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

Primary Purpose

Epidermolysis Bullosa

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine
Anti-thymocyte globulin
Cyclosporine A
Mycophenolate mofetil
Mesenchymal stem cell transplantation
Total body irradiation
Bone marrow or umbilical cord blood (UCG) stem cell transplantation
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epidermolysis Bullosa

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Minnesota Masonic Cancer Center and Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Transplant in Epidermolysis Bullosa

Arm Description

Outcomes

Primary Outcome Measures

Event-free survival rate
Event-free survival rate, with an event defined as death or failure to have a demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition.

Secondary Outcome Measures

Transplant-related mortality (TRM)
Incidence of transplant-related mortality (TRM)
Pattern of biochemical improvement
Describe pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin, or plakin) and related structural and physical changes
Measure patients Quality of Life using a questionnaire
Health quality of life questionnaire or iscorEB as compared to pretreatment results
Durability of HSC and third party MSC engraftment in the skin
Incidence of HSC and third party MSC engraftment in the skin
Probability of Survival
Number of surviving patients one year after engraftment
Number of participants experiencing Acute GVHD
Incidence of acute GCHD

Full Information

First Posted
December 14, 2009
Last Updated
February 7, 2023
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT01033552
Brief Title
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

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
January 2010 (Actual)
Primary Completion Date
August 12, 2021 (Actual)
Study Completion Date
August 12, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epidermolysis Bullosa

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Transplant in Epidermolysis Bullosa
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.
Intervention Type
Drug
Intervention Name(s)
Anti-thymocyte globulin
Other Intervention Name(s)
ATG
Intervention Description
30 mg/kg on Days -4, -3 and -2.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine A
Other Intervention Name(s)
CSA
Intervention Description
Days -3 to 100+ to maintain a level of >200 ng/ml; initial dose 2.5 mg/kg over 2 hours every 8-12 hours for children.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
CellCept(R)
Intervention Description
15 mg/kg intravenous twice per day on days -3 through 30.
Intervention Type
Procedure
Intervention Name(s)
Mesenchymal stem cell transplantation
Other Intervention Name(s)
MSCT
Intervention Description
infused via intravenous drip on Day 0
Intervention Type
Radiation
Intervention Name(s)
Total body irradiation
Intervention Description
300 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
Intervention Type
Procedure
Intervention Name(s)
Bone marrow or umbilical cord blood (UCG) stem cell transplantation
Other Intervention Name(s)
UCBSCT
Intervention Description
Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip.
Primary Outcome Measure Information:
Title
Event-free survival rate
Description
Event-free survival rate, with an event defined as death or failure to have a demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition.
Time Frame
1 year and 2 Years Post-transplant
Secondary Outcome Measure Information:
Title
Transplant-related mortality (TRM)
Description
Incidence of transplant-related mortality (TRM)
Time Frame
180 Days Post Transplant
Title
Pattern of biochemical improvement
Description
Describe pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin, or plakin) and related structural and physical changes
Time Frame
Through 1 Year Post-Transplant
Title
Measure patients Quality of Life using a questionnaire
Description
Health quality of life questionnaire or iscorEB as compared to pretreatment results
Time Frame
Pretreatment, Day 100, 6 months, 1 and 2 years
Title
Durability of HSC and third party MSC engraftment in the skin
Description
Incidence of HSC and third party MSC engraftment in the skin
Time Frame
100 Days
Title
Probability of Survival
Description
Number of surviving patients one year after engraftment
Time Frame
1 Year
Title
Number of participants experiencing Acute GVHD
Description
Incidence of acute GCHD
Time Frame
100 Days

10. Eligibility

Sex
All
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jakub Tolar, MD, PhD
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Minnesota Masonic Cancer Center and Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States

12. IPD Sharing Statement

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

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