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    Summary
    EudraCT Number:2021-000213-16
    Sponsor's Protocol Code Number:Interfant-21
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-05-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-000213-16
    A.3Full title of the trial
    International collaborative treatment protocol for infants under one year with KMT2A-rearranged acute lymphoblastic leukemia or mixed phenotype acute leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of infants under one year with acute lymphoblastic leukemia according to the Interfant-21 protocol
    A.3.2Name or abbreviated title of the trial where available
    Interfant-21
    A.4.1Sponsor's protocol code numberInterfant-21
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05327894
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPrincess Máxima Center for Pediatric Oncology
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAmgen Europe B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPrincess Máxima Center for Pediatric Oncology
    B.5.2Functional name of contact pointTrial manager
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 25
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CS
    B.5.3.4CountryNetherlands
    B.5.6E-mailtrialmanagement@prinsesmaximacentrum.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name BLINCYTO
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/650
    D.3 Description of the IMP
    D.3.1Product nameBlincyto
    D.3.2Product code AMG103
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeImmunotherapy
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute lymphoblastic leukemia
    E.1.1.1Medical condition in easily understood language
    Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to improve the outcome (in terms of event-free survival (EFS) as the primary endpoint) of newly diagnosed KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) compared with the historical results of the Interfant06 protocol.
    E.2.2Secondary objectives of the trial
    1. To estimate overall survival (OS) and compare it with corresponding historical results of the Interfant-06 protocol, in the whole study and by risk group.
    2. To determine outcome (in terms of secondary endpoint 2) according to risk group and compare it with corresponding historical results of the Interfant-06 protocol.
    3. To determined outcome (in terms of secondary endpoint 3) taking into account the protocol-specific definition of resistance.
    4. To assess the response to different treatment phases in term of minimal residual disease (MRD) response.
    5. To evaluate the incidence of CD19 negative relapses
    6. To evaluate the incidence of myeloid lineage switches
    7. To describe the toxicity associated to each treatment phase.
    8. To describe long term cardiotoxicity
    9. To evaluate survival after relapse, overall and by risk group
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1 - The Goldilocks study- Developing biomarkers for CNS leukemia in infant ALL (v1.1 dd 21Apr2022)
    Aim: to develop clinical grade, quality assured, diagnostic and prognostic biomarkers for central nervous system (CNS) leukaemia in infants with acute lymphoblastic leukaemia (ALL).
    2 - Pharmacokinetics of chemotherapeutic agents in infant acute lymphoblastic leukemia to support optimal dosing (v1.0 dd 22Feb2022)
    The objective of this study is to gain better insight in the pharmacokinetics of chemotherapeutic agents in infant ALL, taking into account the influence of maturation and body size in the first year(s) of life. Objectives:
    • Primary objective: Quantification of the effects of maturation and body size on the PK of vincristine, daunorubicin and dexamethasone in infant ALL by means of population PK modelling.
    • Secondary objective: To include the identified age related differences into physiologically-based PK (PBPK) model frameworks allowing extrapolation of the results to other drugs used in this population.
    • To describe the pharmacokinetics of (high-dose and low-dose) methotrexate and 6-mercaptopurine during MARMA phase and maintenance therapy and their association with outcome.

    3- Investigation of the Immune (Micro)environment During ALL Therapy with Blinatumomab (V1.1 dd 25Mar2022)
    Aims:
    1. To define which factors of the host immune system pre- and during treatment may have impact on response to targeted immunotherapy in infant ALL.
    2. To decipher the interaction between host immune system and modifications induced by the bispecific antibody blinatumomab.
    Objectives:
    1. To definitively investigate the immune TME composition in bone marrow and T cell functional status in infant B-cell ALL.
    Specifically, we will identify:
    a. The key cellular effectors mediating blinatumomab therapeutic efficacy in infant ALL, and their biological characteristics.
    b. Composition of the immune milieu in blinatumomab responders versus non-responders.
    c. Predictors of CD19-negative escape or lineage switch, and conversely, determination of the mechanisms by which CD19- infant ALL cells are eliminated during blinatumomab therapy.
    2. Study correlation of response to blinatumomab to functional parameters of the immune cell subset (lymphoid and myeloid) repertoire before start and during blinatumomab (T-cell fitness score)

    4 - Neurotoxicity and treatment-related neurocognitive complications after Interfant-21 treatment (V1.0 dd 27Jan2022)
    Aims:
    1. To examine the incidence, severity, and longitudinal changes in neurodevelopmental impairment in infants treated according to the Interfant-21 protocol during and after therapy.
    2. To identify risk factors for adverse outcomes including whether acute neurotoxic events are associated with poor performance on neurodevelopmental tests compared to patients without acute neurotoxicity.

    E.3Principal inclusion criteria
    1. Patients with newly diagnosed B- precursor ALL or B-cell MPAL according to the WHO classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition 2017, with KMT2A-rearrangement.
    2. ≤ 365 days of age at the 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.
    E.4Principal 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/TLP+ 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is EFS defined as the time from diagnosis to resistance to induction (i.e. no complete remission at the end of induction) , relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up (censored) for patients without events.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continuously through treatment until last patient last visit.
    For this reason, comparison with the historical data will be performed when follow-up is mature enough (median follow-up will be at least 3 years, i.e. at a timepoint which, historically, the vast majority of events have already occurred).
    E.5.2Secondary end point(s)
    1. OS is defined as the time from the date of diagnosis to death from any cause. Patients who are alive will be censored at the date of last follow up. OS will be estimated for the entire study cohort and according to risk group.
    2. The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction (no complete remission at the end of induction) , cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.
    3. The outcome for the entire study cohort and according to risk group will be evaluated in terms of the following protocol specific definition of EFS: the time from diagnosis to resistance to protocol, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up for patients without events. In particular, resistance is defined at the end of the first blinatumomab cycle (while, in the EFS as primary endpoint, resistance is defined at the end of induction to allow the comparison with the historical results of the Interfant-06 protocol). Cumulative incidence (or percentage) of resistance, CIR, death in CR and second malignancy will also be estimated.
    4. MRD response as defined in the protocol and frequencies of MRD levels.
    5. Proportion of CD19 negative relapses in the entire study cohort and according to risk group.
    6. Proportion of myeloid lineage switches in the entire study cohort and according to risk group.
    7. 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.
    8. Proportion of grade ≥2 cardiac disorders (See AESI Table in protocol) at 2 and 5 years after diagnosis
    9. 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Continuously through treatment until last patient last visit.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA125
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Chile
    Hong Kong
    Israel
    Japan
    New Zealand
    Austria
    Finland
    France
    Lithuania
    Poland
    Sweden
    Netherlands
    Spain
    Switzerland
    Czechia
    Germany
    Italy
    Belgium
    Denmark
    Hungary
    Ireland
    Norway
    Portugal
    Slovakia
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 160
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 10
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 150
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Infants
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 160
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No different than the expected normal treatment
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Interfant Study Group
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-05-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-21
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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