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Biochemical Correction of Severe EB by Allo HSCT and "Off-the-shelf" MSCs

University of Minnesota (UMN) logo

University of Minnesota (UMN)

Status and phase

Completed
Phase 2
Phase 1

Conditions

Epidermolysis Bullosa

Treatments

Drug: Myeloablative Busulfan
Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
Drug: Anti-thymocyte globulin
Drug: Fludarabine
Procedure: Mesenchymal stem cell transplantation
Drug: Cyclophosphamide
Radiation: Total body irradiation

Study type

Interventional

Funder types

Other

Identifiers

NCT01033552
0911M74035 (Other Identifier)
MT2009-09

Details and patient eligibility

About

This is an open-label, single institution, phase II study in patients with epidermolysis bullosa (EB). The underlying hypothesis is that the infusion of bone marrow or umbilical cord blood from a healthy unaffected donor will correct the collagen, laminin, integrin, or plakin deficiency and reduce the skin fragility characteristic of severe forms of EB. A secondary hypothesis is that mesenchymal stem cells from a healthy donor will enhance the safety and efficacy of the allogeneic hematopoietic stem cell transplant as well as serve as a source of renewable cells for the treatment of focal areas of residual blistering.

Full description

The primary objective of this study is to estimate the event-free survival rate by 1 year post-transplant with an event defined as a death or failure to have a demonstrable increase in collagen, laminin, integrin, keratin or plakin deposition by 1 year post-transplant or other biochemical, structural or physical measure of improvement.

The secondary objectives of this study are to i) determine the incidence of transplant-related mortality (TRM) at 180 days; ii) describe the pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin or plakin) and related structural and physical changes; iii) describe health quality of life at day 365 and 730 as compared to pretreatment results; iv) describe the pattern and durability of HSC and third party MSC engraftment in the skin; v) determine the probability of survival at 1 year.

Patients with severe epidermolysis bullosa will be screened to meet the eligibility requirements, related or unrelated donor marrow or UCB will be infused, and subjects will be followed for a minimum of 5 years after stem cell transplant. A target accrual of 75 subjects over 5 years will be recruited to the study.

Enrollment

32 patients

Sex

All

Ages

Under 25 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

  • Diagnosis of severe form of epidermolysis bullosa (EB) characterized by collagen, laminin, integrin, keratin or plakin deficiency. Assessment criteria for severe EB:

    • Documented collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis)
  • Adequate Organ Function Criteria

    • Renal: glomerular filtration rate within normal range for age
    • Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal
    • Pulmonary: adequate pulmonary function in the opinion of the enrolling investigator
    • Cardiac: left ventricular ejection fraction ≥ 45%, normal electrocardiogram (EKG) or approved by Cardiology for transplant.
  • Available Healthy HSC Donor (order of preference)

    • Related Donor (marrow or UCB)

      • HLA-A, B, C, DRB1 genotypic identical (sibling) donor
      • HLA-A, B, C, DRB1 phenotypic identical donor
      • 7/8 HLA matched donor at HLA-A, B, C, DRB1
    • Unrelated Donor

      • Marrow

        • HLA-A, B, C, DRB1 phenotypic identical donor
        • 7/8 HLA matched donor at HLA-A, B, C, DRB1
      • UCB

        • HLA-A, B (antigen level) and DRB1 (allele level) matched donor
        • 5/6 HLA matched donor at HLA-A, B, DRB1
        • 4/6 HLA matched donor at HLA-A, B, DRB1
  • Voluntary written consent

Absence of Exclusion Criteria:

  • Active systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days).
  • History of human immunodeficiency virus (HIV) infection
  • Evidence of squamous cell carcinoma
  • Donor has EB
  • Pregnancy females of child-bearing age must have a documented negative pregnancy test and agree to use contraception as a condition for enrollment.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

32 participants in 4 patient groups

RDEB Mac
Experimental group
Description:
Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
Treatment:
Drug: Fludarabine
Drug: Myeloablative Busulfan
Drug: Cyclophosphamide
Procedure: Mesenchymal stem cell transplantation
Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
RDEB RIC
Experimental group
Description:
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
Treatment:
Drug: Fludarabine
Radiation: Total body irradiation
Drug: Anti-thymocyte globulin
Drug: Cyclophosphamide
Procedure: Mesenchymal stem cell transplantation
Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
JEB MAC
Experimental group
Description:
Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
Treatment:
Drug: Fludarabine
Drug: Myeloablative Busulfan
Drug: Cyclophosphamide
Procedure: Mesenchymal stem cell transplantation
Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
JEB RIC
Experimental group
Description:
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
Treatment:
Drug: Fludarabine
Radiation: Total body irradiation
Drug: Anti-thymocyte globulin
Drug: Cyclophosphamide
Procedure: Mesenchymal stem cell transplantation
Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation

Trial documents
2

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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