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

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)

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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