xml: <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/NCT05994690</url>
    </required_header>
    <id_info>
      <org_study_id>2022-002885-34</org_study_id>
      <nct_id>NCT05994690</nct_id>
    </id_info>
    <brief_title>CHIP-AML22/Master: An Open Label Complex Clinical Trial in Newly Diagnosed Pediatric de Novo AML Patients</brief_title>
    <official_title>An Open Label Complex Clinical Trial in Newly Diagnosed Pediatric de Novo AML Patients - a Study by the NOPHO-DB-SHIP Consortium, Master Protocol</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Princess Maxima Center for Pediatric Oncology</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>European Health and Digital Executive Agency</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Princess Maxima Center for Pediatric Oncology</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 CHIP-AML22 Master protocol has the overall aim of increasing the cure rate in newly&#xD;
        diagnosed pediatric de novo AML patients, while avoiding unnecessary toxicity.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a master protocol comprising a complex clinical trial with a stratification approach&#xD;
        to allocate patients to randomized studies described in the master protocol or linked trials.&#xD;
  &#xD;
        The overarching objective of the CHIP-AML22 study is to improve event-free survival (EFS) in&#xD;
        children and adolescents with AML, as compared to NOPHO-DBH 2012.&#xD;
  &#xD;
        The consortium strives to achieve the overarching aim by:&#xD;
  &#xD;
          1. Avoiding unnecessary toxicity. This will be investigated in a randomized setting&#xD;
             (non-inferiority) by omitting a third standard-of-care consolidation course for&#xD;
             standard-risk patients (4 versus 5 courses of chemotherapy).&#xD;
  &#xD;
          2. Introducing quizartinib as FLT3-inhibitor in addition to the first three sequential&#xD;
             chemotherapy courses for all patients with FLT3-ITD/NPM1wt, and as post-SCT continuation&#xD;
             treatment for the subset of patients that have MRD ≥0.1% after course 1 or at any&#xD;
             time-point later on (historical comparison, higher efficacy).&#xD;
  &#xD;
          3. Refining risk-group adapted treatment, by classifying patients with KMT2A-rearrangement&#xD;
             (except KMT2A/MLLT3) and MRD≥0.1% in BM after course 1 as high-risk (historical&#xD;
             comparison, higher efficacy), as well as patients with the RAM-phenotype and/or&#xD;
             CBFA2T3::GLIS2 fusion (historical comparison, higher efficacy). High-risk&#xD;
             (non-FLT3-ITD/NPM1wt patients) will also be concluded for patients having ≥15% leukemic&#xD;
             cells in BM after course 1, or ≥0.1-5% after course 2. Refractory disease will be&#xD;
             defined as ≥5% leukemic cells in bone marrow after 2 courses of induction treatment, or&#xD;
             disease elsewhere, or both.&#xD;
  &#xD;
          4. Recommending the use of the cardioprotective drug dexrazoxane in all courses&#xD;
             incorporating an anthracycline or mitoxantrone (exploratory objective, no statistical&#xD;
             design), with the aim to prevent cardiotoxicity.&#xD;
  &#xD;
          5. Furthermore, a randomized study with gemtuzumab ozogamicin in induction course 1 is&#xD;
             planned and will be added later by amendment. Children with FLT3-ITD/NPM1wt are not&#xD;
             eligible for this randomization.&#xD;
  &#xD;
          6. To explore health-related Quality of Life during and after completion of treatment by&#xD;
             using short questionnaires (exploratory objective, no statistical design).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 2023</start_date>
    <completion_date type="Anticipated">December 2035</completion_date>
    <primary_completion_date type="Anticipated">March 2031</primary_completion_date>
    <phase>Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Overarching primary objective</measure>
      <time_frame>5 years</time_frame>
      <description>Event Free Survival (EFS)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Primary objective Randomisation Consolidation</measure>
      <time_frame>5 years</time_frame>
      <description>Disease Free Survival (DFS)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 1</measure>
      <time_frame>8 months</time_frame>
      <description>• Bone marrow blast counts by morphology and multicolor flow cytometry (MFCM) after course #1 and #2 and before allo-SCT</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 2</measure>
      <time_frame>3 months</time_frame>
      <description>ORR (CR, CRp, and CRi) and morphologic leukemia-free state (MLFS) rates after course #1 and #2;</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 3</measure>
      <time_frame>8 months</time_frame>
      <description>MRD negativity after course #1 and #2 and before allo-SCT</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 4</measure>
      <time_frame>8 months</time_frame>
      <description>Absolute MRD levels after course #1 and #2 and before allo-SCT</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 5</measure>
      <time_frame>5 years</time_frame>
      <description>• OS</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 6</measure>
      <time_frame>5 years</time_frame>
      <description>• DFS</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - efficacy 7</measure>
      <time_frame>5 years</time_frame>
      <description>• CIR</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - toxicity 1</measure>
      <time_frame>5 years</time_frame>
      <description>• Cumulative toxicity, defined as the total of all grades AEs over time, which are graded by NCI CTCAE version 5.0.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overarching secondary objective - toxicity 2</measure>
      <time_frame>5 years</time_frame>
      <description>• NRM.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Secondary objective Randomisation consolidation - safety 1</measure>
      <time_frame>8 months</time_frame>
      <description>• Cumulative toxicity, defined as the total of grade ≥3 AESIs over time, which are graded by NCI CTCAE version 5.0.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Secondary objective Randomisation consolidation - safety 2</measure>
      <time_frame>5 years</time_frame>
      <description>• NRM.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Secondary objective Randomisation consolidation - healthcare resources</measure>
      <time_frame>1 year</time_frame>
      <description>Cumulative Hospitalized Days</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Secondary objective Randomisation consolidation - efficacy 1</measure>
      <time_frame>5 years</time_frame>
      <description>• OS</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Secondary objective Randomisation consolidation - efficacy 2</measure>
      <time_frame>5 years</time_frame>
      <description>• CIR</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">905</enrollment>
    <condition>Acute Myeloid Leukemia in Children</condition>
    <arm_group>
      <arm_group_label>Standard arm</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>3 consolidation courses (HAM + HA3E + FLA)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Investigational arm</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>2 consolidation courses (HAM + FLA)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Standard Intervention</intervention_name>
      <description>3 consolidation courses (HAM + HA3E + FLA)</description>
      <arm_group_label>Standard arm</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Investigational Intervention</intervention_name>
      <description>2 consolidation courses (HAM + FLA)</description>
      <arm_group_label>Investigational arm</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          General inclusion criteria for CHIP-AML22/Master:&#xD;
  &#xD;
          Patients are eligible for the study if they fulfil all four criteria below:&#xD;
  &#xD;
            1. Newly diagnosed AML as defined by the diagnostic criteria in section 8.1. Note that&#xD;
               different blast thresholds may apply for different genetic abnormalities in case of&#xD;
               low blast percentages. The origin of AML must be de novo (not secondary to bone marrow&#xD;
               failure or therapy-related).&#xD;
  &#xD;
            2. Age ≥ day and ≤18 years old at initial diagnosis.&#xD;
  &#xD;
            3. Written informed consent/assent from patients and/or from parents or legal guardians&#xD;
               for minor patients, according to local law and regulations. Informed consent should&#xD;
               ideally be obtained before day 7 of induction course 1, as patients that are eligible&#xD;
               for the linked quizartinib trial should be enrolled before the end of induction course&#xD;
               1, and in view of the planned Mylotarg® randomisation. Thus, standard of care&#xD;
               diagnostics and induction treatment may be started before informed consent has been&#xD;
               obtained.&#xD;
  &#xD;
            4. Able to comply with scheduled follow-up and with management of toxicity.&#xD;
  &#xD;
          Additional inclusions criteria for Rc randomization&#xD;
  &#xD;
            1. Patients included in the CHIP-AML22 protocol and stratified to Standard Risk Group&#xD;
               according to the stratification algorithm of the protocol&#xD;
  &#xD;
            2. Informed consent for participation in randomization Rc&#xD;
  &#xD;
          General exclusion criteria for CHIP-AML22/Master&#xD;
  &#xD;
          Patients are excluded if any of the criteria below are present:&#xD;
  &#xD;
            1. Previous chemotherapy or radiotherapy. This includes patients with therapy-related AML&#xD;
               after previous cancer therapy. These patients may be treated according to the master&#xD;
               protocol but will not be part of the formal study population, and data of these&#xD;
               patients will not be collected.&#xD;
  &#xD;
            2. Patients with a (known) germline predisposition for bone marrow failure, like Fanconi&#xD;
               anemia.&#xD;
  &#xD;
            3. Myeloid Leukemia of Down syndrome (ML-DS). Patients with ML-DS are recommended to be&#xD;
               treated according to the international ML-DS protocol. Patients with AML and DS older&#xD;
               than 5 years who often lack GATA1 mutation and do not have typical myeloid leukemia of&#xD;
               DS may be treated according to the master protocol but will not be part of the formal&#xD;
               study population, hence data of these patients will not be collected.&#xD;
  &#xD;
            4. Acute promyelocytic leukemia (APL).&#xD;
  &#xD;
            5. Myelodysplastic syndrome (MDS).&#xD;
  &#xD;
            6. Juvenile Myelomonocytic Leukemia (JMML).&#xD;
  &#xD;
            7. Known intolerance to any of the chemotherapeutic drugs in the protocol.&#xD;
  &#xD;
            8. Evidence of cardiac dysfunction (shortening fraction below 28%).&#xD;
  &#xD;
            9. Pregnant or lactating patients, or sexually active female patients of childbearing&#xD;
               potential not willing to use an highly effective method of contraception for the&#xD;
               duration of study therapy and up to 7 months after the completion of all study&#xD;
               therapy.&#xD;
  &#xD;
           10. Sexually active, fertile male patients, not willing to use an effective method of&#xD;
               contraception, for the duration of study therapy, and up to 6 months after the&#xD;
               completion of all study therapy.&#xD;
  &#xD;
           11. Concomitant administration of any other experimental drug under investigation, or&#xD;
               concurrent treatment with any other anti-cancer therapy other than specified in this&#xD;
               protocol or in one of the trials linked to this Master protocol, is not allowed.&#xD;
  &#xD;
           12. Patients who in the opinion of the investigator, may not be able to comply with the&#xD;
               study requirements of the study.&#xD;
  &#xD;
           13. Patients with known active hepatitis B, hepatitis C, or HIV infection.&#xD;
  &#xD;
           14. Patients for whom informed consent was not obtained.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>1 Day</minimum_age>
      <maximum_age>18 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Gertjan Kaspers, Prof. Dr.</last_name>
      <role>Study Chair</role>
      <affiliation>Pediatric Oncologist</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Michel Zwaan, Prof. Dr.</last_name>
      <role>Study Director</role>
      <affiliation>Head Trial and Data Center</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Renske Benedictus</last_name>
      <phone>+31889727272</phone>
      <email>CHIP-AML22@prinsesmaximacentrum.nl</email>
    </overall_contact>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 25, 2023</study_first_submitted>
    <study_first_submitted_qc>August 8, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 16, 2023</study_first_posted>
    <last_update_submitted>August 8, 2023</last_update_submitted>
    <last_update_submitted_qc>August 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 16, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>All individual participant data will be used to generate a publication</ipd_description>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_time_frame>Primary CSRs may be completed earlier when the primary objective is completed and may be followed by a final CSR not later than 6 months after the end of the trial.</ipd_time_frame>
      <ipd_access_criteria>A summary of the study results will be made public via clinicaltrials.gov as well as to Ethical committees/ Health Authorities and all participating patients by providing them through their treating physicians a patient letter with a summary of the results.</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05994690
  org study id: 2022-002885-34
  nct id: NCT05994690
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The CHIP-AML22 Master protocol has the overall aim of increasing the cure rate in newly
        diagnosed pediatric de novo AML patients, while avoiding unnecessary toxicity.
  This is a master protocol comprising a complex clinical trial with a stratification approach
        to allocate patients to randomized studies described in the master protocol or linked trials.
  
        The overarching objective of the CHIP-AML22 study is to improve event-free survival (EFS) in
        children and adolescents with AML, as compared to NOPHO-DBH 2012.
  
        The consortium strives to achieve the overarching aim by:
  
          1. Avoiding unnecessary toxicity. This will be investigated in a randomized setting
             (non-inferiority) by omitting a third standard-of-care consolidation course for
             standard-risk patients (4 versus 5 courses of chemotherapy).
  
          2. Introducing quizartinib as FLT3-inhibitor in addition to the first three sequential
             chemotherapy courses for all patients with FLT3-ITD/NPM1wt, and as post-SCT continuation
             treatment for the subset of patients that have MRD ≥0.1% after course 1 or at any
             time-point later on (historical comparison, higher efficacy).
  
          3. Refining risk-group adapted treatment, by classifying patients with KMT2A-rearrangement
             (except KMT2A/MLLT3) and MRD≥0.1% in BM after course 1 as high-risk (historical
             comparison, higher efficacy), as well as patients with the RAM-phenotype and/or
             CBFA2T3::GLIS2 fusion (historical comparison, higher efficacy). High-risk
             (non-FLT3-ITD/NPM1wt patients) will also be concluded for patients having ≥15% leukemic
             cells in BM after course 1, or ≥0.1-5% after course 2. Refractory disease will be
             defined as ≥5% leukemic cells in bone marrow after 2 courses of induction treatment, or
             disease elsewhere, or both.
  
          4. Recommending the use of the cardioprotective drug dexrazoxane in all courses
             incorporating an anthracycline or mitoxantrone (exploratory objective, no statistical
             design), with the aim to prevent cardiotoxicity.
  
          5. Furthermore, a randomized study with gemtuzumab ozogamicin in induction course 1 is
             planned and will be added later by amendment. Children with FLT3-ITD/NPM1wt are not
             eligible for this randomization.
  
          6. To explore health-related Quality of Life during and after completion of treatment by
             using short questionnaires (exploratory objective, no statistical design).
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Overarching primary objective
  time frame: 5 years
  description: Event Free Survival (EFS)
  measure: Primary objective Randomisation Consolidation
  time frame: 5 years
  description: Disease Free Survival (DFS)
  measure: Overarching secondary objective - efficacy 1
  time frame: 8 months
  description: • Bone marrow blast counts by morphology and multicolor flow cytometry (MFCM) after course #1 and #2 and before allo-SCT
  measure: Overarching secondary objective - efficacy 2
  time frame: 3 months
  description: ORR (CR, CRp, and CRi) and morphologic leukemia-free state (MLFS) rates after course #1 and #2;
  measure: Overarching secondary objective - efficacy 3
  time frame: 8 months
  description: MRD negativity after course #1 and #2 and before allo-SCT
  measure: Overarching secondary objective - efficacy 4
  time frame: 8 months
  description: Absolute MRD levels after course #1 and #2 and before allo-SCT
  measure: Overarching secondary objective - efficacy 5
  time frame: 5 years
  description: • OS
  measure: Overarching secondary objective - efficacy 6
  time frame: 5 years
  description: • DFS
  measure: Overarching secondary objective - efficacy 7
  time frame: 5 years
  description: • CIR
  measure: Overarching secondary objective - toxicity 1
  time frame: 5 years
  description: • Cumulative toxicity, defined as the total of all grades AEs over time, which are graded by NCI CTCAE version 5.0.
  measure: Overarching secondary objective - toxicity 2
  time frame: 5 years
  description: • NRM.
  measure: Secondary objective Randomisation consolidation - safety 1
  time frame: 8 months
  description: • Cumulative toxicity, defined as the total of grade ≥3 AESIs over time, which are graded by NCI CTCAE version 5.0.
  measure: Secondary objective Randomisation consolidation - safety 2
  time frame: 5 years
  description: • NRM.
  measure: Secondary objective Randomisation consolidation - healthcare resources
  time frame: 1 year
  description: Cumulative Hospitalized Days
  measure: Secondary objective Randomisation consolidation - efficacy 1
  time frame: 5 years
  description: • OS
  measure: Secondary objective Randomisation consolidation - efficacy 2
  time frame: 5 years
  description: • CIR
  arm group label: Standard arm
  arm group type: Active Comparator
  description: 3 consolidation courses (HAM + HA3E + FLA)
  arm group label: Investigational arm
  arm group type: Experimental
  description: 2 consolidation courses (HAM + FLA)
  intervention type: Drug
  intervention name: Standard Intervention
  description: 3 consolidation courses (HAM + HA3E + FLA)
  arm group label: Standard arm
  intervention type: Drug
  intervention name: Investigational Intervention
  description: 2 consolidation courses (HAM + FLA)
  arm group label: Investigational arm
  criteria: 
  gender: All
  minimum age: 1 Day
  maximum age: 18 Years
  healthy volunteers: No
  last name: Gertjan Kaspers, Prof. Dr.
  role: Study Chair
  affiliation: Pediatric Oncologist
  last name: Michel Zwaan, Prof. Dr.
  role: Study Director
  affiliation: Head Trial and Data Center
  last name: Renske Benedictus
  phone: +31889727272
  email: CHIP-AML22@prinsesmaximacentrum.nl
  responsible party type: Sponsor
  sharing ipd: Yes
  ipd description: All individual participant data will be used to generate a publication
  ipd info type: Clinical Study Report (CSR)
  ipd time frame: Primary CSRs may be completed earlier when the primary objective is completed and may be followed by a final CSR not later than 6 months after the end of the trial.
  ipd access criteria: A summary of the study results will be made public via clinicaltrials.gov as well as to Ethical committees/ Health Authorities and all participating patients by providing them through their treating physicians a patient letter with a summary of the results.