Allogeneic Stem Cell Transplantation (ALLOSCT) in Recessive Dystrophic Epidermolysis Bullosa (RDEB) (RDEB)

A Pilot Study of Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (ALLOSCT) In Children With Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (AlloSCT) from family-related donors and unrelated cord blood (UCB) donors will be safe and well tolerated in selected patients with RDEB.

To determine the event-free survival (EFS) and overall survival (OS) following RIC consisting of busulfan/fludarabine/alemtuzumab (BFA) and AlloSCT in selected patients with RDEB.

Study Overview

• Status: Terminated
• Conditions: Epidermolysis Bullosa
• Intervention / Treatment: Drug: Palifermin; Drug: Fludarabine; Drug: Busulfan; Drug: Lorazepam; Drug: Alemtuzumab; Drug: Tacrolimus

Detailed Description

Epidermolysis bullosa (EB), is a diverse group of genodermatoses, which is considered a rare and orphan disease and affects approximately 1 in 20,000 people in the United States for a cumulative total of close to 20,000[1-4]. There are three major subtypes of inherited EB, including EB simplex (EBS), junctional EB (JEB), and dystrophic EB[1-4]. RDEB is among the most severe and represents approximately 10% of all forms of EB[1-4]. A rough estimate would then project that there are several thousand patients with RDEB in the U.S. at the current time. Up to 30 different clinical phenotypes and mutations in at least 10 structural genes in different sub-types of EB have been reported[4-8]. In addition to heritable subtypes of EB, there is an acquired autoimmune form in which the patients develop auto-antibodies directed against similar proteins of the inherited dystrophic forms of EB, including EB acquisita (EBA).

We have previously reported our experience with RIC with BFA [48] in pediatric AlloSCT recipients (mean age 9.5 yrs [1.4-21], 11/4 M/F, 10 non-malignant, 5 malignant disease, [6 sibling, 5 UCB, 5 matched unrelated donor]); median time to ANC ≥ 500/mm3 and platelet count ≥20K/mm3 was 22 and 30 days, respectively. Probability of day +180 and 365 donor chimerism was 90% (Figure 7), and OS was 95% (Figure 8). This conditioning regimen therefore results in a high degree of donor chimerism and survival with minimal regimen related mortality.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • New York
    • New York, New York, United States, 10032
      • Morgan Stanley Children's Hospital of NYP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Recessive Dystrophic Epidermolysis Bullosa (RDEB)
• Diagnosis of RDEB using molecular diagnosis and sequencing of mutations
• Skin biopsy to determine status of type VII collagen
• Age ≤21 years

• Patient must have adequate organ function as below:

  1. Adequate renal function defined as:

     • Serum creatinine less than or equal to 1.5 x normal, or
     • Creatinine clearance or radioisotope glomerular filtration rate (GFR) =40 ml/min/m2 or > 60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range

  2. Adequate liver function defined as:

     • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase (ALT))< 5.0 x normal

  3. Adequate cardiac function defined as:

     • Shortening fraction of ≥28% by echocardiogram, or
     • Ejection fraction of ≥48% by radionuclide angiogram or echocardiogram

  4. Adequate pulmonary function defined as:

     • Uncorrected diffusing capacity of the lungs for carbon monoxide (DLCO) ≥35% by pulmonary function test
     • For children who are uncooperative, no evidence of dyspnea at rest

Exclusion Criteria:

• Karnofsky/Lansky Performance Score <50%
• Pregnant or nursing
• Uncontrolled bacterial, viral or mold infection
• History or presence of skin squamous cell carcinoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: RIC Group; Reduced Intensity Transplant Conditioning (RIC): Palifermin (Kepivance®) 60 mcg/kg/day for 6 days Fludarabine 30 mg/m2 IV x 1 for 6 days Busulfan 4 mg/kg/day IV divided BID for 4 days Lorazepam 0.02-0.05 mg/kg for 5 days Alemtuzumab 20 mg/m2 IV for 5 days Tacrolimus 0.03mg/kg/24 hours as continuous infusion for 4 days

Drug: Palifermin; 60 mcg/kg/day for 6 days; Other Names: Kepivance; Drug: Fludarabine; 30 mg/m2 IV x 1 for 6 days; Other Names: Fludara; Drug: Busulfan; 4 mg/kg/day IV divided BID for 4 days; Other Names: Myleran; Drug: Lorazepam; 0.02-0.05 mg/kg for 5 days; Other Names: Ativan; Drug: Alemtuzumab; 20 mg/m2 IV for 5 days; Other Names: Lemtrada; Drug: Tacrolimus; 0.03mg/kg/24 hours as continuous infusion for 4 days; Other Names: Prograf; Hecoria; Protopic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival (OS)	Up to 2 years
Event-free survival (EFS)	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of whole blood (CD45), T-cell (CD3), and NK cell (CD56) chimerism following RIC and AlloSCT in selected patients with RDEB	Up to Day +730
Percentage of donor skin dermal chimerism following RIC and AlloSCT in selected patients with RDEB.	Up to Day +730

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Angela Christiano, PhD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2009
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: April 14, 2009
• First Submitted That Met QC Criteria: April 14, 2009
• First Posted (Estimate): April 15, 2009

Study Record Updates

• Last Update Posted (Actual): August 17, 2021
• Last Update Submitted That Met QC Criteria: August 13, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Allogeneic Stem Cell Transplant; RDEB; AlloSCT; recessive dystrophic epidermolysis bullosa
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Collagen Diseases; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Calcineurin Inhibitors; Fludarabine; Tacrolimus; Busulfan; Lorazepam; Alemtuzumab
• Other Study ID Numbers: AAAD5420; CHNY-08-536 (Other Identifier: CUMC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No