<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04418414</url>
  </required_header>
  <id_info>
    <org_study_id>ET3-201</org_study_id>
    <nct_id>NCT04418414</nct_id>
  </id_info>
  <brief_title>Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Expression Therapeutics, LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Expression Therapeutics, LLC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in&#xD;
      approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by&#xD;
      transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the&#xD;
      CD68-ET3 lentiviral vector.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Eligible subjects will undergo CD34+ hematopoietic stem cell collection. These cells will be&#xD;
      transduced ex vivo with CD68-ET3 lentiviral vector and subsequently, following a conditioning&#xD;
      regimen of busulfan and anti-thymocyte globulin, the transduced cells will be infused to&#xD;
      patients. After completion of study treatment, patients are followed up periodically for up&#xD;
      to 15 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">January 2023</start_date>
  <completion_date type="Anticipated">April 2039</completion_date>
  <primary_completion_date type="Anticipated">April 2026</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.</measure>
    <time_frame>12 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>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.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Serious adverse events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.</measure>
    <time_frame>12 weeks</time_frame>
    <description>As assessed by stop and end dates of the SAEs</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to absolute neutrophil count (ANC) recovery.</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Time to ANC recovery (the first day a neutrophil count is &gt;0.5 x 109/L (&gt;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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to platelet recovery.</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Time to platelet recovery (the first day a platelet count is &gt; 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-human factor VIII inhibitor titer</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Assessed via Bethesda assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Immune response to ET3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vector copy number of circulating genetically modified cells as determined by real time PCR</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Vector copy number determined via real time PCR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clonality of circulating genetically modified cells as determined by LAM-PCR and insertion site analysis using DNA sequencing of LAM-PCR products</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Clonality assessment via LAM-PCR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival of autologous HSCT CD68-ET3-LV gene therapy.</measure>
    <time_frame>Up to 12 weeks following treatment</time_frame>
    <description>Survival among subjects who were treated with autologous HSCT with CD68-ET3-LV CD34+.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Factor VIII (fVIII) Activity Level following autologous HSCT</measure>
    <time_frame>Measured up to 5 years.</time_frame>
    <description>Measured by circulating plasma FVIII activity levels and detection of factor VIII and ET3 antigen</description>
  </other_outcome>
  <other_outcome>
    <measure>Annualized bleed rate (ABR) assessed by number of bleeding episodes and in comparison to before gene therapy.</measure>
    <time_frame>Measured through long term follow-up (up to 15 years).</time_frame>
    <description>To evaluate the impact of autologous HSCT with CD68-ET3-LV CD34+ on annualized bleed rate.</description>
  </other_outcome>
  <other_outcome>
    <measure>Consumption of exogenous Factor VIII by evaluating historical clotting factor usage versus usage post-transplant.</measure>
    <time_frame>Historical data from prior to study enrollment versus post-transplant (up to 15 years).</time_frame>
    <description>The percentage of participants with a reduction in exogenous FVIII consumption post-transplant compared with historical consumption.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">7</enrollment>
  <condition>Hemophilia A</condition>
  <arm_group>
    <arm_group_label>Autologous HSCT CD68-ET3-LV gene therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gene therapy</intervention_name>
    <description>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.</description>
    <arm_group_label>Autologous HSCT CD68-ET3-LV gene therapy</arm_group_label>
    <other_name>CD68-ET3-LV CD34+</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Biological</intervention_name>
    <description>G-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis.</description>
    <arm_group_label>Autologous HSCT CD68-ET3-LV gene therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able to provide informed consent for the protocol approved by the Institutional Review&#xD;
             Board.&#xD;
&#xD;
          2. Male subjects who are &gt;= 18 years of age.&#xD;
&#xD;
          3. Diagnosis of severe hemophilia A (&lt;1 IU/dL factor VIII activity) based on one-stage&#xD;
             coagulation assay.&#xD;
&#xD;
          4. Documented history of more than 150 days of factor VIII treatment.&#xD;
&#xD;
          5. Average of at least 4 bleeds requiring treatment per year over the prior three years,&#xD;
             or at least 4 bleeds per year during the 3 years preceding the initiation of&#xD;
             prophylaxis, or evidence of joint damage (knee, elbow or ankle) on physical or&#xD;
             radiographic examination thought to be related to hemophilia.&#xD;
&#xD;
          6. Performance status (Karnofsky score) of at least 70.&#xD;
&#xD;
          7. Willingness to use effective barrier contraception or limit sexual intercourse to&#xD;
             postmenopausal, surgically sterilized, or contraception-practicing partners, for 12&#xD;
             weeks (3 months) after transplantation.&#xD;
&#xD;
          8. Willing and able to comply with the requirements of the protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of spontaneous central nervous system bleeding within the last 5 years.&#xD;
&#xD;
          2. Significant functional deficits in major organs which would interfere with successful&#xD;
             outcome following autologous stem cell transplant, the following guidelines will be&#xD;
             utilized:&#xD;
&#xD;
               1. Cardiac: There should be no evidence of significant cardiac dysfunction (resting&#xD;
                  left ventricular ejection fraction of &lt; 50%) and no marked cardiomegaly. There&#xD;
                  should not be uncontrollable hypertension.&#xD;
&#xD;
               2. Renal: GFR &lt; 60 mL/min/1.73m2 per local institutional standard such as CKD-EPI&#xD;
                  creatinine equation or equivalent.&#xD;
&#xD;
               3. Hepatic: There should be no evidence of hepatic dysfunction which is defined as a&#xD;
                  serum total bilirubin of &gt; 1.5 mg/dL and AST/ALT &gt; 3X the upper limit of normal.&#xD;
&#xD;
               4. Hematologic: Absolute neutrophil counts (ANC) &lt;1000/ µL or platelets counts &lt;&#xD;
                  150,000/µL.&#xD;
&#xD;
               5. Pulmonary function with a corrected carbon monoxide diffusing capacity (cDLCO) &lt;&#xD;
                  50% predicted.&#xD;
&#xD;
          3. History of a fVIII inhibitor (&gt; 0.4 Bethesda Units/mL) including at least 2&#xD;
             measurements done at least a week apart or any single titer &gt; 5 BU/mL.&#xD;
&#xD;
          4. Subjects who have had prior cellular based therapy or gene editing/ gene therapy&#xD;
             including a previous stem cell transplant.&#xD;
&#xD;
          5. Subjects with any evidence of active infection or any immunosuppressive disorder,&#xD;
             including currently detectable HIV viral load&#xD;
&#xD;
          6. Subjects who are RPR, anti-HTLV-1 and II antibody, CMV PCR, VZV antibody and HSV PCR&#xD;
             positive at screening.&#xD;
&#xD;
          7. Subjects who have allergic reactions or hypersensitivity to any of the drugs used in&#xD;
             the study (i.e., anti-thymocyte globulin, plerixafor, G-CSF, busulfan, levetiracetam)&#xD;
             or to the constituents of the investigational product formulation.&#xD;
&#xD;
          8. Evidence of hepatitis B active infection or chronic carrier based on a positive&#xD;
             Hepatitis B DNA testing at screening.&#xD;
&#xD;
          9. Positive (detectable viral load per local institutional standard) for the presence of&#xD;
             Hepatitis C virus (HCV). Subjects who are positive for anti-HCV antibody are eligible&#xD;
             as long as they have a negative undetectable HCV viral load at screening.&#xD;
&#xD;
         10. Subjects diagnosed with any history of clinically relevant coagulation or bleeding&#xD;
             disorder other than hemophilia A.&#xD;
&#xD;
         11. Use of medication(s) that can affect hemostasis (e.g. aspirin, ibuprofen and non-COX-2&#xD;
             selective non-steroid anti-inflammatory drugs).&#xD;
&#xD;
         12. Subjects with a history of a malignancy (except surgically resected non-melanoma skin&#xD;
             cancer) or subjects with a family history of a known cancer syndrome in a first degree&#xD;
             relative.&#xD;
&#xD;
         13. Planned surgery within 6 months of enrollment (other than study procedures).&#xD;
&#xD;
         14. Treatment with any live vaccines or systemic immunosuppressive agents, not including&#xD;
             corticosteroids within 30 days before CD68-ET3-LV CD34+ infusion.&#xD;
&#xD;
         15. Treatment with any investigational product within 30 days or 5 half-lives of the&#xD;
             investigational product (whichever is longer) prior to enrollment.&#xD;
&#xD;
         16. History of autoimmune disease (e.g., inflammatory bowel disease, systemic lupus&#xD;
             erythematosus, vasculitis).&#xD;
&#xD;
         17. Concurrent enrollment in another clinical study, which might interfere with the&#xD;
             requirements of this study or have the potential to impact the evaluation of safety&#xD;
             and efficacy of CD68-ET3-LV CD34+- unless it is a non-interventional observational&#xD;
             study.&#xD;
&#xD;
         18. Any condition in the opinion of the Study Investigators that will negatively impact&#xD;
             the subject's ability to safely undergo an autologous stem cell transplant.&#xD;
&#xD;
         19. Any reason in the opinion of the Study Investigators that will negatively impact the&#xD;
             subject's ability to complete the clinical trial per the trial protocol.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Study Coordinator</last_name>
    <phone>404-850-0123</phone>
    <email>clinicaltrials@expressiontherapeutics.com</email>
  </overall_contact>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>May 20, 2022</last_update_submitted>
  <last_update_submitted_qc>May 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Hematopoietic stem cell transplant</keyword>
  <keyword>Gene therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemophilia A</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04418414
org study id: ET3-201
nct id: NCT04418414
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
time frame: 12 weeks
description: 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.
measure: 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
description: Serious adverse events
measure: Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
time frame: 12 weeks
description: As assessed by stop and end dates of the SAEs
measure: Time to absolute neutrophil count (ANC) recovery.
time frame: Measured up to 5 years.
description: 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.
measure: Time to platelet recovery.
time frame: Measured up to 5 years.
description: 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.
measure: Anti-human factor VIII inhibitor titer
time frame: Measured up to 5 years.
description: Assessed via Bethesda assay
measure: Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma
time frame: Measured up to 5 years.
description: Immune response to ET3
measure: Vector copy number of circulating genetically modified cells as determined by real time PCR
time frame: Measured up to 5 years.
description: Vector copy number determined via real time PCR
measure: 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.
description: Clonality assessment via LAM-PCR
measure: Survival of autologous HSCT CD68-ET3-LV gene therapy.
time frame: Up to 12 weeks following treatment
description: Survival among subjects who were treated with autologous HSCT with CD68-ET3-LV CD34+.
measure: Factor VIII (fVIII) Activity Level following autologous HSCT
time frame: Measured up to 5 years.
description: Measured by circulating plasma FVIII activity levels and detection of factor VIII and ET3 antigen
measure: 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).
description: To evaluate the impact of autologous HSCT with CD68-ET3-LV CD34+ on annualized bleed rate.
measure: 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).
description: The percentage of participants with a reduction in exogenous FVIII consumption post-transplant compared with historical consumption.
arm group label: Autologous HSCT CD68-ET3-LV gene therapy
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Gene therapy
description: 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.
arm group label: Autologous HSCT CD68-ET3-LV gene therapy
other name: CD68-ET3-LV CD34+
intervention type: Other
intervention name: Biological
description: G-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis.
arm group label: Autologous HSCT CD68-ET3-LV gene therapy
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Study Coordinator
phone: 404-850-0123
email: clinicaltrials@expressiontherapeutics.com
responsible party type: Sponsor
mesh term: Hemophilia A
sharing ipd: No