Mesenchymal Stem Cell Transplant in Promoting Stem Cell Engraftment in Patients with Severe Sickle Cell Disease Undergoing Donor Blood Stem Cell Transplant
This phase I clinical trial studies the side effects and best dose of mesenchymal stem (stromal) cells in promoting stem cell engraftment in patients with severe sickle cell disease who are undergoing a donor blood stem cell transplant. Mesenchymal stem cells obtained from the patient and grown outside the body in a laboratory may have a lower chance of being rejected, and may promote tolerance, helping the donor’s immune cells accept the recipient’s body.
Inclusion Criteria
- Patients must weigh > 25 kg at the time of study entry
- Patients must have undergone puberty at the time of study entry to allow pre-transplant fertility preservation to occur, if desired; puberty will be defined as Tanner III or more in male patients (typically age >= 13 years) and menarche in female patients
- Patients must have severe SCD defined as 1 or more of the following: * Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours * History of >= 2 episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea) * History of >= 3 severe pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea) * Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving >= 8 transfusions per year for >= 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome) * An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity >= 2.7 m/sec in adult patients
- Lansky or Karnofsky performance score >= 60
- Left ventricular ejection fraction (LVEF) > 40% or LV shortening fraction > 26% by cardiac echocardiogram or by multi-gated acquisition (MUGA) scan
- Pulse oximetry with a baseline O2 saturation of >= 90% and diffusion capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin)
- Serum creatinine =< 1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance > 70 mL/min/1.73 m^2 OR glomerular filtration rate (GFR) > 70 mL/min/1.73 m^2 by radionuclide GFR
- Serum conjugated (direct) bilirubin < 2 x upper limit of normal for age as per local laboratory
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 x upper limit of normal as per local laboratory
- Patients with hyperbilirubinemia as a consequence of hyperhemolysis or who experience a sudden, profound change in the serum hemoglobin after a RBC transfusion are not excluded
- In patients who have received chronic transfusion therapy for >= 1 year and who have clinical evidence of iron overload by serum ferritin or magnetic resonance imaging (MRI), evaluation by liver biopsy is required; histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis; the absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues
- Patients must be human leukocyte antigen (HLA) typed at high resolution using deoxyribonucleic acid (DNA) based typing at HLA-A, -B, -C and DRB1 and have an available related haploidentical bone marrow donor with 2, 3, or 4 (out of 8) HLA-mismatches; a unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch
Exclusion Criteria
- Availability of an 8 of 8 (HLA-A, B, C and DRB1) HLA matched sibling or matched unrelated donor
- Presence of donor directed HLA antibodies
- Severe pulmonary disease (despite above oxygen saturation and DLCO) including severe and uncontrolled asthma (per 2007 National Heart, Lung, and Blood Institute [NHLBI] Guidelines for the Diagnosis and Treatment of Asthma Expert Panel Report 3), chronic obstructive pulmonary disease, and/or pulmonary hypertension (PH); a diagnosis of PH will be made by finding of mean pulmonary artery pressure (mPAP) < 25 mm Hg on right heart catherization; in patients unable and/or unwilling to undergo cardiac catheterization, patients will be excluded with the following constellation of findings based upon presumptive diagnosis of PH (positive predictive value [PPV] of 62%): TRJ velocity > 2.5 m/sec AND either N-terminal pro-brain natriuretic peptide (NT-pro-BNP) >= 160 pg/ml OR 6-minute walk distance < 333 m
- Uncontrolled bacterial, viral or fungal infection in the 6 week before enrollment
- Seropositivity for human immunodeficiency virus (HIV)
- Previous HCT
- Participation in a clinical trial in which the patient received an investigational drug or device or the off-label use of a drug or device within 3 months of enrollment
- Demonstrated lack of compliance with prior medical care
- Unwilling to use approved contraception for at least 6 months following transplant
- Pregnant or breastfeeding females
- Allergy to any component of MSC suspension (such as human albumin) and/or allergy to any drugs used in HCT conditioning regimen
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03298399.
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of infusing escalating doses of autologous mesenchymal stromal cells (MSCs) in patients with sickle cell disease (SCD) undergoing haploidentical hematopoietic cell transplantation (HCT).
SECONDARY OBJECTIVES:
I. To assess the impact of autologous MSC infusion on standard engraftment outcomes, including the time to neutrophil and platelet engraftment, incidence of primary and secondary graft failure, and percentage lineage-specific donor chimerism.
II. To assess the impact of MSC infusion on incidence and severity of graft-versus-host disease (GVHD).
III. To determine the effect of MSC infusion on immune reconstitution.
OUTLINE: This is a dose-escalation study of autologous mesenchymal stromal cells.
Patients receive autologous mesenchymal stromal cells intravenously (IV) over 10-20 minutes on day 0 or 1. Treatment repeats once or twice weekly for 4-6 doses in the absence of disease progression or unacceptable toxicity.
HCT CONDITIONING REGIMEN: Patients receive hydroxyurea orally (PO) once daily (QD) on days -100 to -10, lapine T-lymphocyte immune globulin IV over 4-6 hours on days -9 to -7, thiotepa IV over 2 hours on day -7, fludarabine phosphate IV over 30 minutes on days -6 to -2, and cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4 in the absence of disease progression or unacceptable toxicity. Patients undergo total-body irradiation (TBI) on day -1, and HCT on day 0. Patients also receive sirolimus PO QD on days 5 to 365 and mycophenolate mofetil PO or IV thrice daily (TID) on days 5 to 35 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 1 year.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationChildren's Healthcare of Atlanta - Arthur M Blank Hospital
Principal InvestigatorElizabeth O'Brien Stenger
- Primary IDEPIC2016-MSC003
- Secondary IDsNCI-2017-01898, IRB00090514
- ClinicalTrials.gov IDNCT03298399