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Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia

Primary Purpose

Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Blinatumomab
Blinatumomab
Sponsored by
Princess Maxima Center for Pediatric Oncology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring infant under one year, KMT2A-rearranged

Eligibility Criteria

1 Day - 365 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients with newly diagnosed B- precursor acute lymphoblastic leukemia (ALL) or B- cell mixed phenotype acute leukemia (MPAL) according to the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition 2017, with KMT2A-rearrangement.
  2. ≤365 days of age at time of diagnosis of ALL
  3. Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.

Exclusion Criteria:

  1. KMT2A-germline patients
  2. T-ALL
  3. Age > 365 days at the time of diagnosis
  4. Relapsed ALL
  5. Treatment with systemic corticosteroids (equivalent prednisone >10 mg/m2/day) for more than one week and/or any chemotherapeutic agent in the 4-week interval prior to diagnosis. Patients who received corticosteroids by aerosol are eligible for the study.

Additional exclusion criteria for blinatumomab:

  1. CD19 negative B-precursor ALL at diagnosis
  2. CNS involvement (CNS2/CNS3 status) at the EOI. Patients with CNS disease at the time of diagnosis are eligible if CNS1 status is achieved prior to the start of the first blinatumomab cycle (lumbar puncture at ~day 33 of induction).
  3. Proven hypersensitivity to the active substance or any of the excipients in blinatumomab.
  4. Patients who have received a live vaccine 28 days prior to blinatumomab administration or plan to receive a live vaccine prior to B-cell recovery after the last dose of blinatumomab.

If exclusion criteria for blinatumomab are met, the patient should be treated according to the protocol but without blinatumomab.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Other

    Other

    Arm Label

    Medium Risk (MR)

    High risk (HR)

    Arm Description

    Subject is defined as MR if > 6months of age at diagnosis, OR < 6 months of age with White Blood cell Count (WBC) < 300 at diagnosis and good prednisone response. Subject gets 1st cycle of blinatumomab. If MRD is >0.01%, after 1st cycle of blinatumomab, subject will be allocated to HR treatment from that phase, and will be eligible for HSCT. If MRD is undetectable or < 0.01% after the 1st cycle of blinatumomab (TP2) patient will be eligible for replacement of MARMA by 2nd cycle of blinatumomab after receipt of lymphoid style consolidation (Protocol IB) or of myeloid style consolidation (ADE/MAE).

    Subject is defined as HR if < 6 months of age with WBC > 300 at diagnosis OR poor prednisone response. Also MR patients with end of induction MRD ≥ 1%, or MRD > 0.01% after the 1st cycle of blinatumomab, will be allocated to HR treatment. Subject gets 1 cycle of blinatumomab. Thereafter patient is eligible for hematopoietic stem cell transplantation (HSCT) with or without experimental therapy in an investigational window.

    Outcomes

    Primary Outcome Measures

    Event free survival (EFS).
    The primary endpoint is EFS, defined as the time from diagnosis to resistance to induction, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up (censored) for patients without events.

    Secondary Outcome Measures

    Overall survival
    The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.
    Endpoints by risk group
    The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.
    Outcome for the entire study cohort and according to risk group
    Outcome for the entire study cohort and according to risk group will be evaluated in terms of the protocol specific definition of EFS follows: the time from diagnosis to, resistance to proto-col, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up for patients without events. Cumulative incidence (or percentage) of resistance, CIR, death in CR and second malignancy will also be estimated.
    Minimal Residual Disease
    MRD response as defined in the protocol and frequencies of MRD levels
    CD19 (cluster of differentiation antigen 19) negative relapse
    Proportion of CD19 negative relapses in the entire study cohort and according to risk group
    Myeloid lineage switches
    Proportion of myeloid lineage switches in the entire study cohort and according to risk group
    Grade ≥3 adverse event
    Proportion of grade ≥3 adverse event (AEs) during the blinatumomab course(s). Proportion of adverse events of special interest (AESIs) and serious adverse events (SAEs) in all protocol phases.
    Grade ≥2 cardiac disorders
    Proportion of grade ≥2 cardiac disorders at 2 and 5 years after diagnosis
    Overall survival after 1st relapse
    Overall survival (OS) after first relapse, defined as the time from first relapse to death from any cause, in the entire study cohort and according to risk group

    Full Information

    First Posted
    April 7, 2022
    Last Updated
    April 7, 2022
    Sponsor
    Princess Maxima Center for Pediatric Oncology
    Collaborators
    Amgen Europe B.V, University of Milano Bicocca
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05327894
    Brief Title
    Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia
    Official Title
    Interfant-21 International Collaborative Treatment Protocol for Infants Under One Year With KMT2A-rearranged Acute Lymphoblastic Leukemia or Mixed Phenotype Acute Leukemia.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    September 2022 (Anticipated)
    Primary Completion Date
    September 2027 (Anticipated)
    Study Completion Date
    September 2030 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Princess Maxima Center for Pediatric Oncology
    Collaborators
    Amgen Europe B.V, University of Milano Bicocca

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This study is a treatment protocol with blinatumomab for infants under 1 year old who are diagnosed with acute lymphoblastic leukemia with a specific unfavorable genetic alteration. The purpose of the study is to improve the outcome of this disease in infants.
    Detailed Description
    All infants that are eligible for this study and for whom the parents/legal representatives give informed consent will be enrolled in this study. All patients will receive one cycle of blinatumomab on top of the standard treatment backbone after induction therapy. Medium risk patients, that respond well to the 1st cycle will be treated with a 2nd cycle of blinatumomab replacing one chemo course after consolidation therapy. If they do not respond well enough they will be treated according to the current treatment standard. Minimal residual disease will be used to determine the response to blinatumomab. High risk patients will be eligible for allogeneic stem cell transplantation after the first blinatumomab cycle if they are Minimal Residual Disease (MRD) negative (defined as < 0.01%). Also medium risk patients with insufficient MRD response after induction or after the 1st cycle of blinatumomab will be allocated to high risk treatment and will be eligible for allogeneic stem cell transplantation.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia
    Keywords
    infant under one year, KMT2A-rearranged

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Sequential Assignment
    Model Description
    Definition: Provide details about the Interventional Study Model. Limit: 1000 characters.
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    160 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Medium Risk (MR)
    Arm Type
    Other
    Arm Description
    Subject is defined as MR if > 6months of age at diagnosis, OR < 6 months of age with White Blood cell Count (WBC) < 300 at diagnosis and good prednisone response. Subject gets 1st cycle of blinatumomab. If MRD is >0.01%, after 1st cycle of blinatumomab, subject will be allocated to HR treatment from that phase, and will be eligible for HSCT. If MRD is undetectable or < 0.01% after the 1st cycle of blinatumomab (TP2) patient will be eligible for replacement of MARMA by 2nd cycle of blinatumomab after receipt of lymphoid style consolidation (Protocol IB) or of myeloid style consolidation (ADE/MAE).
    Arm Title
    High risk (HR)
    Arm Type
    Other
    Arm Description
    Subject is defined as HR if < 6 months of age with WBC > 300 at diagnosis OR poor prednisone response. Also MR patients with end of induction MRD ≥ 1%, or MRD > 0.01% after the 1st cycle of blinatumomab, will be allocated to HR treatment. Subject gets 1 cycle of blinatumomab. Thereafter patient is eligible for hematopoietic stem cell transplantation (HSCT) with or without experimental therapy in an investigational window.
    Intervention Type
    Drug
    Intervention Name(s)
    Blinatumomab
    Other Intervention Name(s)
    Cycle 1
    Intervention Description
    1st cycle: 15 μg/m2/day as a 4 week continuous IV infusion for patients with a M1 marrow. For patients with a M2/M3 marrow a step-dosing strategy is required with a dose of 5 μg/m2/day in week 1 followed by 15 μg/m2/day in weeks 2, 3, and 4.
    Intervention Type
    Drug
    Intervention Name(s)
    Blinatumomab
    Other Intervention Name(s)
    Cycle 2
    Intervention Description
    2nd cycle: 15 μg/m2/day as a 4 week continuous iv infusion
    Primary Outcome Measure Information:
    Title
    Event free survival (EFS).
    Description
    The primary endpoint is EFS, defined as the time from diagnosis to resistance to induction, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up (censored) for patients without events.
    Time Frame
    5 years
    Secondary Outcome Measure Information:
    Title
    Overall survival
    Description
    The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.
    Time Frame
    8 years
    Title
    Endpoints by risk group
    Description
    The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.
    Time Frame
    8 years
    Title
    Outcome for the entire study cohort and according to risk group
    Description
    Outcome for the entire study cohort and according to risk group will be evaluated in terms of the protocol specific definition of EFS follows: the time from diagnosis to, resistance to proto-col, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up for patients without events. Cumulative incidence (or percentage) of resistance, CIR, death in CR and second malignancy will also be estimated.
    Time Frame
    8 years
    Title
    Minimal Residual Disease
    Description
    MRD response as defined in the protocol and frequencies of MRD levels
    Time Frame
    8 years
    Title
    CD19 (cluster of differentiation antigen 19) negative relapse
    Description
    Proportion of CD19 negative relapses in the entire study cohort and according to risk group
    Time Frame
    8 years
    Title
    Myeloid lineage switches
    Description
    Proportion of myeloid lineage switches in the entire study cohort and according to risk group
    Time Frame
    8 years
    Title
    Grade ≥3 adverse event
    Description
    Proportion of grade ≥3 adverse event (AEs) during the blinatumomab course(s). Proportion of adverse events of special interest (AESIs) and serious adverse events (SAEs) in all protocol phases.
    Time Frame
    8 years
    Title
    Grade ≥2 cardiac disorders
    Description
    Proportion of grade ≥2 cardiac disorders at 2 and 5 years after diagnosis
    Time Frame
    5 years
    Title
    Overall survival after 1st relapse
    Description
    Overall survival (OS) after first relapse, defined as the time from first relapse to death from any cause, in the entire study cohort and according to risk group
    Time Frame
    8 years

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    1 Day
    Maximum Age & Unit of Time
    365 Days
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients with newly diagnosed B- precursor acute lymphoblastic leukemia (ALL) or B- cell mixed phenotype acute leukemia (MPAL) according to the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition 2017, with KMT2A-rearrangement. ≤365 days of age at time of diagnosis of ALL Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations. Exclusion Criteria: KMT2A-germline patients T-ALL Age > 365 days at the time of diagnosis Relapsed ALL Treatment with systemic corticosteroids (equivalent prednisone >10 mg/m2/day) for more than one week and/or any chemotherapeutic agent in the 4-week interval prior to diagnosis. Patients who received corticosteroids by aerosol are eligible for the study. Additional exclusion criteria for blinatumomab: CD19 negative B-precursor ALL at diagnosis CNS involvement (CNS2/CNS3 status) at the EOI. Patients with CNS disease at the time of diagnosis are eligible if CNS1 status is achieved prior to the start of the first blinatumomab cycle (lumbar puncture at ~day 33 of induction). Proven hypersensitivity to the active substance or any of the excipients in blinatumomab. Patients who have received a live vaccine 28 days prior to blinatumomab administration or plan to receive a live vaccine prior to B-cell recovery after the last dose of blinatumomab. If exclusion criteria for blinatumomab are met, the patient should be treated according to the protocol but without blinatumomab.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Judith Hoevenaars
    Phone
    0031 6 5017 30 12
    Email
    trialmanagement@prinsesmaximacentrum.nl
    First Name & Middle Initial & Last Name or Official Title & Degree
    Peggy Scholte-Van Houtem
    Phone
    0031 6 50 17 30 43
    Email
    trialmanagement@prinsesmaximacentrum.nl
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Janine Stutterheim, Dr
    Organizational Affiliation
    Princess Maxima Center for Pediatric Oncology in The Netherlands
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    all individual participant data that underlie results in a publication
    IPD Sharing Time Frame
    The Clinical Study Report (CSR) will be made available within 6 months upon study end.
    IPD Sharing Access Criteria
    A summary of the study results will be made public via www.clinical trials.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.

    Learn more about this trial

    Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia

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