This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the CD68-ET3 lentiviral vector.
Eligible subjects will undergo CD34+ hematopoietic stem cell collection. These cells will be transduced ex vivo with CD68-ET3 lentiviral vector and subsequently, following a conditioning regimen of busulfan and anti-thymocyte globulin, the transduced cells will be infused to patients. After completion of study treatment, patients are followed up periodically for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
7
CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector (encoding human factor VIII gene) is administered by IV infusion following conditioning regimen with busulfan and anti-thymocyte globulin.
G-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis.
Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
As assessed by physical examination, vital signs, clinical labs, and FVIII inhibitor levels (Bethesda assay). Serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly.
Time frame: 12 weeks
Severity of serious adverse events following administration of CD68-ET3-LV CD34+ as assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.
Serious adverse events
Time frame: 12 weeks
Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
As assessed by stop and end dates of the SAEs
Time frame: 12 weeks
Time to absolute neutrophil count (ANC) recovery.
Time to ANC recovery (the first day a neutrophil count is \>0.5 x 109/L (\>500/µL) on three consecutive days) following busulfan/ anti-thymocyte globulin conditioning and infusion of autologous CD34+ hematopoietic stem and progenitor cells (HSPC) transduced with CD68-ET3-LV.
Time frame: Measured up to 5 years.
Time to platelet recovery.
Time to platelet recovery (the first day a platelet count is \> 50,000/µL on three consecutive days without platelet transfusions during the prior 7 days) following infusion of autologous CD34+ cells transduced with CD68-ET3-LV.
Time frame: Measured up to 5 years.
Anti-human factor VIII inhibitor titer
Assessed via Bethesda assay
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Time frame: Measured up to 5 years.
Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma
Immune response to ET3
Time frame: Measured up to 5 years.
Vector copy number of circulating genetically modified cells as determined by real time PCR
Vector copy number determined via real time PCR
Time frame: Measured up to 5 years.
Clonality of circulating genetically modified cells as determined by LAM-PCR and insertion site analysis using DNA sequencing of LAM-PCR products
Clonality assessment via LAM-PCR
Time frame: Measured up to 5 years.
Survival of autologous HSCT CD68-ET3-LV gene therapy.
Survival among subjects who were treated with autologous HSCT with CD68-ET3-LV CD34+.
Time frame: Up to 12 weeks following treatment