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

Sponsor

Columbia University (Other)

Overall Status

Terminated

CT.gov ID

NCT00881556

Collaborator

(none)

Enrollment

Locations

Arm

72.4

Actual Duration (Months)

Patient Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Epidermolysis Bullosa	Drug: Palifermin Drug: Fludarabine Drug: Busulfan Drug: Lorazepam Drug: Alemtuzumab Drug: Tacrolimus	Early Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 20, 2009

Actual Primary Completion Date :

Sep 1, 2015

Actual Study Completion Date :

Sep 1, 2015

Arms and Interventions

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 Protopic Hecoria

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

Protopic

Hecoria

Outcome Measures

Primary Outcome Measures

Event-free survival (EFS) [Up to 2 years]
Overall Survival (OS) [Up to 2 years]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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

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

Adequate cardiac function defined as:

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital	Aurora	Colorado	United States	80045
2	Children's Memorial Hospital	Chicago	Illinois	United States	60614
3	Morgan Stanley Children's Hospital of NYP	New York	New York	United States	10032