<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/NCT03812263</url>
  </required_header>
  <id_info>
    <org_study_id>RP-L201-0318</org_study_id>
    <nct_id>NCT03812263</nct_id>
  </id_info>
  <brief_title>A Clinical 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/II 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>
    <collaborator>
      <agency>California Institute for Regenerative Medicine (CIRM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rocket Pharmaceuticals Inc.</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>
      The primary purpose of the Phase I portion of the study is to assess the therapeutic safety&#xD;
      and preliminary efficacy of a hematopoietic cell-based gene therapy consisting of autologous&#xD;
      CD34+ enriched cells transduced with the therapeutic lentiviral vector, Chim-CD18-WPRE,&#xD;
      RP-L201. The primary objectives of the Phase II portion of the study are evaluation of&#xD;
      survival, as determined by the proportion of subjects alive at age 2 (24 months) and at least&#xD;
      1-year post-infusion without allogeneic hematopoietic stem cell transplant (HSCT) and&#xD;
      characterization of the safety and toxicity associated with the infusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a pediatric non-randomized open-label Phase I/II clinical trial. The Phase I portion&#xD;
      will include a safety evaluation and preliminary assessment of the efficacy of hematopoietic&#xD;
      gene therapy consisting of autologous CD34+ enriched cells transduced with a lentiviral&#xD;
      vector carrying the ITGB2 gene in subjects with severe LAD-I. CD34+ cells will be transduced&#xD;
      ex vivo with the therapeutic vector followed by cryopreservation. If the number of CD34+&#xD;
      cells that are available for infusion is at least 2x10e6 total CD34+ cells/kg, subjects will&#xD;
      undergo myeloablative conditioning with intravenous busulfan. Subjects will then receive&#xD;
      infusion of gene-corrected hematopoietic cells approximately 24 hours following the final&#xD;
      busulfan dose.&#xD;
&#xD;
      The active agent is a self-inactivating lentiviral vector carrying the therapeutic ITGB2&#xD;
      gene, encoding for the human CD18 receptor (β2 integrin subunit). The therapeutic product is&#xD;
      the subject's autologous hematopoietic stem cells that have been transduced with the&#xD;
      lentiviral vector.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 30, 2019</start_date>
  <completion_date type="Anticipated">February 2023</completion_date>
  <primary_completion_date type="Anticipated">November 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <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>Phase I: 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>Phase II: 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>
  <primary_outcome>
    <measure>Phase II: Number of participants with treatment-related adverse events as assessed by CTCAE v.5.0</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of safety associated with treatment with RP-L201</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%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Genetic correction 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 at least 10% of peripheral blood neutrophils carrying the therapeutic Chim-CD18-WPRE lentiviral vector 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 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 skin rash 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 rash 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 24 months and beyond the initial year subsequent to investigational therapy)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">9</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 cells transduced with Chim-CD18-WPRE lentiviral vector administered as a single intravenous infusion</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)). Subjects in&#xD;
             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 NCI CTCAE, v5.0,&#xD;
             Grade ≥2). This criterion is not required for subjects with documented family history&#xD;
             who meet the above inclusion criteria.&#xD;
&#xD;
          -  Age ≥3 months.&#xD;
&#xD;
          -  Considered to be an appropriate candidate for autologous transplantation of&#xD;
             hematopoietic stem cells.&#xD;
&#xD;
          -  A competent custodial parent with legal capacity to execute an institutional review&#xD;
             board (IRB)/ethics committee (EC)-approved consent form must be available to&#xD;
             participate in the consent process. (Informed assent will be sought from capable&#xD;
             subjects, in accordance with the directive of the IRB/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. Subjects may not be included in this trial as an alternative to a&#xD;
             clinically-indicated and feasible HLA-matched sibling donor hematopoietic stem cell&#xD;
             transplant. If an HLA-identical sibling is identified, but mobilized peripheral blood&#xD;
             or bone marrow hematopoietic stem cell collection is not feasible (for example: donor&#xD;
             is in utero, is a newborn from whom cord blood was not collected, or is unable to&#xD;
             undergo donation procedure because of medical impairments), then inclusion may be&#xD;
             permitted per Investigator 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;
          -  Renal dysfunction as defined by either Grade 3 or higher abnormalities in serum&#xD;
             sodium, potassium, calcium, magnesium or phosphate as defined by NCI CTCAE v5.0, or&#xD;
             the requirement for either peritoneal dialysis or hemodialysis.&#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;
             (Subjects 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 leukapheresis 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 Investigator renders&#xD;
             the subject unfit for trial participation or at higher than acceptable risk for&#xD;
             participation.&#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>Donald B Kohn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, Los Angeles</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Claire Booth, MBBS, PhD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University College London Great Ormond Street Institute of Child Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Julián Sevilla Navarro, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Infantil Universitario Niño Jesús</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095-1489</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Infantil Universitario Niño Jesús (HIUNJ)</name>
      <address>
        <city>Madrid</city>
        <zip>28009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College London Great Ormond Street Institute of Child Health</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>November 19, 2021</last_update_submitted>
  <last_update_submitted_qc>November 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 22, 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>
  <keyword>ITGB2 mutation</keyword>
  <keyword>CD18 deficiency</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tissue Adhesions</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/NCT03812263
org study id: RP-L201-0318
nct id: NCT03812263
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The primary purpose of the Phase I portion of the study is to assess the therapeutic safety
      and preliminary efficacy of a hematopoietic cell-based gene therapy consisting of autologous
      CD34+ enriched cells transduced with the therapeutic lentiviral vector, Chim-CD18-WPRE,
      RP-L201. The primary objectives of the Phase II portion of the study are 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 (HSCT) and
      characterization of the safety and toxicity associated with the infusion.
This is a pediatric non-randomized open-label Phase I/II clinical trial. The Phase I portion
      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 LAD-I. CD34+ cells will be transduced
      ex vivo with the therapeutic vector followed by cryopreservation. If the number of CD34+
      cells that are available for infusion is at least 2x10e6 total CD34+ cells/kg, subjects will
      undergo myeloablative conditioning with intravenous busulfan. Subjects will then receive
      infusion of gene-corrected hematopoietic cells approximately 24 hours following the final
      busulfan dose.

      The active agent is a self-inactivating lentiviral vector carrying the therapeutic ITGB2
      gene, encoding for the human CD18 receptor (β2 integrin subunit). The therapeutic product is
      the subject's autologous hematopoietic stem cells that have been transduced with the
      lentiviral vector.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase I: 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: Phase II: 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: Phase II: Number of participants with treatment-related adverse events as assessed by CTCAE v.5.0
time frame: 2 years
description: Evaluation of safety associated with treatment with RP-L201
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%
measure: Genetic correction after infusion of RP-L201
time frame: 2 years
description: Determination of the percentage of subjects in whom infusion of RP-L201 results in at least 10% of peripheral blood neutrophils carrying the therapeutic Chim-CD18-WPRE lentiviral vector 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 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 skin rash or periodontal abnormalities after infusion of RP-L201
time frame: 2 years
description: Evaluation of resolution (partial or complete) of any underlying skin rash or periodontal abnormalities
measure: Assessment of overall survival after infusion of RP-L201
time frame: 2 years
description: Evaluation of overall survival (beyond age 24 months 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 cells transduced with Chim-CD18-WPRE lentiviral vector administered as a single intravenous infusion
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: Donald B Kohn, MD
role: Principal Investigator
affiliation: University of California, Los Angeles
last name: Claire Booth, MBBS, PhD, MSc
role: Principal Investigator
affiliation: University College London Great Ormond Street Institute of Child Health
last name: Julián Sevilla Navarro, MD, PhD
role: Principal Investigator
affiliation: Hospital Infantil Universitario Niño Jesús
facility: 
facility: 
facility: 
country: Spain
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Tissue Adhesions
sharing ipd: No