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

NCT03298399 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: IRB000905141K23HL133446
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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).

Conditions

Sickle Cell Disease

Keywords

Hematopoietic cell transplantation (HCT); Haploidentical; Mesenchymal stromal cells

Outcome Measures

Primary Outcomes (1)

• 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).

  30 days after last MSC infusion

Secondary Outcomes (11)

• Primary graft rejection

  42 days after HCT

• Late graft rejection

  One year after HCT

• Time to neutrophil engraftment

  Up to one year after HCT

• Time to platelet engraftment

  Up to one year after HCT

• Lineage specific donor chimerism

  Up to one year after HCT

Study Arms (3)

MSC dose level 1

EXPERIMENTAL

The first three subjects (minimum) will receive four weekly infusions of MSCs.

Biological: Autologous MSCs

MSC dose level 2

EXPERIMENTAL

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

MSC dose level 3

EXPERIMENTAL

If dose level 2 is well tolerated, then subsequent subjects will receive six infusions MSCs given twice weekly.

Biological: Autologous MSCs

Interventions

Autologous MSCs BIOLOGICAL

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.

MSC dose level 1

Eligibility Criteria

• Age: 12 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• 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.
• Have adequate physical function as measured by:
• Lansky or Karnofsky performance score ≥60
• Cardiac function: left ventricular ejection fraction (LVEF) \>40% or LV shortening fraction \> 26% by cardiac echocardiogram or by multigated acquisition (MUGA) scan.
• Pulmonary function: pulse oximetry with a baseline O2 saturation of ≥90% and DLCO \>40% (corrected for hemoglobin)
• 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.
• 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.
• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Emory University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Elizabeth Stenger, MD

  Emory University

  PRINCIPAL INVESTIGATOR

• Lakshmanan Krishnamurti, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 27, 2017
• First Posted: October 2, 2017
• Study Start: December 21, 2017
• Primary Completion: October 25, 2018
• Study Completion: October 25, 2018
• Last Updated: November 7, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share