Clinical trial NCT01033552: Biochemical Correction of Severe EB by Allo HSCT and "Off-the-shelf" MSCs
Official title: MT2009-09: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell Transplantation and "Off-the-shelf" Mesenchymal Stem Cells
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Epidermolysis Bullosa
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2009-12-16
Enrollment: 32
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With Event-free Survival
timeFrame: 1 year and 2 Years Post-transplant
Secondary outcomes:
measure: Percentage of Participants Transplant-related Mortality (TRM)
timeFrame: 180 Days Post Transplant
measure: Average Biochemical Improvement
timeFrame: 1 Year Post-Transplant
measure: Measure Patients Quality of Life Using a Questionnaire
timeFrame: Pretreatment and 1 year
measure: Durability of HSC Donor Engraftment in the Skin
timeFrame: 100 Days
measure: Probability of Survival
timeFrame: 1 Year
measure: Percentage of Participants Who Experienced Acute GVHD
timeFrame: 100 Days
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota Masonic Cancer Center and Medical Center
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Jakub Tolar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: