<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/NCT04499573</url>
  </required_header>
  <id_info>
    <org_study_id>NCPHOI-2020-07</org_study_id>
    <nct_id>NCT04499573</nct_id>
  </id_info>
  <brief_title>Bispecific CD19/CD22 CAR-T for Treatment of Children and Young Adults With r/r B-ALL</brief_title>
  <official_title>Safety and Efficiency of Anti-CD19/CD22 Tandem Fully Human Chimeric Antigen Receptor (CAR)-Transduced T-cell Therapy for Pediatric and Young Adult Patients With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: a Single Centre, Non-randomised, Open Label Phase I-II Clinical Trial of Automatically Produced Cell Therapy Product MB-CAR-T19-22 Using CliniMACS Prodigy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Federal Research Institute of Pediatric Hematology, Oncology and Immunology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Federal Research Institute of Pediatric Hematology, Oncology and Immunology</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and efficiency of autologous CD19/CD22&#xD;
      CAR-T lymphocytes in a cohort of pediatric and young adult patients with relapsed /refractory&#xD;
      B-lineage acute lymphoblastic leukemia&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main objectives of the study are:&#xD;
&#xD;
        -  To investigate the incidence of adverse events of grade 3-5 within after CD19/CD22 CAR&#xD;
           lymphocyte infusion by day 28,&#xD;
&#xD;
        -  To evaluate the incidence of complete remission and MRD-negative CR by day 28&#xD;
&#xD;
        -  To evaluate the long-term effectiveness of CD19/CD22 CAR-T therapy (cumulative incidence&#xD;
           of relapse, event-free survival, overall survival) at 1, 2, and 5 years after infusion.&#xD;
&#xD;
        -  To evaluate the persistence of CD19/CD22 CAR-T cells and duration of B-cell aplasia (&lt;1%&#xD;
           B-cells in the blood) and hypogammaglobulinemia In order to prevent the development of&#xD;
           CRS, all patients will receive an infusion of tocilizumab at 8 mg/kg body weight on day&#xD;
           0 before CAR-T cells infusion.&#xD;
&#xD;
      Step-down and step-up dosing will be used to adapt the trial to the scenario of excess&#xD;
      toxicity and/or suboptimal effect. Reevaluation of dosing will be done for each cohort&#xD;
      separately after the enrollment 5th study subject reaches day 28 or earlier if the threshold&#xD;
      for excess toxicity or suboptimal effect is achieved.&#xD;
&#xD;
      Based on interim analysis in March 2021 after the enrollment 5th study subject reaches day 28&#xD;
      study population will be divided into three cohorts:&#xD;
&#xD;
        1. CD19-positive (both CD19 and CD22 expressed on over 50% of leukemia cells), low and high&#xD;
           disease burden.&#xD;
&#xD;
        2. CD19-negative (CD22 expressed on over 50% of leukemia cells) low and high disease&#xD;
           burden;&#xD;
&#xD;
        3. Allogeneic HSCT+ allogeneic CAR-T cohort&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 27, 2020</start_date>
  <completion_date type="Anticipated">March 13, 2027</completion_date>
  <primary_completion_date type="Actual">March 13, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</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>incidence of grade 3-5 SAE</measure>
    <time_frame>1 month</time_frame>
    <description>Safety:&#xD;
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:&#xD;
- incidence of grade 3-5 SAE (according CTCAE v.5.0)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>incidence of grade 3-5 Severe Cytokine Release Syndrome</measure>
    <time_frame>1 month</time_frame>
    <description>Safety:&#xD;
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:&#xD;
- incidence of grade 3-5 Severe Cytokine Release Syndrome (according ASTCT consensus)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>incidence of grade 3-5 ICANS</measure>
    <time_frame>1 month</time_frame>
    <description>Safety:&#xD;
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:&#xD;
- incidence of grade 3-5 ICANS (according to ASTCT consensus)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of complete remission</measure>
    <time_frame>1 month</time_frame>
    <description>Efficacy:&#xD;
- Rate of complete remission among all enrolled patients (Intent-to-Treat population)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of MRD-negative remission</measure>
    <time_frame>1 month</time_frame>
    <description>Efficacy:&#xD;
- Rate of MRD-negative remission among all patients (Intent-to-treat population)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>March 2021 amendment: incidence of graft failure before day 100 (only for HSCT cohort)</measure>
    <time_frame>100 days</time_frame>
    <description>Safety:</description>
  </primary_outcome>
  <primary_outcome>
    <measure>March 2021 amendment: incidence of aGVHD grade 2-4 (only for HSCT cohort)</measure>
    <time_frame>100 days</time_frame>
    <description>Safety:</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of MRD-negative remission</measure>
    <time_frame>2 years</time_frame>
    <description>Efficacy:</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Persistence/frequency of CD19/CD22 lymphocytes in peripheral blood (flow cytometry)</measure>
    <time_frame>2 years</time_frame>
    <description>Efficacy:</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of B-cell aplasia and hypogammaglobulinemia</measure>
    <time_frame>2 years</time_frame>
    <description>Efficacy:</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>5 years</time_frame>
    <description>Efficacy:</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and adverse effects long-term</measure>
    <time_frame>5 years</time_frame>
    <description>Safety:</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>March 2021 amendment: Incidence of chronic GVHD (only for HSCT cohort)</measure>
    <time_frame>5 years</time_frame>
    <description>Safety:</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>B-ALL</condition>
  <arm_group>
    <arm_group_label>intervention/treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention:&#xD;
Patient (cohort 1 and 2) or donor (cohort 3) leukapheresis&#xD;
Drug therapy:&#xD;
Fludarabine 120 mg/m2&#xD;
Cyclophosphamide 750 mg/m2&#xD;
Etoposide 450 mg/m2&#xD;
Cytarabine 900 mg/m2&#xD;
Dexamethasone 30 mg/m2&#xD;
Tocilizumab 8 mg/kg BW&#xD;
Biological:&#xD;
Cohort 1 and 2: autologous CD19/CD22 CAR-T lymphocytes, dose 0.15 - 1.5х106/kg&#xD;
Cohort 3: allogeneic CD19/CD22 CAR-T lymphocytes, dose 0.1х106/kg + allogeneic HSCT from a haploidentical or matched related donor</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CD19/CD22 CAR-T</intervention_name>
    <description>The treatment plan will be based on stratification by the initial leukemia burden.&#xD;
Patients with &quot;low disease burden&quot; will receive a lymphodepletion chemotherapy of fludarabine (total dose 120mg/m2) and cyclophosphamide (total dose 750mg/m2) over 5 days.&#xD;
Patients will &quot;high disease burden&quot; will receive a lymphodepletion chemotherapy of fludarabine (total dose 120 mg/m2), cyclophosphamide (total dose 750 mg/m2), cytarabine (total dose 900 mg/m2), etoposide (total dose 450 mg/m2), dexamethasone (total dose 30 mg/m2) over 5 days.&#xD;
Based on interim analysis the following dosing approach will be implemented starting April 2021:&#xD;
Cohort 1: CD19+ disease, low and high burden: 1st dose - 150k/kg, 2nd dose - 850k/kg Cohort 2: CD19- disease, low and high burden: 1st dose - 500k/kg, 2nd dose - 500k/kg Cohort 3: HSCT+CAR-T: 100k/kg</description>
    <arm_group_label>intervention/treatment</arm_group_label>
    <other_name>Fludarabine</other_name>
    <other_name>Cyclophosphamide</other_name>
    <other_name>Cytarabine</other_name>
    <other_name>Etoposide</other_name>
    <other_name>Dexamethasone</other_name>
    <other_name>Tocilizumab</other_name>
    <other_name>Allogeneic HSCT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to give informed consent (for patients &gt; 14 years old). For subjects &lt; 18&#xD;
             years old their legal guardian must give informed consent&#xD;
&#xD;
          -  CD19 or CD22 expression must be detected on greater than 50% of leukemic cells by flow&#xD;
             cytometry&#xD;
&#xD;
          -  Presence of a measurable mass of tumor cells in the bone marrow or extramedullary&#xD;
             sites at the time of patient's inclusion in the study&#xD;
&#xD;
          -  Patients with relapsed or refractory CD19 and CD22-expressing B-cell ALL:&#xD;
&#xD;
               -  Induction failure&#xD;
&#xD;
               -  MRD ≥ 0,1% after 2nd chemotherapy course for high-risk group patients.&#xD;
&#xD;
               -  First bone marrow or combined relapse of acute lymphoblastic leukemia, no CR or&#xD;
                  MRD ≥ 0,1% after 1-course 2nd line therapy&#xD;
&#xD;
               -  Second and further relapse of ALL&#xD;
&#xD;
               -  Relapse or MRD ≥ 0,1% of ALL after hematopoietic stem cell transplant (&gt; 60 days&#xD;
                  post alloHSCT)o There must be no available alternative approved curative&#xD;
                  therapies&#xD;
&#xD;
          -  Patient Clinical Performance Status: Karnofsky &gt;50% or Lansky &gt;50%&#xD;
&#xD;
          -  Patient Life Expectancy &gt; 4 weeks&#xD;
&#xD;
          -  Patients recovered from acute toxic effects of prior chemotherapy, immune- or&#xD;
             radiotherapy&#xD;
&#xD;
          -  Patient absolute blood naïve (CD45RA+) T-lymphocyte count ≥ 50/mm3&#xD;
&#xD;
          -  Patient cardiac function left ventricular ejection fraction greater than or equal to&#xD;
             40% by MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by&#xD;
             ECHO or left ventricular ejection fraction greater than or equal to 50% by ECHO.&#xD;
&#xD;
          -  Patients who agree to long-term follow up for up to 5 years (if received CD19/CD22&#xD;
             CAR-T cell infusion)&#xD;
&#xD;
          -  March 2021 amendment: Healthy HLA-matched related or haploidentical donor (only for&#xD;
             HSCT cohort)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  &lt;50% expression of both CD19 and CD22 on the leukemic population&#xD;
&#xD;
          -  Active (detectable viremia) hepatitis B, C or HIV infection&#xD;
&#xD;
          -  Oxygen saturation ≤ 90%&#xD;
&#xD;
          -  Bilirubin &gt;3x upper norma limit&#xD;
&#xD;
          -  Creatinine &gt;3x upper norma limit&#xD;
&#xD;
          -  Active acute GVHD overall grade ≥2 (Seattle criteria)&#xD;
&#xD;
          -  Moderate/severe chronic GVHD (NIH consensus) requiring systemic steroids&#xD;
&#xD;
          -  Clinical signs of grade &gt; 3 CNS disorders (seizure disorder, paresis, aphasia,&#xD;
             cerebrovascular, ischemia/hemorrhage, severe brain injuries, dementia, cerebellar&#xD;
             disease, organic brain syndrome, psychosis, coordination or movement disorder)&#xD;
&#xD;
          -  Pregnant or lactating women.&#xD;
&#xD;
          -  Active (unresolved) severe infection&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Maschan</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Research Center for Pediatric Hematology , Moscow, Russian Federation</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Federal Research Institute of Pediatric Hematology, Oncology and Immunology</name>
      <address>
        <city>Moscow</city>
        <zip>117198</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 31, 2020</study_first_submitted>
  <study_first_submitted_qc>July 31, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>February 21, 2023</last_update_submitted>
  <last_update_submitted_qc>February 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>B-ALL</keyword>
  <keyword>acute lymphoblastic leukemia</keyword>
  <keyword>CAR-T</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Etoposide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04499573
org study id: NCPHOI-2020-07
nct id: NCT04499573
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate the safety and efficiency of autologous CD19/CD22
      CAR-T lymphocytes in a cohort of pediatric and young adult patients with relapsed /refractory
      B-lineage acute lymphoblastic leukemia
The main objectives of the study are:

        -  To investigate the incidence of adverse events of grade 3-5 within after CD19/CD22 CAR
           lymphocyte infusion by day 28,

        -  To evaluate the incidence of complete remission and MRD-negative CR by day 28

        -  To evaluate the long-term effectiveness of CD19/CD22 CAR-T therapy (cumulative incidence
           of relapse, event-free survival, overall survival) at 1, 2, and 5 years after infusion.

        -  To evaluate the persistence of CD19/CD22 CAR-T cells and duration of B-cell aplasia (<1%
           B-cells in the blood) and hypogammaglobulinemia In order to prevent the development of
           CRS, all patients will receive an infusion of tocilizumab at 8 mg/kg body weight on day
           0 before CAR-T cells infusion.

      Step-down and step-up dosing will be used to adapt the trial to the scenario of excess
      toxicity and/or suboptimal effect. Reevaluation of dosing will be done for each cohort
      separately after the enrollment 5th study subject reaches day 28 or earlier if the threshold
      for excess toxicity or suboptimal effect is achieved.

      Based on interim analysis in March 2021 after the enrollment 5th study subject reaches day 28
      study population will be divided into three cohorts:

        1. CD19-positive (both CD19 and CD22 expressed on over 50% of leukemia cells), low and high
           disease burden.

        2. CD19-negative (CD22 expressed on over 50% of leukemia cells) low and high disease
           burden;

        3. Allogeneic HSCT+ allogeneic CAR-T cohort
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: incidence of grade 3-5 SAE
time frame: 1 month
description: Safety:
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:
- incidence of grade 3-5 SAE (according CTCAE v.5.0)
measure: incidence of grade 3-5 Severe Cytokine Release Syndrome
time frame: 1 month
description: Safety:
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:
- incidence of grade 3-5 Severe Cytokine Release Syndrome (according ASTCT consensus)
measure: incidence of grade 3-5 ICANS
time frame: 1 month
description: Safety:
Toxicity evaluation following CD19/CD22 CAR T-cell infusion:
- incidence of grade 3-5 ICANS (according to ASTCT consensus)
measure: Rate of complete remission
time frame: 1 month
description: Efficacy:
- Rate of complete remission among all enrolled patients (Intent-to-Treat population)
measure: Rate of MRD-negative remission
time frame: 1 month
description: Efficacy:
- Rate of MRD-negative remission among all patients (Intent-to-treat population)
measure: March 2021 amendment: incidence of graft failure before day 100 (only for HSCT cohort)
time frame: 100 days
description: Safety:
measure: March 2021 amendment: incidence of aGVHD grade 2-4 (only for HSCT cohort)
time frame: 100 days
description: Safety:
measure: Duration of MRD-negative remission
time frame: 2 years
description: Efficacy:
measure: Persistence/frequency of CD19/CD22 lymphocytes in peripheral blood (flow cytometry)
time frame: 2 years
description: Efficacy:
measure: Duration of B-cell aplasia and hypogammaglobulinemia
time frame: 2 years
description: Efficacy:
measure: Overall survival
time frame: 5 years
description: Efficacy:
measure: Safety and adverse effects long-term
time frame: 5 years
description: Safety:
measure: March 2021 amendment: Incidence of chronic GVHD (only for HSCT cohort)
time frame: 5 years
description: Safety:
arm group label: intervention/treatment
arm group type: Experimental
description: Intervention:
Patient (cohort 1 and 2) or donor (cohort 3) leukapheresis
Drug therapy:
Fludarabine 120 mg/m2
Cyclophosphamide 750 mg/m2
Etoposide 450 mg/m2
Cytarabine 900 mg/m2
Dexamethasone 30 mg/m2
Tocilizumab 8 mg/kg BW
Biological:
Cohort 1 and 2: autologous CD19/CD22 CAR-T lymphocytes, dose 0.15 - 1.5х106/kg
Cohort 3: allogeneic CD19/CD22 CAR-T lymphocytes, dose 0.1х106/kg + allogeneic HSCT from a haploidentical or matched related donor
intervention type: Drug
intervention name: CD19/CD22 CAR-T
description: The treatment plan will be based on stratification by the initial leukemia burden.
Patients with "low disease burden" will receive a lymphodepletion chemotherapy of fludarabine (total dose 120mg/m2) and cyclophosphamide (total dose 750mg/m2) over 5 days.
Patients will "high disease burden" will receive a lymphodepletion chemotherapy of fludarabine (total dose 120 mg/m2), cyclophosphamide (total dose 750 mg/m2), cytarabine (total dose 900 mg/m2), etoposide (total dose 450 mg/m2), dexamethasone (total dose 30 mg/m2) over 5 days.
Based on interim analysis the following dosing approach will be implemented starting April 2021:
Cohort 1: CD19+ disease, low and high burden: 1st dose - 150k/kg, 2nd dose - 850k/kg Cohort 2: CD19- disease, low and high burden: 1st dose - 500k/kg, 2nd dose - 500k/kg Cohort 3: HSCT+CAR-T: 100k/kg
arm group label: intervention/treatment
other name: Fludarabine
other name: Cyclophosphamide
other name: Cytarabine
other name: Etoposide
other name: Dexamethasone
other name: Tocilizumab
other name: Allogeneic HSCT
criteria: 
gender: All
minimum age: 3 Months
maximum age: 25 Years
healthy volunteers: No
last name: Michael Maschan
role: Principal Investigator
affiliation: National Research Center for Pediatric Hematology , Moscow, Russian Federation
facility: 
country: Russian Federation
responsible party type: Sponsor
mesh term: Cytarabine
mesh term: Dexamethasone
mesh term: Cyclophosphamide
mesh term: Fludarabine
mesh term: Etoposide
sharing ipd: Undecided