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

• ClinicalTrials.gov Identifier: NCT02800070
• Recruitment Status: Active, not recruiting
• First Posted: June 15, 2016
• Last Update Posted: April 22, 2020
• Sponsor: University Health Network, Toronto
• Collaborator: Ozmosis Research Inc.
• Information provided by (Responsible Party): University Health Network, Toronto

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Fabry Disease	Biological: Lentivirus Alpha-gal A transduced stem cells	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: July 2016
• Estimated Primary Completion Date: February 2024
• Estimated Study Completion Date: February 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Arm; Patients will receive Health Canada approved transduced autologous CD34+ cell product.	Biological: Lentivirus Alpha-gal A transduced stem cells

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment [ Time Frame: 5 years ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male patients 18-50 years of age at the time of enrollment
2. Diagnosis of Fabry disease (FD) as defined by very low or absent α-gal A activity
3. Classic FD Type I phenotype with alpha-galactosidase A (GLA) genotyping
4. Patients on enzyme replacement therapy (ERT) prior to enrollment
5. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
6. Adequate organ function within 21 days prior to Pre-Treatment Phase:
7. Willing and capable of signing and giving written informed consent in accordance with Research Ethics Board (REB) requirements
8. 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
9. 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.
10. 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:

1. Males with variant Fabry Disease.
2. Female gender
3. Use of immunosuppressive agents or any anticoagulant
4. Ongoing ERT-related infusion associated reactions of moderate-to-severe intensity
5. Presence of anti-agalsidase immunoglobulin (Ig)G antibodies above a threshold (5-fold above normal;) or evidence of high titre neutralizing antibodies
6. 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).
7. Uncontrolled bacterial, viral, or fungal infections
8. Prior malignancies except resected basal cell carcinoma
9. Chronic Kidney Disease (CKD) stage >2
10. History of heart failure or left ventricle ejection fraction (LVEF) <45% or moderate to severe diastolic dysfunction by standard criteria
11. Arrhythmia: bundle branch block, heart block degree II or III, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, cardiac arrest, pacemaker, implantable cardiac defibrillator
12. 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
13. Uncontrolled hypertension
14. Diabetes mellitus
15. Advanced liver disease, liver failure, cirrhosis
16. Immune deficiency state
17. Moderate-to-severe chronic obstructive pulmonary disease (COPD)
18. Any hematological condition with white blood cells (WBC) <3.0 x109/L, platelet count <100 x109/L, and/or hemoglobin <100 g/L
19. Prior bone marrow transplant (BMT) or organ transplant
20. Any condition that would preclude use of Melphalan
21. Use of a drug with cytotoxic or immunosuppressive effect within 60 days of trial entry
22. Uncontrolled psychiatric disorder
23. Active chronic infection
24. Prior tuberculosis
25. Any other serious concurrent disease
26. Cognitive impairment that would prevent informed consent
27. Use of an investigational drug within 30 days of stem cell transplant (SCT)

Contacts and Locations

Locations

Canada, Alberta

Alberta Children's Hospital, University of Calgary

Calgary, Alberta, Canada

Canada, Nova Scotia

QE II Health Sciences Centre

Halifax, Nova Scotia, Canada

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

Sponsors and Collaborators

University Health Network, Toronto

Ozmosis Research Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Khan A, Barber DL, Huang J, Rupar CA, Rip JW, Auray-Blais C, Boutin M, O'Hoski P, Gargulak K, McKillop WM, Fraser G, Wasim S, LeMoine K, Jelinski S, Chaudhry A, Prokopishyn N, Morel CF, Couban S, Duggan PR, Fowler DH, Keating A, West ML, Foley R, Medin JA. Lentivirus-mediated gene therapy for Fabry disease. Nat Commun. 2021 Feb 25;12(1):1178. doi: 10.1038/s41467-021-21371-5.

• Responsible Party: University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT02800070
• Other Study ID Numbers: OZM-074
• First Posted: June 15, 2016
• Last Update Posted: April 22, 2020
• Last Verified: April 2020

Keywords provided by University Health Network, Toronto:

autologous stem cell transplant; gene therapy; Fabry disease; lentivirus; haematopoietic stem cell transplant

Additional relevant MeSH terms:

Fabry Disease; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders