<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/NCT03282656</url>
  </required_header>
  <id_info>
    <org_study_id>P00026188</org_study_id>
    <nct_id>NCT03282656</nct_id>
  </id_info>
  <brief_title>Gene Transfer for Sickle Cell Disease</brief_title>
  <official_title>Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>David Williams</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boston Children's Hospital</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>
      A promising approach for the treatment of genetic diseases is called gene therapy. Gene&#xD;
      therapy is a relatively new field of medicine that uses genetic material (mostly DNA) from&#xD;
      the patient to treat his or her own disease. In gene therapy, the investigators introduce new&#xD;
      genetic material in order to fix or replace the patient's disease gene, with the goal of&#xD;
      curing the disease. The procedure is similar to a bone marrow transplant, in that the&#xD;
      patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but&#xD;
      it is different because instead of using a different person's (donor) blood stem cells for&#xD;
      the transplant, the patient's own blood stem cells are given back after the new genetic&#xD;
      material has been introduced into those cells. This approach has the advantage of eliminating&#xD;
      any risk of GVHD, reducing the risk of graft rejection, and may also allow less chemotherapy&#xD;
      to be utilized for the conditioning portion of the transplant procedure. The method used to&#xD;
      introduce the gene into the patient's own blood stem cells is to engineer and use a modified&#xD;
      version of a virus (called a 'vector') that efficiently inserts the &quot;correcting&quot; genetic&#xD;
      material into the cells. The vector is a specialized biological medicine that has been&#xD;
      formulated for use in human beings.&#xD;
&#xD;
      The investigators have recently discovered a gene that is very important in the control of&#xD;
      fetal hemoglobin expression. Increasing the expression of this gene in sickle cell patients&#xD;
      could increase the amount of fetal hemoglobin while simultaneously reducing the amount of&#xD;
      sickle hemoglobin in their blood, and therefore potentially cure the condition. In summary,&#xD;
      the advantages of a gene therapy approach include: 1) it can be used even if the patient does&#xD;
      not have a matched donor available; 2) it may allow a reduction in the amount of chemotherapy&#xD;
      required to prepare the patient for the transplant; and 3) it will avoid the strong medicines&#xD;
      often required to prevent and treat GVHD and rejection. The goal is to test whether this&#xD;
      approach is safe, and whether using gene therapy to change the expression of this particular&#xD;
      gene will lead to increased fetal hemoglobin production in people with sickle cell disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, non-randomized, single center, pilot and feasibility, single arm&#xD;
      cohort study involving a single infusion of autologous bone marrow derived CD34+ HSC cells&#xD;
      transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a.&#xD;
      Accrual will be a maximum of 7 evaluable patients with SCD. The study will have three strata:&#xD;
&#xD;
        1. Stratum 1: ages ≥18-40&#xD;
&#xD;
        2. Stratum 2: ages ≥12-&lt;18&#xD;
&#xD;
        3. Stratum 3: ages ≥3-&lt;12&#xD;
&#xD;
      To determine the feasibility and safety of administering a lentiviral gene transfer vector&#xD;
      encoding a small hairpin (sh) RNA targeting the γ-globin gene repressor, BCL11A, in patients&#xD;
      with severe SCD.&#xD;
&#xD;
      Patients will undergo standard work-up for autologous bone marrow transplantation according&#xD;
      to institutional guidelines and then undergo two bone marrow harvests at a minimum of 4 weeks&#xD;
      apart that will be used for a back-up marrow (minimum of 2 x 106 CD34+ cells/kg) and for a&#xD;
      harvest of autologous bone marrow for gene transfer.&#xD;
&#xD;
      Patients will receive blood transfusions for a period of 3 months prior to the planned date&#xD;
      of product infusion, with a goal of achieving a HbS level ≤ 30% by the time of gene transfer.&#xD;
      If the subject is already on a chronic transfusion regimen as part of baseline disease&#xD;
      management, the regimen may be continued. The timing of transfusions will be coordinated to&#xD;
      occur within 7 days prior to any procedures requiring anesthesia such as bone marrow harvest.&#xD;
&#xD;
      Hematopoietic cells will be collected from the patient in advance of the treatment, to serve&#xD;
      as a salvage procedure (&quot;back-up graft&quot;), should there be no hematopoietic recovery observed&#xD;
      following the injection of genetically-manipulated cells, or should manipulated cells fail to&#xD;
      meet release criteria. Bone marrow (up to 20 mL/kg) will be harvested from the patient under&#xD;
      general anesthesia from the posterior iliac crests on both sides by multiple punctures at a&#xD;
      minimum of 4 weeks prior to gene therapy. A portion of the bone marrow containing at least 2&#xD;
      x 106 CD34+ cells/kg will be frozen and stored unmanipulated according to standard clinical&#xD;
      procedures for autologous bone marrow collection to constitute the back-up graft. If the&#xD;
      number of CD34+ cells that exceeds 2 x 106 cells/kg is greater than or equal to 1 x 106&#xD;
      cells/kg, these excess cells would be processed for transduction, transduced, and then&#xD;
      frozen. Transduction will be carried out on the selected CD34+ cells and transduced cells&#xD;
      will be cryopreserved. If cells from the first harvest were transduced and frozen, these&#xD;
      gene-modified cells will be thawed and prepared for infusion in parallel with the product&#xD;
      from the subsequent harvest(s). In this case two separate products would be infused. All cell&#xD;
      manipulation procedures and release testing will be performed in the transduction facility in&#xD;
      accordance with Good Manufacturing Practice (GMP) following process specific standard&#xD;
      operating procedures. Final Drug Product will be accompanied by a Certificate of Analysis,&#xD;
      documenting that all release testing is complete and within specification. Subjects will&#xD;
      receive myeloablative conditioning with Busulfan administered on days -5 to -2, prior to&#xD;
      infusion of transduced cells. Cells will be infused intravenously over 30-45 minutes after&#xD;
      standard prehydration and premedication according to Boston Children's Hospital Hematopoietic&#xD;
      Stem Cell Transplantation Unit standard guidelines. This standard requires that the patient&#xD;
      be on continuous cardiac, respiratory and oxygen saturation monitor throughout the infusion&#xD;
      and for 30 minutes afterwards. Vital signs will be measured and recorded pre-transfusion, 15&#xD;
      minutes into transfusion, every hour for duration of infusion, and end of transfusion. The RN&#xD;
      will stay with the patient for the first 5 minutes of the transfusion. If two transduction&#xD;
      products are administered, the second transduced product will be administered without delay&#xD;
      after the first.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 13, 2018</start_date>
  <completion_date type="Anticipated">November 13, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 13, 2024</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>
    <intervention_model_description>Open-label, non-randomized, single center, pilot and feasibility, single arm cohort study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rescue of hematopoiesis after conditioning</measure>
    <time_frame>within 7 weeks following infusion of gene transfer product</time_frame>
    <description>Rescue of hematopoiesis after conditioning (defined by absolute neutrophil count (ANC) greater than or equal to 0.5 x 109 /L for three consecutive days), achieved within 7 weeks following infusion (i.e., &quot;primary engraftment&quot;).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Expression of transgene</measure>
    <time_frame>at 6 weeks post gene transfer then every 6 months until 2 years after gene transfer</time_frame>
    <description>a. Presence of the transgene (vector copy number) in the following samples: i) Peripheral blood cells [measured in whole blood, mononuclear cells, and the following sorted populations: CD3+, CD15+, CD19+, and CD56+] at 6 weeks, and then every 6 months until 2 years after gene transfer.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>Treatment arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>open-label, non-randomized, single center, pilot and feasibility, single arm cohort study of a single infusion of autologous bone marrow derived CD34+ HSC cells transduced with lentiviral vector containing a short-hairpin RNA targeting BC11A.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a</intervention_name>
    <description>single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a</description>
    <arm_group_label>Treatment arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of SCD with genotype HbSS, HbS/0 thalassemia, HbSD, or HbSO&#xD;
&#xD;
          -  Severe symptomatic SCD, defined by the presence of one or more of the following&#xD;
             clinical complications:&#xD;
&#xD;
               1. Minimum of two episodes of acute chest syndrome (ACS) in the 2 years before study&#xD;
                  entry.&#xD;
&#xD;
               2. History of three or more episodes of severe pain events requiring a visit to a&#xD;
                  medical facility and treatment with parenteral opioids in the 2 years before&#xD;
                  study entry.&#xD;
&#xD;
               3. Recurrent priapism (&gt; 2 episodes) in the 2 years before study entry.&#xD;
&#xD;
               4. Red-cell alloimmunization (&gt;2 antibodies) during long-term transfusion therapy.&#xD;
&#xD;
               5. Receiving, or indicated to receive (based on prior stroke or elevated&#xD;
                  transcranial Doppler (TCD) results), chronic transfusions for primary or&#xD;
                  secondary stroke prophylaxis.&#xD;
&#xD;
          -  Age 3 years to 40 years .&#xD;
&#xD;
          -  Failure of hydroxyurea therapy due to lack of clinical improvement or inability to&#xD;
             tolerate due to side effects (e.g., myelosuppression, gastrointestinal symptoms, or&#xD;
             hepatic enzyme elevations). Clinical criteria must be met despite taking hydroxyurea&#xD;
             for greater than or equal to 6 months, unless contraindicated or not tolerated.&#xD;
             Patients taking hydroxyurea who still meet all inclusion criteria are eligible for the&#xD;
             trial.&#xD;
&#xD;
          -  No HLA-genotypically identical related bone marrow donor available&#xD;
&#xD;
          -  Parental/guardian/patient signed informed consent&#xD;
&#xD;
          -  Willingness to return for follow-up for 15 years&#xD;
&#xD;
          -  White blood cell (WBC) count within the range of 3.0 - 20.0 x 109 /L Hemoglobin within&#xD;
             the range of 5 - 11 g/dL Platelet count within the range of 100 - 600 x 109 /L PT and&#xD;
             PTT within normal limits, unless prolonged due to anticoagulation requirement.&#xD;
&#xD;
          -  Adequate organ function and performance status:&#xD;
&#xD;
               1. Performance status ≥70% (Lansky play for age &lt;16 years, Karnofsky for age ≥16&#xD;
                  years)&#xD;
&#xD;
               2. Left ventricular ejection fraction &gt;40% or shortening fraction &gt;25%&#xD;
&#xD;
               3. Direct bilirubin ≤ 2.0 mg/dL&#xD;
&#xD;
               4. Serum creatinine &lt;/= 1.5 times the upper limit of normal for age, and creatinine&#xD;
                  clearance or GFR &gt;/= 70 mL/min/1.73 m2.&#xD;
&#xD;
               5. For ages &gt; 7 years, DLCO (corrected for hemoglobin), FEV1, FVC &gt;50% of predicted;&#xD;
                  if age &lt; 7 years, then oxygen saturation &gt;92% on room air.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to bone marrow harvest, or to administration of conditioning&#xD;
             medication (busulfan).&#xD;
&#xD;
          -  Subjects who have undergone allogeneic transplant previously.&#xD;
&#xD;
          -  Known positive HIV serology or HIV nucleic acid testing, or positive serology for HCV,&#xD;
             HBV, or HTLV.&#xD;
&#xD;
          -  Uncontrolled infection.&#xD;
&#xD;
          -  Active malignancy.&#xD;
&#xD;
          -  Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics.&#xD;
&#xD;
          -  Receipt of an investigational study drug or procedure within 90 days of study&#xD;
             enrollment.&#xD;
&#xD;
          -  Pregnancy, or breastfeeding in a postpartum female, or absence of adequate&#xD;
             contraception for fertile subjects. Females of child-bearing potential must agree to&#xD;
             use a medically acceptable method of birth control such as oral contraceptive,&#xD;
             intrauterine device, barrier and spermicide, or contraceptive implant/injection from&#xD;
             Screening through at least 6 months after drug product infusion. Male subjects must&#xD;
             agree to use effective contraception (including condoms) from Screening through at&#xD;
             least 6 months after drug product infusion.&#xD;
&#xD;
          -  Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on&#xD;
             prior biopsy.&#xD;
&#xD;
          -  An assessment by the Investigators that the subject will not comply with the study&#xD;
             procedures outlined in the study protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Erica Esrick, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCLA - Mattel Children's Hospital</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>August 9, 2023</last_update_submitted>
  <last_update_submitted_qc>August 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Boston Children's Hospital</investigator_affiliation>
    <investigator_full_name>David Williams</investigator_full_name>
    <investigator_title>Chief Scientific Officer</investigator_title>
  </responsible_party>
  <keyword>Gene therapy</keyword>
  <keyword>lentivirus vector</keyword>
  <keyword>BCL11A</keyword>
  <keyword>Fetal Hemoglobin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</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/NCT03282656
org study id: P00026188
nct id: NCT03282656
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
A promising approach for the treatment of genetic diseases is called gene therapy. Gene
      therapy is a relatively new field of medicine that uses genetic material (mostly DNA) from
      the patient to treat his or her own disease. In gene therapy, the investigators introduce new
      genetic material in order to fix or replace the patient's disease gene, with the goal of
      curing the disease. The procedure is similar to a bone marrow transplant, in that the
      patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but
      it is different because instead of using a different person's (donor) blood stem cells for
      the transplant, the patient's own blood stem cells are given back after the new genetic
      material has been introduced into those cells. This approach has the advantage of eliminating
      any risk of GVHD, reducing the risk of graft rejection, and may also allow less chemotherapy
      to be utilized for the conditioning portion of the transplant procedure. The method used to
      introduce the gene into the patient's own blood stem cells is to engineer and use a modified
      version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic
      material into the cells. The vector is a specialized biological medicine that has been
      formulated for use in human beings.

      The investigators have recently discovered a gene that is very important in the control of
      fetal hemoglobin expression. Increasing the expression of this gene in sickle cell patients
      could increase the amount of fetal hemoglobin while simultaneously reducing the amount of
      sickle hemoglobin in their blood, and therefore potentially cure the condition. In summary,
      the advantages of a gene therapy approach include: 1) it can be used even if the patient does
      not have a matched donor available; 2) it may allow a reduction in the amount of chemotherapy
      required to prepare the patient for the transplant; and 3) it will avoid the strong medicines
      often required to prevent and treat GVHD and rejection. The goal is to test whether this
      approach is safe, and whether using gene therapy to change the expression of this particular
      gene will lead to increased fetal hemoglobin production in people with sickle cell disease.
This is an open-label, non-randomized, single center, pilot and feasibility, single arm
      cohort study involving a single infusion of autologous bone marrow derived CD34+ HSC cells
      transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a.
      Accrual will be a maximum of 7 evaluable patients with SCD. The study will have three strata:

        1. Stratum 1: ages ≥18-40

        2. Stratum 2: ages ≥12-<18

        3. Stratum 3: ages ≥3-<12

      To determine the feasibility and safety of administering a lentiviral gene transfer vector
      encoding a small hairpin (sh) RNA targeting the γ-globin gene repressor, BCL11A, in patients
      with severe SCD.

      Patients will undergo standard work-up for autologous bone marrow transplantation according
      to institutional guidelines and then undergo two bone marrow harvests at a minimum of 4 weeks
      apart that will be used for a back-up marrow (minimum of 2 x 106 CD34+ cells/kg) and for a
      harvest of autologous bone marrow for gene transfer.

      Patients will receive blood transfusions for a period of 3 months prior to the planned date
      of product infusion, with a goal of achieving a HbS level ≤ 30% by the time of gene transfer.
      If the subject is already on a chronic transfusion regimen as part of baseline disease
      management, the regimen may be continued. The timing of transfusions will be coordinated to
      occur within 7 days prior to any procedures requiring anesthesia such as bone marrow harvest.

      Hematopoietic cells will be collected from the patient in advance of the treatment, to serve
      as a salvage procedure ("back-up graft"), should there be no hematopoietic recovery observed
      following the injection of genetically-manipulated cells, or should manipulated cells fail to
      meet release criteria. Bone marrow (up to 20 mL/kg) will be harvested from the patient under
      general anesthesia from the posterior iliac crests on both sides by multiple punctures at a
      minimum of 4 weeks prior to gene therapy. A portion of the bone marrow containing at least 2
      x 106 CD34+ cells/kg will be frozen and stored unmanipulated according to standard clinical
      procedures for autologous bone marrow collection to constitute the back-up graft. If the
      number of CD34+ cells that exceeds 2 x 106 cells/kg is greater than or equal to 1 x 106
      cells/kg, these excess cells would be processed for transduction, transduced, and then
      frozen. Transduction will be carried out on the selected CD34+ cells and transduced cells
      will be cryopreserved. If cells from the first harvest were transduced and frozen, these
      gene-modified cells will be thawed and prepared for infusion in parallel with the product
      from the subsequent harvest(s). In this case two separate products would be infused. All cell
      manipulation procedures and release testing will be performed in the transduction facility in
      accordance with Good Manufacturing Practice (GMP) following process specific standard
      operating procedures. Final Drug Product will be accompanied by a Certificate of Analysis,
      documenting that all release testing is complete and within specification. Subjects will
      receive myeloablative conditioning with Busulfan administered on days -5 to -2, prior to
      infusion of transduced cells. Cells will be infused intravenously over 30-45 minutes after
      standard prehydration and premedication according to Boston Children's Hospital Hematopoietic
      Stem Cell Transplantation Unit standard guidelines. This standard requires that the patient
      be on continuous cardiac, respiratory and oxygen saturation monitor throughout the infusion
      and for 30 minutes afterwards. Vital signs will be measured and recorded pre-transfusion, 15
      minutes into transfusion, every hour for duration of infusion, and end of transfusion. The RN
      will stay with the patient for the first 5 minutes of the transfusion. If two transduction
      products are administered, the second transduced product will be administered without delay
      after the first.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open-label, non-randomized, single center, pilot and feasibility, single arm cohort study
primary purpose: Treatment
masking: None (Open Label)
measure: Rescue of hematopoiesis after conditioning
time frame: within 7 weeks following infusion of gene transfer product
description: Rescue of hematopoiesis after conditioning (defined by absolute neutrophil count (ANC) greater than or equal to 0.5 x 109 /L for three consecutive days), achieved within 7 weeks following infusion (i.e., "primary engraftment").
measure: Expression of transgene
time frame: at 6 weeks post gene transfer then every 6 months until 2 years after gene transfer
description: a. Presence of the transgene (vector copy number) in the following samples: i) Peripheral blood cells [measured in whole blood, mononuclear cells, and the following sorted populations: CD3+, CD15+, CD19+, and CD56+] at 6 weeks, and then every 6 months until 2 years after gene transfer.
arm group label: Treatment arm
arm group type: Experimental
description: open-label, non-randomized, single center, pilot and feasibility, single arm cohort study of a single infusion of autologous bone marrow derived CD34+ HSC cells transduced with lentiviral vector containing a short-hairpin RNA targeting BC11A.
intervention type: Biological
intervention name: single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a
description: single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a
arm group label: Treatment arm
criteria: 
gender: All
minimum age: 3 Years
maximum age: 40 Years
healthy volunteers: No
last name: Erica Esrick, MD
role: Principal Investigator
affiliation: Boston Children's Hospital
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Boston Children's Hospital
investigator full name: David Williams
investigator title: Chief Scientific Officer
mesh term: Anemia, Sickle Cell
sharing ipd: No