A Phase 1 interventional study of Autologous MSCs and Autologous MSCs in Sickle Cell Disease, sponsored by Emory University. Withdrawn. Open to participants aged 12 Years to 40 Years. Per ClinicalTrials.gov, last updated 2018-11-07.
Sponsored by Emory University · Phase 1, Interventional, and Treatment
This trial is being conducted as a step toward testing the long-term hypothesis that freshly cultured, autologous mesenchymal stromal cells (MSCs) grown in platelet lysate-containing medium will modulate recipient T-cell immune responses and promote engraftment in haploidentical hematopoietic cell transplant (HCT) recipients. As a phase I, dose escalation trial of autologous MSCs in patients with sickle cell disease (SCD) undergoing haploidentical HCT, the main aim is to evaluate the safety of this therapy with a secondary aim to evaluate its effects on engraftment and graft-versus-host disease (GVHD).
This is a single center, phase I, open label dose escalation study designed to determine the safety and tolerability of autologous, bone marrow-derived MSCs (EPIC2016-MSC003) in patients with SCD undergoing haploidentical HCT.
Study participants are assigned to one of three MSC dose levels: four infusions of MSCs given once per week, four infusions given twice per week, or six infusions given twice per week. Bone marrow (1-2 ml/kg, max 60 ml) will be collected from study participants for autologous MSC expansion a minimum of 28 days prior to first planned MSC infusion. MSCs will be expanded ex vivo in human platelet lysate to the specified dose level. All MSC infusions will be dosed at 2 x 10\^6 MSCs/kg recipient weight, with first infusion given on day 0 (day of haploidentical HCT) or day +1. This phase I trial will enroll 12-18 patients with severe SCD undergoing haploidentical HCT, with subjects followed for 1 year following HCT (and MSC infusions).
Prior to MSC infusions, study participants will undergo transplant conditioning and GVHD prophylaxis as follows:
Day -100 to -10: Hydroxyurea 30 mg/kg PO Qday
Day -9: Rabbit anti-thymocyte globulin (ATG) 0.5 mg/kg IV
Day -8: Rabbit ATG 2 mg/kg IV
Day -7: Rabbit ATG 2 mg/kg IV; Thiotepa 10 mg/kg IV
Day -6: Fludarabine 30 mg/m2 IV; Cyclophosphamide 14.5 mg/kg IV
Day -5: Fludarabine 30 mg/m2 IV; Cyclophosphamide 14.5 mg/kg IV
Day -4: Fludarabine 30 mg/m2 IV
Day -3: Fludarabine 30 mg/m2 IV
Day -2: Fludarabine 30 mg/m2 IV
Day -1: Total body irradiation (TBI) 200 centigray (cGy)
Day 0: Haploidentical bone marrow stem cell infusion
Day +3: Cyclophosphamide 50 mg/kg IV
Day +4: Cyclophosphamide 50 mg/kg IV
Day +5: Sirolimus (through day +365); mycophenolate mofetil (MMF) 15 mg/kg/dose three times per day (TID) (through day +35)
Have severe sickle cell disease (SCD) defined as 1 or more of the following:
Have adequate physical function as measured by:
Exclusion Criteria:
The first three subjects (minimum) will receive four weekly infusions of MSCs.
Biological: Autologous MSCs
If no significant side effects are encountered at dose level 1, then subsequent subjects will receive four infusions of MSCs given twice weekly.
Biological: Autologous MSCs
If dose level 2 is well tolerated, then subsequent subjects will receive six infusions MSCs given twice weekly.
Biological: Autologous MSCs
Participants at dose level 1 receive four infusions of MSCs, given once per week. The first MSC infusion will be given no sooner than 4 hours after the bone marrow transplant. The total number of cells delivered to each patient will depend on their weight and assigned dose level. The maximal individual dose of MSCs any patient will receive is 2 x 10\^6 cells/kg, which will be delivered via intravenous infusion. The infusion can be administered to patients in the inpatient or outpatient setting.
Participants at dose level 2 receive four infusions of MSCs, given twice per week. The first MSC infusion will be given no sooner than 4 hours after the bone marrow transplant. The total number of cells delivered to each patient will depend on their weight and assigned dose level. The maximal individual dose of MSCs any patient will receive is 2 x 10\^6 cells/kg, which will be delivered via intravenous infusion. The infusion can be administered to patients in the inpatient or outpatient setting.
Participants at dose level 3 receive six infusions of MSCs, given twice per week. The first MSC infusion will be given no sooner than 4 hours after the bone marrow transplant. The total number of cells delivered to each patient will depend on their weight and assigned dose level. The maximal individual dose of MSCs any patient will receive is 2 x 10\^6 cells/kg, which will be delivered via intravenous infusion. The infusion can be administered to patients in the inpatient or outpatient setting.
Safety and tolerability of EPIC2016-MSC003 based upon dose limiting toxicities (DLTs)
DLTs will be defined as any grade ≥3 adverse reaction that is unexpected or considered attributable to the MSC infusion (attribution listed as at least probable). Because of the medical complexity of subjects on this trial and the lack of described DLTs to MSC infusion, all reported DLTs will be reviewed by the Data and Safety Monitoring Committee (DSMC).
Time frame: 30 days after last MSC infusion
Primary graft rejection
Defined as the absence of donor cells assessed by peripheral blood chimerism assays on day 42.
Time frame: 42 days after HCT
Late graft rejection
Defined as the absence of donor hematopoietic cells in peripheral blood beyond day 42 in a patient who had initial evidence of hematopoietic recovery with \> 20% donor cells.
Time frame: One year after HCT
Time to neutrophil engraftment
Defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of 500/µL after conditioning.
Time frame: Up to one year after HCT
Time to platelet engraftment
Defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count \> 50,000/µL AND did not receive a platelet transfusion in the previous 7 days.
Time frame: Up to one year after HCT
Lineage specific donor chimerism
Genomic deoxyribonucleic acid (DNA) extracted from peripheral blood will be analyzed for variable number of tandem repeats (VNTR) to detect donor engraftment in myeloid and lymphoid fractions.
Time frame: Up to one year after HCT
Immune reconstitution
Immune reconstitution will be assessed post-transplant by standard clinical testing and research testing.
Time frame: Up to one year after HCT
Acute GVHD
Incidence of grade II-IV and III-IV acute GVHD
Time frame: One year after HCT
Chronic GVHD
Incidence and severity of chronic GVHD
Time frame: One year after HCT
Transplant-related mortality (TRM)
Defined as any death occurring in continuous complete remission
Time frame: One year after HCT
Event-free survival (EFS)
Defined as survival with stable donor erythropoiesis and no new clinical evidence SCD. Primary or late graft rejection with disease recurrence or death will count as events for this endpoint.
Time frame: One year after HCT
Overall survival (OS)
Defined as survival with or without SCD after HCT
Time frame: One year after HCT
No study locations are listed for this record.
Plan to share: No
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This study is withdrawn, as verified in Nov 2018. You cannot join it, but the record below documents what was studied.
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Emory University