<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/NCT03792633</url>
  </required_header>
  <id_info>
    <org_study_id>831916</org_study_id>
    <secondary_id>18CT014</secondary_id>
    <nct_id>NCT03792633</nct_id>
  </id_info>
  <brief_title>Study of huCART19 for Very High-Risk (VHR) Subsets of Pediatric B-ALL</brief_title>
  <official_title>Phase 2 Study of Humanized CD19-directed Chimeric Antigen Receptor-modified T Cells (huCART19) for Very High-Risk Subsets of B Cell Acute Lymphoblastic Leukemia (B-ALL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Children's Hospital of Philadelphia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</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 phase 2 study to evaluate humanized CD19 redirected autologous T cells (or huCART19&#xD;
      cells) with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia. This&#xD;
      study is targeting pediatric and young adult patients aged 1-29 years with CD19+ B cell&#xD;
      malignancies in newly diagnosed B-ALL patients predicted to have an exceedingly poor outcome&#xD;
      with conventional chemotherapy, in high-risk first relapse, or and in second or greater&#xD;
      relapse in this phase 2 trial. In addition, a second cohort will test the efficacy of&#xD;
      huCART19 in patients with poor response to prior B cell directed engineered cell therapy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 18, 2019</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">August 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>1-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>1-year Event-Free Survival in patients with poor response to prior B cell directed engineered cell therapy</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Remission Rate (Cohort A)</measure>
    <time_frame>28 Days</time_frame>
    <description>Overall remission rate as determined by the response at day 28, computed as the proportion of subjects with CR or Cri, in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Remission Rate (Cohort B)</measure>
    <time_frame>28 Days</time_frame>
    <description>Overall remission rate as determined by the response at day 28, computed as the proportion of subjects with CR or Cri, in patients with poor response to prior B cell directed engineered cell therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL (cohort A).</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-year Event-Free Survival in patients with poor response to prior B cell directed engineered cell therapy (cohort B)</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-year Relapse-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL (cohort A).</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-year Relapse-Free Survival in patients with poor response to prior B cell directed engineered cell therapy (cohort B)</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency and severity of adverse events</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Acute Lymphoid Leukemia</condition>
  <arm_group>
    <arm_group_label>Newly Diagnosed VHR B-ALL or High-Risk Relapse of B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Poor Response to Prior B Cell Directed Engineered cell therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>huCART19</intervention_name>
    <description>huCART19 infusion</description>
    <arm_group_label>Newly Diagnosed VHR B-ALL or High-Risk Relapse of B</arm_group_label>
    <arm_group_label>Poor Response to Prior B Cell Directed Engineered cell therapy</arm_group_label>
    <other_name>huCTL019</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed informed consent form must be obtained.&#xD;
&#xD;
          2. Relapsed or refractory B-cell ALL:&#xD;
&#xD;
             a. Cohort A: Patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL who&#xD;
             meet one of the following criteria:&#xD;
&#xD;
             i. Newly diagnosed NCI HR B-ALL with induction failure: M3 marrow (&gt;25% blasts) at end&#xD;
             of induction OR&#xD;
&#xD;
             ii. First marrow relapse of B-ALL at &lt; 36 months from diagnosis OR iii. 2nd or greater&#xD;
             relapse OR&#xD;
&#xD;
             iv. Any relapse after allogeneic HSCT and ≥ 4 months from SCT at enrollment OR&#xD;
&#xD;
             v. Refractory disease defined as having not achieved an MRD-negative and/or&#xD;
             CSF-negative CR after ≥ 2 chemotherapy regimens/cycles of frontline therapy or 1 cycle&#xD;
             of reinduction therapy for patients in first relapse OR&#xD;
&#xD;
             vi. Ineligible for allogeneic SCT because of:&#xD;
&#xD;
        1. Comorbid disease 2. Other contraindications to allogeneic SCT conditioning regimen 3.&#xD;
        Lack of suitable donor 4. Prior SCT 5. Declines allogeneic SCT as the therapeutic option&#xD;
        after documented discussion, with expected outcomes, about the role of SCT with a BMT&#xD;
        physician not part of the study team b. Cohort B: Patients previously treated with B cell&#xD;
        directed engineered cell therapy who meet one of the following criteria: i. partial&#xD;
        response or no response to prior cell therapy ii. CD19+ relapse after prior cell therapy&#xD;
        iii. demonstrated early (≤6 months from infusion) B cell recovery suggesting loss of&#xD;
        engineered cells c. Patients with prior or current history of CNS3 disease will be eligible&#xD;
        if CNS disease is responsive to therapy (at infusion, must meet criteria in Section 5.3) 3.&#xD;
        Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor&#xD;
        tissue by flow cytometry at relapse (or a recent sample in the case of refractory disease).&#xD;
        If the patient has received CD19-directed therapy, then the flow cytometry should be&#xD;
        obtained after this therapy to show CD19 expression.&#xD;
&#xD;
        4. Adequate organ function defined as:&#xD;
&#xD;
          1. A serum creatinine based on age/gender 4&#xD;
&#xD;
          2. ALT≤ 500 U/L&#xD;
&#xD;
          3. Bilirubin ≤2.0 mg/dl&#xD;
&#xD;
          4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea, &lt; Grade 3&#xD;
             hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as&#xD;
             determined by the treating investigator&#xD;
&#xD;
          5. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45%&#xD;
             confirmed by ECHO, or adequate ventricular function documented by a scan or a&#xD;
             cardiologist.&#xD;
&#xD;
             5. Age 3 months to 29 years. 6. Adequate performance status (Lansky or Karnofsky score&#xD;
             ≥50). 7. Subjects of reproductive potential must agree to use acceptable birth control&#xD;
             methods.&#xD;
&#xD;
             Exclusion Criteria:&#xD;
&#xD;
               1. Active hepatitis B or active hepatitis C.&#xD;
&#xD;
               2. HIV Infection.&#xD;
&#xD;
               3. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic&#xD;
                  therapy.&#xD;
&#xD;
               4. Concurrent use of systemic steroids or immunosuppression at the time of cell&#xD;
                  infusion or cell collection, or a condition, in the treating physician's opinion,&#xD;
                  that is likely to require steroid therapy or immunosuppression during collection&#xD;
                  or after infusion. Steroids for disease treatment at times other than cell&#xD;
                  collection or at the time of infusion are permitted. Use of physiologic&#xD;
                  replacement hydrocortisone or inhaled steroids is permitted as well.&#xD;
&#xD;
               5. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that&#xD;
                  might increase the risk of CNS toxicity.&#xD;
&#xD;
               6. Pregnant or nursing (lactating) women.&#xD;
&#xD;
               7. Uncontrolled active infection.&#xD;
&#xD;
               8. Active medical disorder that, in the opinion of the investigator, would&#xD;
                  substantially increase the risk of uncontrollable CRS or neurotoxicity.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>29 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shannon Maude, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital of Philadelphia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</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>January 2, 2019</study_first_submitted>
  <study_first_submitted_qc>January 2, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 3, 2019</study_first_posted>
  <last_update_submitted>August 7, 2023</last_update_submitted>
  <last_update_submitted_qc>August 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</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/NCT03792633
org study id: 831916
secondary id: 18CT014
nct id: NCT03792633
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase 2 study to evaluate humanized CD19 redirected autologous T cells (or huCART19
      cells) with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia. This
      study is targeting pediatric and young adult patients aged 1-29 years with CD19+ B cell
      malignancies in newly diagnosed B-ALL patients predicted to have an exceedingly poor outcome
      with conventional chemotherapy, in high-risk first relapse, or and in second or greater
      relapse in this phase 2 trial. In addition, a second cohort will test the efficacy of
      huCART19 in patients with poor response to prior B cell directed engineered cell therapy.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 1-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL
time frame: 1 year
measure: 1-year Event-Free Survival in patients with poor response to prior B cell directed engineered cell therapy
time frame: 1 year
measure: Overall Remission Rate (Cohort A)
time frame: 28 Days
description: Overall remission rate as determined by the response at day 28, computed as the proportion of subjects with CR or Cri, in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL.
measure: Overall Remission Rate (Cohort B)
time frame: 28 Days
description: Overall remission rate as determined by the response at day 28, computed as the proportion of subjects with CR or Cri, in patients with poor response to prior B cell directed engineered cell therapy.
measure: 2-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL (cohort A).
time frame: 2 years
measure: 2-year Event-Free Survival in patients with poor response to prior B cell directed engineered cell therapy (cohort B)
time frame: 2 years
measure: 2-year Relapse-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL (cohort A).
time frame: 2 years
measure: 2-year Relapse-Free Survival in patients with poor response to prior B cell directed engineered cell therapy (cohort B)
time frame: 2 years
measure: Frequency and severity of adverse events
time frame: 2 years
arm group label: Newly Diagnosed VHR B-ALL or High-Risk Relapse of B
arm group type: Experimental
arm group label: Poor Response to Prior B Cell Directed Engineered cell therapy
arm group type: Experimental
intervention type: Biological
intervention name: huCART19
description: huCART19 infusion
arm group label: Newly Diagnosed VHR B-ALL or High-Risk Relapse of B
arm group label: Poor Response to Prior B Cell Directed Engineered cell therapy
other name: huCTL019
criteria: 
gender: All
minimum age: 3 Months
maximum age: 29 Years
healthy volunteers: No
last name: Shannon Maude, MD, PhD
role: Principal Investigator
affiliation: Children's Hospital of Philadelphia
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma