Allogeneic Hematopoietic Stem Cell Transplant For Epidermolysis Bullosa

• ClinicalTrials.gov Identifier: NCT00478244
• Recruitment Status: Terminated
• First Posted: May 24, 2007
• Results First Posted: February 11, 2013
• Last Update Posted: December 28, 2017
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

Tracking Information

• First Submitted Date: May 23, 2007
• First Posted Date: May 24, 2007
• Results First Submitted Date: July 17, 2012
• Results First Posted Date: February 11, 2013
• Last Update Posted Date: December 28, 2017
• Study Start Date: April 2007
• Actual Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 4, 2013)

Number of Patients With Detectable Collagen Type VII [ Time Frame: Day 100 Post Transplant ]

Number of patients with epidermolysis bullosa who had collagen type VII. Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers.

• Original Primary Outcome Measures (submitted: May 23, 2007): Incidence of detectable donor-derived collagen type VII by day 100

Current Secondary Outcome Measures (submitted: January 4, 2013)

• Number of Patients With >70% Donor Chimerism [ Time Frame: Days 21, 100, 180, 365 and 730 Post Transplant ]
  Number of patients with donor chimerism - percentage of donor cells in the patient via the peripheral blood or bone marrow.
• Number of Patients With Transplant-Related Mortality [ Time Frame: Day 180 Post Transplant ]
  Number of patients who died due to complications of the transplant (includes all deaths without previous relapse or progression).
• Number of Patients With Platelet Engraftment [ Time Frame: Day 180 Post Transplant ]
  Number of patients with a platelet count >5 x 10^10 cells/liter for 3 consecutive measurements.
• Number of Patients With Acute Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ]
  Number of patients with GVHD. Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
• Number of Patients With Chronic Graft-Versus-Host Disease (cGVHD) [ Time Frame: Day 365 Post Transplant ]
  Number of patients with cGVHD; a severe long-term complication created by infusion of donor cells into a foreign host.
• Overall Survival [ Time Frame: 1 year and 2 years Post Transplant ]
  Survival is defined as the number of patients that were alive post transplant.
• Number of Patients With Donor Derived Cells in Skin [ Time Frame: Day 90 Post Transplant ]
  Number of patients who had donor skin chimerism - donor cells in the patient's epidermis (a state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease).
• Number of Patients With Resistance to Blister Formation [ Time Frame: Month 1 through Month 24 Inclusive ]
  Resistance to Blister Formation demonstrated by response to negative pressure.
• Number of Patients With Neutrophil Engraftment [ Time Frame: Day 42 Post Transplant ]
  Number of patients with an absolute neutrophil count >5 x 10^8 cells/liter for 3 consecutive days.

Original Secondary Outcome Measures (submitted: May 23, 2007)

• Incidence of transplant-related mortality at 180 days
• Incidence of chimerism at 21, 100, 180, 365, and 730 days
• Incidence of neutrophil recovery at day 42 and platelet recovery at 180 days
• Incidence of acute graft-versus-host disease (GVHD) at day 100
• Incidence of chronic GVHD at 1 year
• Probability of survival and disease-free survival at 1 and 2 years
• Incidence of donor skin-derived epidermal cell survival 90 days after epidermal cell transplantation

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Allogeneic Hematopoietic Stem Cell Transplant For Epidermolysis Bullosa
• Official Title: Allogeneic Hematopoietic Cell Transplantation to Correct the Biochemical Defect and Create Tolerance to Donor Tissue in Subjects With Epidermolysis Bullosa

Brief Summary

RATIONALE: In animal models, stem cells have been shown to home to the skin and repair the biochemical and structural abnormalities associated with recessive dystrophic epidermolysis bullosa (RDEB) (collagen 7 deficiency).

PURPOSE: To determine the safety and effectiveness of stem cell infusion in the treatment of RDEB.

Detailed Description

OBJECTIVES:

Primary

• Estimate the incidence of detectable donor-derived collagen type VII at day 100 in patients with epidermolysis bullosa by donor.

Secondary

• Determine the incidence of transplant-related mortality at day 180
• Determine the incidence of blood chimerism at days 21, 100, 180, 365, and 730
• Determine the incidence of neutrophil recovery at day 42 and platelet recovery at day 180
• Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day 100
• Determine the incidence of chronic GVHD at 1 year
• Determine the probability of survival at 1 and 2 years
• Determine the incidence of donor derived cells in the skin
• Determine resistance to blister formation OUTLINE: This is an open-label, pilot study.
• Conditioning regimen: Busulfan intravenously (IV) over 2 hours every 6 hours on days -9 to -4, fludarabine phosphate IV over 1 hour on days -5 to -3, and high-dose cyclophosphamide IV over 1 hour on days -5 to -2.
• Stem cell transplantation on day 0.

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: 30 patients

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Epidermolysis Bullosa

Intervention

• Drug: busulfan
  Day -9 through Day -6: 1.1 mg/kg if < 12 kg IV every 6 hours; 0.8 mg/kg if > 12 kg.
  Other Name: Bulsulfex
• Drug: cyclophosphamide
  Day -5 through Day -2: 50 mg/kg IV over 120 min.
  Other Name: Cytoxan
• Drug: fludarabine phosphate
  Day -5 through Day -3: 25 mg/m2 IV over 60 min.
  Other Names:

  • Fludarabine
  • Fludara
• Procedure: hematopoietic bone marrow transplantation
  allogeneic bone marrow, peripheral stem cell or umbilical cord blood transplantation
  Other Name: Bone marrow transplant

Study Arms

Experimental: Epidermolysis Bullosa (EB) Patients

Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant.

Interventions:

• Drug: busulfan
• Drug: cyclophosphamide
• Drug: fludarabine phosphate
• Procedure: hematopoietic bone marrow transplantation

• Publications *: Wagner JE, Ishida-Yamamoto A, McGrath JA, Hordinsky M, Keene DR, Woodley DT, Chen M, Riddle MJ, Osborn MJ, Lund T, Dolan M, Blazar BR, Tolar J. Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med. 2010 Aug 12;363(7):629-39. doi: 10.1056/NEJMoa0910501. Erratum in: N Engl J Med. 2010 Sep 30;363(14):1383. Woodley, David T [added]; Chen, Mei [added].

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 31, 2012): 7
• Original Enrollment (submitted: May 23, 2007): 10
• Actual Study Completion Date: August 2011
• Actual Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Diagnosis of epidermolysis bullosa (EB)

  • Documented collagen type VII deficiency by:

    • Antigenic mapping (LH7.2 antibody)
    • Ultrastructure analysis of anchoring fibrils
    • DNA mutation analysis
• Performance status: >50% Lansky; >50% Karnofsky

• Adequate organ function

  • Renal: glomerular filtration rate > 60ml/min/1.73m2 patients aged ≤ 10 years
  • Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal 4.2.3 Pulmonary: oxygen saturation >92% 4.2.4 Cardiac: left ventricular ejection fraction > 45%.

• Healthy related hematopoietic stem cell donor available and meeting 1 of the following criteria:

  • HLA-A, B, DRB1-identical sibling bone marrow and/or umbilical cord blood donor (first priority)
  • HLA-A, B, DRB1-matched or partially matched related donor (second priority)
  • Donor may be a carrier but must be unaffected by EB
  • 8/8 HLA A, B, C, DRB1 allele level matched unrelated marrow donor (third priority)
  • 7/8 HLA-A, B, C, DRB1 allele level matched unrelated marrow donor or 4/6 HLA-A, B (antigen level), DRB1 (allele level) matched unrelated cord blood donor (fourth priority)

Exclusion criteria:

• Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days)
• Squamous cell carcinoma of the skin
• History of human immunodeficiency virus (HIV) infection
• Prior transplantation with donor skin

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00478244
• Other Study ID Numbers: MT2006-15; CDR0000546620 ( Other Identifier: PDQ ); UMN-0702M01504 ( Other Identifier: IRB, University of Minnesota )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Masonic Cancer Center, University of Minnesota
• Study Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: Not Provided

Investigators

• Study Chair: John E. Wagner, MD; Masonic Cancer Center, University of Minnesota

• PRS Account: Masonic Cancer Center, University of Minnesota
• Verification Date: December 2017