<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/NCT03825783</url>
  </required_header>
  <id_info>
    <org_study_id>RP-L201-0218</org_study_id>
    <nct_id>NCT03825783</nct_id>
  </id_info>
  <brief_title>A Gene Therapy Trial to Evaluate the Safety and Efficacy of RP-L201 in Subjects With Leukocyte Adhesion Deficiency-I</brief_title>
  <official_title>Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I): A Phase I Clinical Trial to Evaluate the Safety and Efficacy of the Infusion of Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector Encoding the ITGB2 Gene.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rocket Pharmaceuticals Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rocket Pharmaceuticals Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary purpose of the Phase I portion of the study is to determine the safety profile&#xD;
      and preliminary evidence of efficacy associated with infusion of autologous gene-corrected&#xD;
      hematopoietic stem cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is a pediatric non-randomized open-label Phase I clinical trial. This will include&#xD;
      a safety evaluation and preliminary assessment of the efficacy of hematopoietic gene therapy&#xD;
      consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying&#xD;
      the ITGB2 gene in subjects with severe Leukocyte Adhesion Deficiency-I (LAD-I). Subjects will&#xD;
      undergo mobilization and collection of peripheral blood hematopoietic stem cells (HSCs) with&#xD;
      granulocyte-colony stimulating factor (G-CSF) and plerixafor or bone marrow harvest in select&#xD;
      circumstances.&#xD;
&#xD;
      HSCs will then be transduced with the therapeutic vector (Chim.hCD18-LV), with the intent of&#xD;
      enabling stable integration of the provirus in the genome of stem and progenitor cells.&#xD;
&#xD;
      If the number of CD34+ cells that are cryopreserved is at least 4×10E6 total CD34+ cells/kg,&#xD;
      subjects will receive myeloablative conditioning with intravenous busulfan. The gene-modified&#xD;
      CD34+ cells will be then transplanted back into the subject.&#xD;
&#xD;
      Once engrafted, it is anticipated that the gene-modified stem and progenitor cells will&#xD;
      enable hematopoiesis, generating blood cells in which the integrated therapeutic gene (ITGB2)&#xD;
      will be transcribed and translated to produce the therapeutic CD18 protein with a&#xD;
      preferential high expression in mature myeloid cells. Leukocytes expressing a functional CD18&#xD;
      will have the capability to arrest on endothelial surfaces and extravasate to infectious&#xD;
      sites, enabling a competent antimicrobial response and reversing the clinical disorder.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Patients were enrolled under global Phase 1/2 protocol RP-L201-0318.&#xD;
  </why_stopped>
  <start_date type="Actual">April 15, 2019</start_date>
  <completion_date type="Anticipated">October 2021</completion_date>
  <primary_completion_date type="Anticipated">October 2021</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 participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of safety associated with treatment with RP-L201</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Survival following infusion of RP-L201</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of survival as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post infusion without allogeneic hematopoietic stem cell transplant</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CD18 expression after infusion of RP-L201</measure>
    <time_frame>2 years</time_frame>
    <description>Determination of the percentage of subjects in whom infusion of RP-L201 results in a change in the percentage of neutrophils expressing CD18 to at least 10% in 2 years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Genetic correction after infusion of RP-L201</measure>
    <time_frame>6 months</time_frame>
    <description>Determination of whether infusion of RP-L201 results in vector copy number/cell of at least 0.1 in peripheral blood neutrophils carrying the therapeutic Chim.hCD18-LV provirus at 6 months post-infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of infections after infusion of RP-L201</measure>
    <time_frame>2 years</time_frame>
    <description>Determination of the incidence and severity of bacterial or other infections (subsequent to hematopoietic reconstitution)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of number of participants with a change in LAD-I-associated neutrophilia after infusion of RP-L201</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of change to partially normal or to normal levels of LAD-I-associated neutrophilia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of number of participants with a change in skin lesions or periodontal abnormalities after infusion of RP-L201</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of resolution (partial or complete) of any underlying skin lesions or periodontal abnormalities</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of overall survival after infusion of RP-L201</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of overall survival (beyond age 2 years and beyond the initial year subsequent to investigational therapy)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Leukocyte Adhesion Defect - Type I</condition>
  <arm_group>
    <arm_group_label>RP-L201</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>RP-L201 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic stem cells transduced with Chim-CD18-WPRE lentiviral vector administered as a single infusion in subjects with severe LAD-I</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>RP-L201</intervention_name>
    <description>CD34+ enriched hematopoietic stem cells from subjects with severe LAD-I transduced ex vivo with lentiviral vector carrying the ITGB2 gene, Chim-CD18-WPRE.</description>
    <arm_group_label>RP-L201</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  A confirmed diagnosis of severe LAD-I as demonstrated by flow cytometry indicating&#xD;
             CD18 expression on &lt;2% neutrophils (polymorphonuclear neutrophils [PMNs]). (Patients&#xD;
             in which CD18+ PMNs are &gt;2% will be considered eligible with &lt;2% CD11a or CD11b&#xD;
             expressing PMNs and if there is a documented ITGB2 mutation and clinical history&#xD;
             consistent with LAD-I (or known family history).&#xD;
&#xD;
          -  At least one (1) prior significant bacterial or fungal infection (US National Cancer&#xD;
             Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], v5.0, Grade&#xD;
             ≥2). This criteria is not required for patients with documented family history who&#xD;
             meet the above inclusion criteria.&#xD;
&#xD;
          -  Age ≥3 months.&#xD;
&#xD;
          -  Considered to be an appropriate candidate for autologous transplantation of HSCs.&#xD;
&#xD;
          -  A competent custodial parent with legal capacity to execute an Ethics Committee&#xD;
             (EC)-approved consent form must be available to participate in the consent process.&#xD;
             (Informed assent will be sought from capable patients, in accordance with the&#xD;
             directive of the EC and with local requirements.)&#xD;
&#xD;
          -  Ability to comply with trial procedures including investigational therapy and&#xD;
             follow-up evaluations.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Availability of a medically-eligible human leukocyte antigen (HLA)-identical sibling&#xD;
             donor transplant. Patients may not be included in this trial as an alternative to a&#xD;
             clinically-indicated and feasible HLA-matched sibling donor HSC transplant. If an&#xD;
             HLA-identical sibling is identified, but mobilized peripheral blood or bone marrow HSC&#xD;
             collection is not feasible (for example: donor is in utero, is a newborn from whom&#xD;
             cord blood was not collected, or is unable to undergo donation procedure because of&#xD;
             medical impairments), then inclusion may be permitted per the Principal Investigator&#xD;
             discretion.&#xD;
&#xD;
          -  Hepatic dysfunction as defined by either:&#xD;
&#xD;
               -  Bilirubin &gt; 1.5 × the upper limit of normal (ULN) or&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) &gt;2.5×ULN&#xD;
&#xD;
          -  Pulmonary dysfunction as defined by either:&#xD;
&#xD;
               -  Need for supplemental oxygen during the prior 2 weeks (in absence of acute&#xD;
                  infection).&#xD;
&#xD;
               -  Oxygen saturation (by pulse oximetry) &lt;90%.&#xD;
&#xD;
          -  Evidence of active metastatic or locoregionally advanced malignancy (including&#xD;
             hematologic malignancy) for which survival is anticipated to be less than 3 years.&#xD;
&#xD;
          -  Serious infections with persistent bloodstream pathogens at time of trial entry.&#xD;
             (Patients with active infections [e.g., unresolved ulcerative lesions, skin or oral&#xD;
             infections] are permitted as long as appropriate antibiotic therapy has been [or is&#xD;
             being] administered).&#xD;
&#xD;
          -  Any medical or other contraindication for both leukopheresis and bone marrow harvest&#xD;
             procedure, as determined by the treating investigator.&#xD;
&#xD;
          -  Any medical or other contraindication for the administration of conditioning therapy,&#xD;
             as determined by the treating investigator.&#xD;
&#xD;
          -  Significant medical conditions, including documented human immunodeficiency virus&#xD;
             (HIV) infection, poorly-controlled diabetes, poorly-controlled hypertension,&#xD;
             poorly-controlled cardiac arrhythmia or congestive heart failure; or arterial&#xD;
             thromboembolic events (including stroke or myocardial infarction) within the 6 prior&#xD;
             months.&#xD;
&#xD;
          -  Any medical or psychiatric condition that in the opinion of the Principal Investigator&#xD;
             renders the patient unfit for trial participation or at higher than acceptable risk&#xD;
             for participation.&#xD;
&#xD;
        Patients who are evaluated for the trial and determined ineligible may be subsequently&#xD;
        evaluated and declared eligible if the criteria by which they were considered ineligible is&#xD;
        reversible (for example: bloodstream infection, transient increase in liver enzymes) and&#xD;
        there is documented and plausible evidence of its resolution in the opinion of the&#xD;
        Principal Investigator.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Julián Sevilla Navarro, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Infantil Universitario Niño Jesús (HIUNJ)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Infantil Universitario Niño Jesús (HIUNJ)</name>
      <address>
        <city>Madrid</city>
        <zip>28009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>January 25, 2019</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>November 23, 2021</last_update_submitted>
  <last_update_submitted_qc>November 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Leukocyte Adhesion Deficiency- Type I</keyword>
  <keyword>LAD-I</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tissue Adhesions</mesh_term>
  </condition_browse>
  <!-- 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/NCT03825783
org study id: RP-L201-0218
nct id: NCT03825783
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The primary purpose of the Phase I portion of the study is to determine the safety profile
      and preliminary evidence of efficacy associated with infusion of autologous gene-corrected
      hematopoietic stem cells.
The study is a pediatric non-randomized open-label Phase I clinical trial. This will include
      a safety evaluation and preliminary assessment of the efficacy of hematopoietic gene therapy
      consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying
      the ITGB2 gene in subjects with severe Leukocyte Adhesion Deficiency-I (LAD-I). Subjects will
      undergo mobilization and collection of peripheral blood hematopoietic stem cells (HSCs) with
      granulocyte-colony stimulating factor (G-CSF) and plerixafor or bone marrow harvest in select
      circumstances.

      HSCs will then be transduced with the therapeutic vector (Chim.hCD18-LV), with the intent of
      enabling stable integration of the provirus in the genome of stem and progenitor cells.

      If the number of CD34+ cells that are cryopreserved is at least 4×10E6 total CD34+ cells/kg,
      subjects will receive myeloablative conditioning with intravenous busulfan. The gene-modified
      CD34+ cells will be then transplanted back into the subject.

      Once engrafted, it is anticipated that the gene-modified stem and progenitor cells will
      enable hematopoiesis, generating blood cells in which the integrated therapeutic gene (ITGB2)
      will be transcribed and translated to produce the therapeutic CD18 protein with a
      preferential high expression in mature myeloid cells. Leukocytes expressing a functional CD18
      will have the capability to arrest on endothelial surfaces and extravasate to infectious
      sites, enabling a competent antimicrobial response and reversing the clinical disorder.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0
time frame: 2 years
description: Evaluation of safety associated with treatment with RP-L201
measure: Survival following infusion of RP-L201
time frame: 2 years
description: Evaluation of survival as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post infusion without allogeneic hematopoietic stem cell transplant
measure: CD18 expression after infusion of RP-L201
time frame: 2 years
description: Determination of the percentage of subjects in whom infusion of RP-L201 results in a change in the percentage of neutrophils expressing CD18 to at least 10% in 2 years
measure: Genetic correction after infusion of RP-L201
time frame: 6 months
description: Determination of whether infusion of RP-L201 results in vector copy number/cell of at least 0.1 in peripheral blood neutrophils carrying the therapeutic Chim.hCD18-LV provirus at 6 months post-infusion
measure: Incidence of infections after infusion of RP-L201
time frame: 2 years
description: Determination of the incidence and severity of bacterial or other infections (subsequent to hematopoietic reconstitution)
measure: Assessment of number of participants with a change in LAD-I-associated neutrophilia after infusion of RP-L201
time frame: 2 years
description: Evaluation of change to partially normal or to normal levels of LAD-I-associated neutrophilia
measure: Assessment of number of participants with a change in skin lesions or periodontal abnormalities after infusion of RP-L201
time frame: 2 years
description: Evaluation of resolution (partial or complete) of any underlying skin lesions or periodontal abnormalities
measure: Assessment of overall survival after infusion of RP-L201
time frame: 2 years
description: Evaluation of overall survival (beyond age 2 years and beyond the initial year subsequent to investigational therapy)
arm group label: RP-L201
arm group type: Experimental
description: RP-L201 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic stem cells transduced with Chim-CD18-WPRE lentiviral vector administered as a single infusion in subjects with severe LAD-I
intervention type: Biological
intervention name: RP-L201
description: CD34+ enriched hematopoietic stem cells from subjects with severe LAD-I transduced ex vivo with lentiviral vector carrying the ITGB2 gene, Chim-CD18-WPRE.
arm group label: RP-L201
criteria: 
gender: All
minimum age: 3 Months
maximum age: N/A
healthy volunteers: No
last name: Julián Sevilla Navarro, MD, PhD
role: Principal Investigator
affiliation: Hospital Infantil Universitario Niño Jesús (HIUNJ)
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Tissue Adhesions