MT2009-09: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell Transplantation and "Off-the-shelf" Mesenchymal Stem Cells
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Event-free Survival
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •HLA-A, B, C, DRB1 phenotypic identical donor
- •7/8 HLA matched donor at HLA-A, B, C, DRB1
- •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
排除标准
- •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.
研究组 & 干预措施
RDEB Mac
Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Cyclophosphamide (Drug)
RDEB Mac
Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Fludarabine (Drug)
RDEB Mac
Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Myeloablative Busulfan (Drug)
RDEB Mac
Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Mesenchymal stem cell transplantation (Procedure)
RDEB Mac
Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Bone marrow or umbilical cord blood (UCG) stem cell transplantation (Procedure)
RDEB RIC
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Cyclophosphamide (Drug)
RDEB RIC
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Fludarabine (Drug)
RDEB RIC
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Anti-thymocyte globulin (Drug)
RDEB RIC
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Mesenchymal stem cell transplantation (Procedure)
RDEB RIC
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Total body irradiation (Radiation)
RDEB RIC
Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Bone marrow or umbilical cord blood (UCG) stem cell transplantation (Procedure)
JEB MAC
Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Cyclophosphamide (Drug)
JEB MAC
Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Fludarabine (Drug)
JEB MAC
Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Myeloablative Busulfan (Drug)
JEB MAC
Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Mesenchymal stem cell transplantation (Procedure)
JEB MAC
Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
干预措施: Bone marrow or umbilical cord blood (UCG) stem cell transplantation (Procedure)
JEB RIC
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Cyclophosphamide (Drug)
JEB RIC
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Fludarabine (Drug)
JEB RIC
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Anti-thymocyte globulin (Drug)
JEB RIC
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Mesenchymal stem cell transplantation (Procedure)
JEB RIC
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Total body irradiation (Radiation)
JEB RIC
Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
干预措施: Bone marrow or umbilical cord blood (UCG) stem cell transplantation (Procedure)
结局指标
主要结局
Percentage of Participants With Event-free Survival
时间窗: 1 year and 2 Years Post-transplant
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. Assessed at follow up appointments through questionnaire and patient samples.
次要结局
- Probability of Survival(1 Year)
- Average Biochemical Improvement(1 Year Post-Transplant)
- Measure Patients Quality of Life Using a Questionnaire(Pretreatment and 1 year)
- Percentage of Participants Transplant-related Mortality (TRM)(180 Days Post Transplant)
- Percentage of Participants Who Experienced Acute GVHD(100 Days)
- Durability of HSC Donor Engraftment in the Skin(100 Days)