Mesenchymal Stromal Cells for Haplo Hematopoietic Cell Transplantation for Sickle Cell Disease

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)

Inclusion Criteria:

- Must weigh >25 kg at the time of study entry.

- 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.

- Have severe sickle cell disease (SCD) defined as 1 or more of the following:

1. Clinically significant neurologic event (stroke) or any neurological deficit
lasting > 24 hours;

2. 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);

3. 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);

4. 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);

5. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity
≥2.7 m/sec in adult patients.

- Have adequate physical function as measured by:

1. Lansky or Karnofsky performance score ≥60

2. Cardiac function: left ventricular ejection fraction (LVEF) >40% or LV shortening
fraction > 26% by cardiac echocardiogram or by multigated acquisition (MUGA)
scan.

3. Pulmonary function: pulse oximetry with a baseline O2 saturation of ≥90% and DLCO
>40% (corrected for hemoglobin)

4. Renal function: 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 m2 or
glomerular filtration rate (GFR) >70 mL/min/1.73 m2 by radionuclide GFR.

5. Hepatic function: serum conjugated (direct) bilirubin <2x upper limit of normal
for age as per local laboratory and alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) <5x 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.

6. In patients who have received chronic transfusion therapy for ≥1 year and who
have clinical evidence of iron overload by serum ferritin or 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 (1995).

- Must be HLA typed at high resolution using 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) human leukocyte antigen (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 NHLBI Guidelines for the Diagnosis and Treatment of
Asthma Expert Panel Report 3;
http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report),
chronic obstructive pulmonary disease, and/or pulmonary hypertension (PH). A diagnosis
of pulmonary hypertension (PH) will be made by finding of mean pulmonary artery
pressure (mPAP) <25 mm Hg on right heart catheterization. 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 (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 hematopoietic cell transplantation (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 mesenchymal stromal cell (MSC) suspension (such as human
albumin) and/or allergy to any drugs used in HCT conditioning regimen.