCB Cell dose, expressed per kilogram of recipient body weight, is the best predictor of outcomes after UCB transplantation. Cell dose thresholds strongly correlating with outcomes have been identified.
In subjects receiving lower cell doses, while durable engraftment will ultimately occur, there are significant delays in myeloid and platelet engraftment which, at best, result in longer hospitalization and significant increases in resource utilization and in the worst cases, result in increased early deaths from infection and regimen-related toxicity.
In infants and children weighing <40kg, it is possible to find a sufficiently matched UCB unit that will deliver a dose of cells critical for successful engraftment (defined as 5 x 10^7 nucleated cells/kg) within a reasonable time frame in >90% of subjects. In teenagers and adults weighing >40kg, this is not always possible. Because UCB units contain a relatively fixed number of total nucleated cells, units delivering optimal cell dosing for subjects weighing >70kg will only be identified <10% of the time. Attempts to increase the dose of cells available for UCBT have included ex vivo expansion and combined unit transplantation. While expansion of UCB cells ex vivo is possible, infusion of these expanded cells have not resulted in shortening of engraftment times. Likewise, combinations of up to 5 UCB units for a single myeloablative transplant have not shortened time to neutrophil or platelet engraftment.
In this study, we take an alternative approach to facilitating early myeloid engraftment in subjects undergoing UCB transplantation therapy. In subjects who cannot only identify a donor delivering a cell dose >2 x 10^7 nucleated cells/kg, we will augment the UCBT with a lower dose of haplo-identical, T-cell depleted stem cells from a related adult donor to facilitate early, short-term engraftment with the primary goal of minimizing early infections and other non-relapse mortality while the UCB cells engraft as the durable and permanent graft. As the immunocompetent UCB cells engraft, we expect that they will reject the immunologically incompetent haplo-identical adult stem cells. Thus, after approximately 100-180 days post transplant, the subject should convert to 100% donor chimerism with the UCB donor graft.
In this study, we will investigate the use of unrelated UCB obtained from the umbilical cord blood banks supplements with related, haplo-identical, T-cell depleted stem cells in subjects with high risk refractory malignancies, myelodysplasia or severe aplastic anemia amenable to stem cell transplantation therapy but lacking conventional related or unrelated donors.
- To determine the safety of co-transplantation of unrelated umbilical cord blood supplemented with related, haplo-identical, T-cell depleted stem cells in subjects with high risk malignancies.
- To describe the rates of neutrophil and platelet engraftment and immune reconstitution in these subjects.
- To determine whether short and long term lymphohematopoietic engraftment is derived from one or both donor sources.
The primary endpoint of the study is number of days to ANC of 500/uL
The secondary endpoints of the study are:
- 180 day survival
- Non-relapse mortality in the first 180 days post transplant
- Number of days to untransfused platelet count of 50K/uL
- Incidence of primary and secondary graft failure
- Incidence and severity of acute and chronic graft-versus-host disease (GVHD)
- Pace and quality of immune reconstitution
- Rates of leukemic relapse
- Donor chimerism
Please refer to this study by its ClinicalTrials.gov identifier: NCT00673114
|United States, North Carolina|
|Duke University Medical Center Pediatric Blood and Marrow Transplant|
|Durham, North Carolina, United States, 27705|
|Principal Investigator:||Joanne Kurtzberg, MD||Duke University Medical Center Pediatric Blood and Marrow Transplant|