MT2015-20: Biochemical Correction of Severe EB by Allo HSCT and Serial Donor MSCs

Study Overview
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Brief Summary
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This is a single-institution, phase II study to determine the event-free survival at 1 year post allogeneic transplant and serial mesenchymal stem cell (MSC) infusions from a related donor (HLA identical, mismatched or haploidentical) or matched unrelated donor for the biochemical correction of severe epidermolysis bullosa (EB).

Official Title
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MT2015-20: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Cell Transplantation and Serial Donor Mesenchymal Cell Infusions

Conditions
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Epidermolysis Bullosa

Intervention / Treatment
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* Drug: Thymoglobulin
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Radiation: Total Body Irradiation
* Procedure: Bone marrow infusion
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Biological: Donor mesenchymal stem cell infusions
* Drug: Busulfan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of severe form of EB characterized by collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis). Adequate organ function within 4 weeks of study registration defined as: Renal: glomerular filtration rate within normal range for age Hepatic: Hepatic: bilirubin, AST/ALT, 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 EKG or approved by Cardiology for transplant Sexually active participants must agree to use adequate birth control for the during the study period (from before the start of the preparative chemotherapy through 1 year post-transplant) Available donor per section 5: targeted MFI < 1,000 (MFI exceeding 1000 must be approved by the PI and treatment team.) Voluntary written consent - adult or parent (with information sheet for minors, if applicable) prior to any research related procedures or treatment Exclusion Criteria: beta 3 laminin JEB mutants Active untreated systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days) History of HIV infection Evidence of squamous cell carcinoma Pregnant or breast feeding. Females of child-bearing potential must have a negative pregnancy test prior to study registration as the agents administered in this study are Pregnancy Category C and D.

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLOSED TO ACCRUAL Arm A: HCT with 300 cGy of TBI<br>Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant without mesenchymal stem cell infusions. | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Tacrolimus<br>* Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors)<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;|
| Experimental: CLOSED TO ACCRUAL Arm B: HCT plus MSC, 300 cGy of TBI<br>Epidermolysis bullosa patients treated per study regimen with chemotherapy and hematopoietic stem cell transplant with mesenchymal stem cell infusions using 300 cGY of TBI. | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Tacrolimus<br>* Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors)<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;Biological: Donor mesenchymal stem cell infusions<br>* Day 60, 100 and 180 (collected during donor BM harvest for graft)<br>|
| Experimental: Arm C: Re-Transplant with 300 cGy of TBI<br>Epidermolysis bullosa patients treated regardless of original transplant arm with re-transplant using 300 cGy of TBI. | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Tacrolimus<br>* Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors)<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;Biological: Donor mesenchymal stem cell infusions<br>* Day 60, 100 and 180 (collected during donor BM harvest for graft)<br>|
| Experimental: Arm D: HCT with 200 cGy BID of TBI<br>HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGY BID of TBI (400 cGy total). | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;|
| Experimental: Arm E: HCT plus MSC, 200 cGy BID of TBI<br>HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant plus serial MSC infusions using 200 cGY BID of TBI (400 cGy total) | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;Biological: Donor mesenchymal stem cell infusions<br>* Day 60, 100 and 180 (collected during donor BM harvest for graft)<br>|
| Experimental: Arm F: HCT Alone, 200 cGy BID of TBI<br>HLA-mismatched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGy BID of TBI (400 cGy total) + addition of low dose busulfan for recipients of HLA-mismatched bone marrow | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Tacrolimus<br>* Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors)<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;Drug: Busulfan<br>* busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)<br>|
| Experimental: Arm G: HCT plus MSC, 200 cGy<br>HLA-mismatched epidermolysis bullosa patients treated with hematopoietic cell transplant plus serial MSC infusions using 200 cGy BID of TBI (400 cGy total) + addition of low dose busulfan for recipients of HLA-mismatched bone marrow | Drug: Thymoglobulin<br>* 0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2<br>* Other names: anti-thymocyte globulin;Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 IV over 60 minutes days -6 through day -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* See arm description for dosing.<br>* Other names: TBI;Procedure: Bone marrow infusion<br>* Bone marrow infusion on Day 0<br>* Other names: HCT;Drug: Tacrolimus<br>* Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors)<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35<br>* Other names: MMF;Biological: Donor mesenchymal stem cell infusions<br>* Day 60, 100 and 180 (collected during donor BM harvest for graft)<br>Drug: Busulfan<br>* busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | An event defined as death or a 50% increase in a patient's IScoreEB from baseline | 1 year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change of a patient's iscorEB | iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa. | 1 and 2 year post-transplant | 
| Transplant-related mortality | Cumulative incidence will be used to estimate the probability of relapse treating non-relapse death as a competing risk and transplant-related mortality conversely treating relapse as a competing risk. | 180 days post-transplant | 
| Quality of life | Measured by the Lansky or Karnofsky score (10-100) | 1 year post-transplant | 
| Quality of life | Measured by the Lansky or Karnofsky score (10-100) | 2 years post-transplant | 
| Lymphoid Chimerism | Proportion of lymphoid chimerism at various time-points. | Day 28, 60, 100, 180, and year 1 and 2 post-transplant | 
| Myeloid Chimerism | Proportion of myeloid chimerism at various time points. | Day 28, 60, 100, 180, and year 1 and 2 post-transplant |