May 28, 2020
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June 5, 2020
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February 20, 2024
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September 1, 2024
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August 2029 (Final data collection date for primary outcome measure)
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- Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks. [ Time Frame: 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.
- 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. [ Time Frame: 12 weeks ]
Serious adverse events
- Duration of the serious adverse events following administration of CD68-ET3-LV CD34+. [ Time Frame: 12 weeks ]
As assessed by stop and end dates of the SAEs
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Same as current
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- Time to absolute neutrophil count (ANC) recovery. [ Time Frame: Measured up to 5 years. ]
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 to platelet recovery. [ Time Frame: Measured up to 5 years. ]
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.
- Anti-human factor VIII inhibitor titer [ Time Frame: Measured up to 5 years. ]
Assessed via Bethesda assay
- Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma [ Time Frame: Measured up to 5 years. ]
Immune response to ET3
- Vector copy number of circulating genetically modified cells as determined by real time PCR [ Time Frame: Measured up to 5 years. ]
Vector copy number determined via real time PCR
- Clonality of circulating genetically modified cells as determined by LAM-PCR and insertion site analysis using DNA sequencing of LAM-PCR products [ Time Frame: Measured up to 5 years. ]
Clonality assessment via LAM-PCR
- Survival of autologous HSCT CD68-ET3-LV gene therapy. [ Time Frame: Up to 12 weeks following treatment ]
Survival among subjects who were treated with autologous HSCT with CD68-ET3-LV CD34+.
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- Survival of autologous HSCT CD68-ET3-LV gene therapy. [ Time Frame: Up to 12 weeks following treatment ]
Survival among subjects who were treated with autologous HSCT with CD68-ET3-LV CD34+.
- Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma [ Time Frame: Through long term follow-up (up to 15 years) ]
Immune response to ET3
- Time to absolute neutrophil count (ANC) recovery. [ Time Frame: Measured through study completion (up to 15 years). ]
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 to platelet recovery. [ Time Frame: Measured through study completion (up to 15 years). ]
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 busulfan/ anti-thymocyte globulin conditioning and infusion of autologous CD34+ cells transduced with CD68-ET3-LV.
- Vector copy number of circulating genetically modified cells as determined by real time PCR [ Time Frame: Through long term follow-up (up to 15 years) ]
Vector copy number determined via real time PCR
- Clonality of circulating genetically modified cells as determined by LAM-PCR through long term follow-up (up to 15 years) [ Time Frame: Through long term follow-up (up to 15 years) ]
Clonality assessment via LAM-PCR
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- Factor VIII (fVIII) Activity Level following autologous HSCT [ Time Frame: Measured up to 5 years. ]
Measured by circulating plasma FVIII activity levels and detection of factor VIII and ET3 antigen
- Annualized bleed rate (ABR) assessed by number of bleeding episodes and in comparison to before gene therapy. [ Time Frame: Measured through long term follow-up (up to 15 years). ]
To evaluate the impact of autologous HSCT with CD68-ET3-LV CD34+ on annualized bleed rate.
- Consumption of exogenous Factor VIII by evaluating historical clotting factor usage versus usage post-transplant. [ Time Frame: Historical data from prior to study enrollment versus post-transplant (up to 15 years). ]
The percentage of participants with a reduction in exogenous FVIII consumption post-transplant compared with historical consumption.
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- Plasma Factor VIII (fVIII) Activity Level based on one-stage clotting and chromogenic assays. [ Time Frame: From screening visit to long term follow-up (up to 15 years) ]
Circulating plasma FVIII activity level
- Annualized bleed rate (ABR) assessed by number of bleeding episodes and in comparison to before gene therapy. [ Time Frame: Measured through long term follow-up (up to 15 years). ]
To evaluate the impact of autologous HSCT with CD68-ET3-LV CD34+ on annualized bleed rate.
- Consumption of exogenous Factor VIII by evaluating historical clotting factor usage versus usage post-transplant. [ Time Frame: Historical data from prior to study enrollment versus post-transplant (up to 15 years). ]
The percentage of participants with a reduction in exogenous FVIII consumption post-transplant compared with historical consumption.
- Number of participants with evidence of engraftment of transduced CD68-ET3-LV CD34+ cells (genetically modified cells). [ Time Frame: From screening visit to long term follow-up (up to 15 years). ]
As measured by the presence of ET3 transgene in blood.
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Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A
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ET3-201: Phase 1 Study of Hematopoietic Stem Cell Transplantation (HSCT) Gene Therapy Incorporating a Lentiviral Vector (LV) Encoding a High Expressing Factor VIII Transgene for Treatment of Severe Hemophilia A
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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.
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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.
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Interventional
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Phase 1
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Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
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Hemophilia A
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- Drug: Gene therapy
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.
Other Name: CD68-ET3-LV CD34+
- Other: Biological
G-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis.
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Experimental: Autologous HSCT CD68-ET3-LV gene therapy
G-CSF/Plerixafor mobilization and apheresis will be used for collection of hematopoietic stem cells and subjects will receive transplantation of autologous CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector encoding the human factor VIII gene.
Interventions:
- Drug: Gene therapy
- Other: Biological
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Not Provided
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Not yet recruiting
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7
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Same as current
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August 2039
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August 2029 (Final data collection date for primary outcome measure)
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Inclusion Criteria:
- Able to provide informed consent for the protocol approved by the Institutional Review Board.
- Male subjects who are >= 18 years of age.
- Diagnosis of severe hemophilia A (<1 IU/dL factor VIII activity) based on one-stage coagulation assay.
- Documented history of more than 150 days of factor VIII treatment.
- Average of at least 4 bleeds requiring treatment per year over the prior three years, or at least 4 bleeds per year during the 3 years preceding the initiation of prophylaxis, or evidence of joint damage (knee, elbow or ankle) on physical or radiographic examination thought to be related to hemophilia.
- Performance status (Karnofsky score) of at least 70.
- Willingness to use effective barrier contraception or limit sexual intercourse to postmenopausal, surgically sterilized, or contraception-practicing partners, for 12 weeks (3 months) after transplantation.
- Willing and able to comply with the requirements of the protocol.
Exclusion Criteria:
- History of spontaneous central nervous system bleeding within the last 5 years.
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Significant functional deficits in major organs which would interfere with successful outcome following autologous stem cell transplant, the following guidelines will be utilized:
- Cardiac: There should be no evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of < 50%) and no marked cardiomegaly. There should not be uncontrollable hypertension.
- Renal: GFR < 60 mL/min/1.73m2 per local institutional standard such as CKD-EPI creatinine equation or equivalent.
- Hepatic: There should be no evidence of hepatic dysfunction which is defined as a serum total bilirubin of > 1.5 mg/dL and AST/ALT > 3X the upper limit of normal.
- Hematologic: Absolute neutrophil counts (ANC) <1000/ µL or platelets counts < 150,000/µL.
- Pulmonary function with a corrected carbon monoxide diffusing capacity (cDLCO) < 50% predicted.
- History of a fVIII inhibitor (> 0.4 Bethesda Units/mL) including at least 2 measurements done at least a week apart or any single titer > 5 BU/mL.
- Subjects who have had prior cellular based therapy or gene editing/ gene therapy including a previous stem cell transplant.
- Subjects with any evidence of active infection or any immunosuppressive disorder, including currently detectable HIV viral load
- Subjects who are RPR, anti-HTLV-1 and II antibody, CMV PCR, VZV antibody and HSV PCR positive at screening.
- Subjects who have allergic reactions or hypersensitivity to any of the drugs used in the study (i.e., anti-thymocyte globulin, plerixafor, G-CSF, busulfan, levetiracetam) or to the constituents of the investigational product formulation.
- Evidence of hepatitis B active infection or chronic carrier based on a positive Hepatitis B DNA testing at screening.
- Positive (detectable viral load per local institutional standard) for the presence of Hepatitis C virus (HCV). Subjects who are positive for anti-HCV antibody are eligible as long as they have a negative undetectable HCV viral load at screening.
- Subjects diagnosed with any history of clinically relevant coagulation or bleeding disorder other than hemophilia A.
- Use of medication(s) that can affect hemostasis (e.g. aspirin, ibuprofen and non-COX-2 selective non-steroid anti-inflammatory drugs).
- Subjects with a history of a malignancy (except surgically resected non-melanoma skin cancer) or subjects with a family history of a known cancer syndrome in a first degree relative.
- Planned surgery within 6 months of enrollment (other than study procedures).
- Treatment with any live vaccines or systemic immunosuppressive agents, not including corticosteroids within 30 days before CD68-ET3-LV CD34+ infusion.
- Treatment with any investigational product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to enrollment.
- History of autoimmune disease (e.g., inflammatory bowel disease, systemic lupus erythematosus, vasculitis).
- Concurrent enrollment in another clinical study, which might interfere with the requirements of this study or have the potential to impact the evaluation of safety and efficacy of CD68-ET3-LV CD34+- unless it is a non-interventional observational study.
- Any condition in the opinion of the Study Investigators that will negatively impact the subject's ability to safely undergo an autologous stem cell transplant.
- Any reason in the opinion of the Study Investigators that will negatively impact the subject's ability to complete the clinical trial per the trial protocol.
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Sexes Eligible for Study: |
Male |
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18 Years and older (Adult, Older Adult)
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No
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Not Provided
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NCT04418414
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ET3-201
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Yes
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Studies a U.S. FDA-regulated Drug Product: |
Yes |
Studies a U.S. FDA-regulated Device Product: |
No |
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Expression Therapeutics, LLC
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Same as current
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Expression Therapeutics, LLC
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Same as current
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Not Provided
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Not Provided
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Expression Therapeutics, LLC
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February 2024
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