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

NCT02582775 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 2015LS076
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Epidermolysis Bullosa

Outcome Measures

Primary Outcomes (1)

• Event-free Survival

  An event defined as death or a 50% increase in a patient's IScoreEB from baseline

  1 year post-transplant

Secondary Outcomes (7)

• Change of a Patient's iscorEB

  1 year post-transplant

• Transplant-related Mortality

  180 days post-transplant

• Average Change in Quality of Life

  1 year post-transplant

• Average Change in Quality of Life

  2 years post-transplant

• Lymphoid Chimerism

  Day 28, 60, 100, 180, and year 1 and 2 post-transplant

Study Arms (8)

RDEB: HCT plus MSC Arm B

EXPERIMENTAL

Recessive dominant epidermolysis bullosa (RDEB) patients treated per study regimen on a post-transplant cyclophosphamide allogeneic hematopoietic cell transplant (HCT) platform conditioned with reduced intensity chemotherapy and low dose total body irradiation (300 cGy), followed post-HCT by serial infusions of donor-derived mesenchymal stromal cells (MSC).

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

JEB: HCT plus MSC Arm B

EXPERIMENTAL

Junctional epidermolysis bullosa (JEB) patient treated per study regimen on a post-transplant cyclophosphamide allogeneic hematopoietic cell transplant (HCT) platform conditioned with reduced intensity chemotherapy and low dose total body irradiation (300 cGy), followed post-HCT by serial infusions of donor-derived mesenchymal stromal cells (MSC).

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

RDEB: HCT Plus MSC Arm E

EXPERIMENTAL

Recessive dominant epidermolysis bullosa (RDEB) patients treated per study regimen on a post-transplant cyclophosphamide allogeneic hematopoietic cell transplant (HCT) platform conditioned with reduced intensity chemotherapy and low dose total body irradiation (400 cGy), followed post-HCT by serial infusions of donor-derived mesenchymal stromal cells (MSC).

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

HCT with 300 cGy of TBI Arm A

EXPERIMENTAL

Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant without mesenchymal stem cell infusions.

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

Re-Transplant Arm C

EXPERIMENTAL

Epidermolysis bullosa patients treated regardless of original transplant arm with re-transplant using 300 cGy of TBI.

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

HCT Arm D

EXPERIMENTAL

HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGY BID of TBI (400 cGy total).

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

HCT Alone Arm F

EXPERIMENTAL

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; 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

HCT plus MSC Arm G

EXPERIMENTAL

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; 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

Interventions

Thymoglobulin DRUG

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

Also known as: ATG, anti-thymocyte globulin

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Cyclophosphamide DRUG

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

Also known as: Cytoxan

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Fludarabine DRUG

30 mg/m2 IV over 60 minutes days -6 through day -2

Also known as: fludarabine phosphate, Fludara

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Total Body Irradiation RADIATION

See arm description for dosing.

Also known as: TBI

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Bone marrow infusion PROCEDURE

Bone marrow infusion on Day 0

Also known as: HCT

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Tacrolimus DRUG

Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors). When used in non-MSD recipients, tapered over 6-8 weeks starting at day +100.

Also known as: Prograf

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Mycophenolate Mofetil DRUG

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

Also known as: MMF

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Donor mesenchymal stem cell infusions BIOLOGICAL

Day 60, 100 and 180 (collected during donor BM harvest for graft)

HCT Alone Arm F; HCT Arm D; HCT plus MSC Arm G; HCT with 300 cGy of TBI Arm A; JEB: HCT plus MSC Arm B; RDEB: HCT Plus MSC Arm E; RDEB: HCT plus MSC Arm B; Re-Transplant Arm C

Busulfan DRUG

busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)

HCT Alone Arm F; HCT plus MSC Arm G

Eligibility Criteria

• Age: Up to 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

University of Minnesota Masonic Cancer Center and Medical Center

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (1)

• Ebens CL, McGrath JA, Tamai K, Hovnanian A, Wagner JE, Riddle MJ, Keene DR, DeFor TE, Tryon R, Chen M, Woodley DT, Hook K, Tolar J. Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts. Br J Dermatol. 2019 Dec;181(6):1238-1246. doi: 10.1111/bjd.17858. Epub 2019 Jun 28.

  PMID: 30843184 DERIVED

MeSH Terms

Conditions

Epidermolysis Bullosa

Interventions

thymoglobulin; Antilymphocyte Serum; Cyclophosphamide; fludarabine; fludarabine phosphate; Whole-Body Irradiation; Tacrolimus; Mycophenolic Acid; Busulfan

Condition Hierarchy (Ancestors)

Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Vesiculobullous

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Dr. Christen Ebens
• Organization: University of Minnesota, Masonic Cancer Center

ebens012@umn.edu

(612) 626-5654

Study Officials

• Jakub Tolar, MD, PhD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 16, 2015
• First Posted: October 21, 2015
• Study Start: March 1, 2016
• Primary Completion: November 15, 2022
• Study Completion: July 26, 2023
• Last Updated: September 19, 2024
• Results First Posted: September 19, 2024

Record last verified: 2024-08

Locations

US (1)