Autologous Stem Cell Transplantation of Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease

Study Overview
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Brief Summary
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This is a first-in-human study for the treatment of Fabry disease. Eligible patients will have an autologous stem cell transplantation using CD34+ cells that are transduced with the lentivirus vector containing the human alpha-gal A gene. The researchers of this study would like to see if the re-introduction of transduced cells will help increase the levels of alpha-gal A enzyme levels and to determine the safety and toxicity of autologous stem cell transplantation using CD34+ cells transduced with lentivirus vector containing the alpha-gal A gene. This study's objective is to determine the safety and toxicity of lentivirus alpha-gal A transduced CD34+ cells in adult males with Fabry disease.

Official Title
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Clinical Pilot Study of Autologous Stem Cell Transplantation of Cluster of Differentiation 34 Positive (CD34+) Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease

Conditions
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Fabry Disease

Intervention / Treatment
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* Biological: Lentivirus Alpha-gal A transduced stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male patients 18-50 years of age at the time of enrollment Diagnosis of Fabry disease (FD) as defined by very low or absent α-gal A activity Classic FD Type I phenotype with alpha-galactosidase A (GLA) genotyping Patients on enzyme replacement therapy (ERT) prior to enrollment Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1 Adequate organ function within 21 days prior to Pre-Treatment Phase: Willing and capable of signing and giving written informed consent in accordance with Research Ethics Board (REB) requirements Willing to comply with all procedures outlined in the study protocol, cooperative with the protocol schedule, able to return for safety evaluation, or otherwise likely to complete the study Willing to abstain from sexual activity or willing to use condoms during sexual intercourse from day of Melphalan administration on day -1 of Phase 3 until after 12 months follow-up post-transplant. Willing to not donate sperm after receiving Melphalan. Sperm banking will be recommended to any patient who would like to father children in the future. Exclusion Criteria: Males with variant Fabry Disease. Female gender Use of immunosuppressive agents or any anticoagulant Ongoing ERT-related infusion associated reactions of moderate-to-severe intensity Presence of anti-agalsidase immunoglobulin (Ig)G antibodies above a threshold (5-fold above normal;) or evidence of high titre neutralizing antibodies Blood test positive for Hepatitis B virus (HBV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (HTLV-1), human T-cell lymphotropic virus type 1 (HTLV-2), or Venereal Disease Research Laboratory test (VDRL; Transmissible Disease (TD) testing will be done in Pre-Treatment Phase 2 - see section 5.1 for full panel of TD tests. Patients will only be excluded from the study if positive for the TD tests listed here in this exclusion). Uncontrolled bacterial, viral, or fungal infections Prior malignancies except resected basal cell carcinoma Chronic Kidney Disease (CKD) stage >2 History of heart failure or left ventricle ejection fraction (LVEF) <45% or moderate to severe diastolic dysfunction by standard criteria Arrhythmia: bundle branch block, heart block degree II or III, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, cardiac arrest, pacemaker, implantable cardiac defibrillator Coronary artery disease with angina, prior myocardial infarction, percutaneous transluminal coronary angioplasty with or without stent, coronary artery bypass graft surgery, moderate to severe valvular heart disease, valve replacement surgery Uncontrolled hypertension Diabetes mellitus Advanced liver disease, liver failure, cirrhosis Immune deficiency state Moderate-to-severe chronic obstructive pulmonary disease (COPD) Any hematological condition with white blood cells (WBC) <3.0 x109/L, platelet count <100 x109/L, and/or hemoglobin <100 g/L Prior bone marrow transplant (BMT) or organ transplant Any condition that would preclude use of Melphalan Use of a drug with cytotoxic or immunosuppressive effect within 60 days of trial entry Uncontrolled psychiatric disorder Active chronic infection Prior tuberculosis Any other serious concurrent disease Cognitive impairment that would prevent informed consent Use of an investigational drug within 30 days of stem cell transplant (SCT)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Patients will receive Health Canada approved transduced autologous CD34+ cell product. | Biological: Lentivirus Alpha-gal A transduced stem cells<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment | Safety measurement will be based on all clinical and laboratory assessment post-baseline. The assessment will be the frequency of clinically notable abnormal vital signs and laboratory values, and the frequency of treatment-related adverse events. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alpha-gal A enzyme activity levels | Increase in α-gal A enzyme activity within the plasma, leukocytes, and Bone marrow aspirate. | 5 years | 
| Gb3 levels | Reduction of Gb3 in plasma and urine | 5 years | 
| lyso-Gb3 levels | Reduction of lyso-Gb3 in plasma and urine | 5 years | 
| lyso-Gb3 analogue (-28) | Reduction of lyso-Gb3 (-28) in plasma and urine | 5 years | 
| lyso-Gb3 analogue (-2) | Reduction of lyso-Gb3 (-2) in plasma and urine | 5 years | 
| lyso-Gb3 analogue (+16) | Reduction of lyso-Gb3 (+16) in plasma and urine | 5 years | 
| lyso-Gb3 analogue (+34) | Reduction of lyso-Gb3 (+34) in plasma and urine | 5 years | 
| lyso-Gb3 analogue (+50) | Reduction of lyso-Gb3 (+50) in plasma and urine | 5 years | 
| vector copy number per genome on the CD34+ cell population | Persistence of LV-transduced cells as measured by quantitative (q)PCR | 5 years | 
| transduction efficiency | Vector copy number per genome on the CD34+ cell population | 5 years | 
| transduction efficiency | Number of colonies positive by PCR for the provirus out of number plated in the colony assay | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lentivirus, autologous stem cell transplant, gene therapy, Fabry disease, haematopoietic stem cell transplant