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    Clinical Trial Results:
    A pilot study to test the feasibility, safety and efficacy of the addition of the BiTE antibody Blinatumomab to the Interfant-06 backbone in infants with MLL-rearranged acute lymphoblastic leukemia. A collaborative study of the Interfant network.

    Summary
    EudraCT number
    		 2016-004674-17
    Trial protocol
    		 NL   AT   BE   DK   DE   CZ   FR   IT  
    Global end of trial date
    07 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Mar 2025
    First version publication date
    23 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NL59901.078.17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trialregister: NL5993 (= NTR6359)
    Sponsors
    Sponsor organisation name
    Princess Máxima Center for Pediatric Oncology
    Sponsor organisation address
    Heidelberglaan 25, Utrecht, Netherlands, 3584 CS
    Public contact
    Secretariat TDC, Princess Máxima Center for Pediatric Oncology, 0031 889727272, trialmanagement@prinsesmaximacentrum.nl
    Scientific contact
    I.M. van der Sluis, Princess Máxima Center for Pediatric Oncology, 0031 889727272, trialmanagement@prinsesmaximacentrum.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    31 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety of 1 course of blinatumomab added to the Interfant-06 backbone in infants with newly diagnosed ALL.
    Protection of trial subjects
    The interests of the trial subjects are safeguarded by informing the parents verbally and in writing (informed consent), by the possibility of consulting an independent physician, by the possibility of withdrawing from the study without giving reasons, and by following the NVK "Directive on Resistance" and by the monitors involved, monitoring that the trial is conducted, recorded and reported in accordance with the protocol, ICH-GCP and the applicable regulatory requirement(s).
    Background therapy
    		 Chemotherapy according to the Interfant-06 protocol (= Induction (IA), IB, MARMA, OCTADAD and Maintenance).
    Evidence for comparator
    		 Clinical studies show that blinatumomab is effective and well tolerated in children and adults with ALL who are already pre-treated with intensive chemotherapy.
    Actual start date of recruitment
    31 Jul 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    30
    EEA total number of subjects
    22
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    30
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study initiation date/first subject first visit: 31 July 2018 Last Patient in: 05 July 2021 Study completion date/last subject last visit: 07 March 2024 30 subjects enrolled

    Pre-assignment
    Screening details
    		 Newly diagnosed infants with ALL, who are treated according to the Interfant-06 protocol, stratified into the medium or high risk group, and have M1 or M2 marrow at the end of induction (~day 33 bone marrow).

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Blinatumomab
    Arm description
    		 1 course of blinatumomab 15 μg/m2/day as a 4 week continuous infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blinatumomab
    Investigational medicinal product code
    AMG103
    Other name
    Blincyto
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    1 course of blinatumomab 15 μg/m2/day as a 4 week continuous infusion

    Number of subjects in period 1
    		Blinatumomab
    Started
    30
    interim analysis
    30
    Completed
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 30 30
    Age categorical
    Age at diagnosis
    Units: Subjects
        < 3 months
    		 8 8
        3 - 6 months
    		 11 11
        6 - 9 months
    		 6 6
        9 - 12 months
    		 5 5
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 12 12
    Risk Group
    Units: Subjects
        Medium Risk
    		 21 21
        High Risk
    		 9 9
    WBC
    Units: Subjects
        < 100 x 10^9/L
    		 7 7
        ≥ 100 x 10^9/L, <300 x 10^9/L
    		 11 11
        ≥ 300 x 10^9/L
    		 12 12
        Not known
    		 0 0
    Immunophenotype
    Units: Subjects
        B-lineage – CD10 negative
    		 24 24
        B-lineage – CD10 positive
    		 5 5
        B-lineage – CD10 not known
    		 1 1
        Not known
    		 0 0
    CNS-Involvement
    Units: Subjects
        CNS1
    		 9 9
        CNS2
    		 13 13
        CNS3
    		 3 3
        Not evaluable
    		 5 5
    KMT2A-rearrangement
    Units: Subjects
        t(4;11)
    		 15 15
        t(9;11)
    		 3 3
        t(11;19)
    		 6 6
        Other partner
    		 3 3
        Partner not known
    		 3 3
    Prednisone Response
    Units: Subjects
        Prednisone Good Response
    		 23 23
        Prednisone Poor Response
    		 7 7
        Not known
    		 0 0
    End of Induction MRD
    Units: Subjects
        <5x10^-4
    		 18 18
        ≥5x10^-4
    		 12 12

    End points

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    End points reporting groups
    Reporting group title
    Blinatumomab
    Reporting group description
    		 1 course of blinatumomab 15 μg/m2/day as a 4 week continuous infusion

    Subject analysis set title
    Primary - Safety of blinatumomab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence of clinically relevant toxicities defined as any toxicity that is possibly or definitely attributable to blinatumomab AND results in permanent discontinuation of blinatumomab or death.

    Subject analysis set title
    Secondary - Toxicity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incidence and severity of serious adverse events till start of protocol IB, independently to relationship with blinatumomab

    Subject analysis set title
    Secondary - Interruptions due to Blinatumomab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of treatment interruptions due to toxicity occurring during blinatumomab

    Subject analysis set title
    Secondary - Patients with full course of Blinatumomab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Proportion of patients that receive a full course (4 weeks) of blinatumomab

    Subject analysis set title
    Secondary - MRD response TP2, TPBlina1, TPBlina2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MRD response at the following time-points: TP2 d33 (end of induction), TPblina1 d15 (after initial 15 days of blinatumomab) and TPblina2 d29 (after the complete course of blinatumomab)

    Subject analysis set title
    Secondary - MRD response TP4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MRD response at the following time-point: TP4 (end of Protocol IB)

    Subject analysis set title
    Secondary - MRD response in MR patients before OCTADAD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Proportion of MR patients with MRD >= 5x10-4 before OCTADAD (indication for SCT)

    Subject analysis set title
    Secondary - cCR/CR and post-induction EFS/long term EFS/OS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    cCR/CR and 6 months post-induction EFS and the long-term EFS and OS

    Subject analysis set title
    Secondary - MRD response at TP2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MRD response at the following time-point: TP2 d33 (end of induction)

    Subject analysis set title
    Secondary - MRD response at TP4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MRD response at the following time-point: TP4 (end of Protocol IB)

    Subject analysis set title
    Secondary - MRD response TPBlina1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MRD response at the following time-point: TPblina1 d15 (after initial 15 days of blinatumomab)

    Subject analysis set title
    Secondary - MRD response TPBlina2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MRD response at the following time-point: TPblina2 d29 (after the complete course of blinatumomab)

    Primary: Safety

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    End point title
    		 Safety [1]
    End point description
    Incidence of clinically relevant toxicities defined as any toxicity that is possibly or definitely attributable to blinatumomab AND results in permanent discontinuation of blinatumomab OR death.
    End point type
    Primary
    End point timeframe
    From start of blinatumomab till start of chemotherapy according to protocol IB.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The incidence of clinically relevant toxicities defined as any toxicity that is possibly or definitely attributable to blinatumomab AND results in permanent discontinuation of blinatumomab OR death will be described as percentage of patients and also estimated with the exposure-adjusted incidence rate, calculated as the ratio between the number of these adverse events and the total time at risk form study entry, in weeks. In addition, incidence of death will be calculated.
    End point values
    		 Primary - Safety of blinatumomab
    Number of subjects analysed
    30
    Units: toxic effects
        permanent discontinuation of blinatumomab
    0
        death
    0
    No statistical analyses for this end point

    Secondary: Toxicity - SAEs

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    End point title
    		 Toxicity - SAEs
    End point description
    Incidence and severity of serious adverse events till start of protocol IB, independently to relationship with blinatumomab
    End point type
    Secondary
    End point timeframe
    From start of blinatumomab until start of protocol IB
    End point values
    		 Secondary - Toxicity
    Number of subjects analysed
    30
    Units: toxic events
        No. of adverse events of any grade
    61
        No. of adverse events of CTCAE grade⩾3
    16
        No. of serious adverse events
    10
    No statistical analyses for this end point

    Secondary: MRD response - TP2, TPBlina1 and TPBlina2

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    End point title
    		 MRD response - TP2, TPBlina1 and TPBlina2
    End point description
    MRD response at the following time-points: TP2 d33 (end of induction), TPblina1 d15 (after initial 15 days of blinatumomab) and TPblina2 d29 (after the complete course of blinatumomab)
    End point type
    Secondary
    End point timeframe
    From start to end of Blinatumomab course
    End point values
    		 Secondary - MRD response at TP2 Secondary - MRD response TPBlina1 Secondary - MRD response TPBlina2
    Number of subjects analysed
    30
    30
    30
    Units: MRD
        MRD Negative
    8
    16
    16
        MRD < 5x10-4
    10
    11
    12
        MRD ≥ 5 x10-4
    12
    3
    2
    No statistical analyses for this end point

    Secondary: Toxicity - treatment interruptions

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    End point title
    		 Toxicity - treatment interruptions
    End point description
    Number of treatment interruptions due to toxicity occurring during blinatumomab
    End point type
    Secondary
    End point timeframe
    Blinatumomab course
    End point values
    		 Secondary - Interruptions due to Blinatumomab
    Number of subjects analysed
    30
    Units: Number of times
        Blinatumomab Discontinuation
    0
    No statistical analyses for this end point

    Secondary: Toxicity - Patients who received full course of Blinatumomab

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    End point title
    		 Toxicity - Patients who received full course of Blinatumomab
    End point description
    Proportion of patients that receive a full course (4 weeks) of blinatumomab
    End point type
    Secondary
    End point timeframe
    During Blinatumomab course
    End point values
    		 Secondary - Patients with full course of Blinatumomab
    Number of subjects analysed
    30
    Units: Number of patients
        Patients who received full blinatumomab course
    30
    No statistical analyses for this end point

    Secondary: MRD response - TP2 and TP4

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    End point title
    		 MRD response - TP2 and TP4
    End point description
    MRD response at the following time-points: TP2 d33 (end of induction) and TP4 (end of Protocol IB)
    End point type
    Secondary
    End point timeframe
    From Blinatumomab until the end of Protocol Ib
    End point values
    		 Secondary - MRD response at TP2 Secondary - MRD response at TP4
    Number of subjects analysed
    30
    28
    Units: Number of patients
        MRD Negative
    8
    15
        MRD Positive < 5x10-4
    10
    11
        MRD Positive ≥ 5x10-4
    12
    2
    No statistical analyses for this end point

    Secondary: MRD Response before OCTADAD/HSCT

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    End point title
    		 MRD Response before OCTADAD/HSCT
    End point description
    Proportion of MR patients with MRD ≥ 5x10^-4 before OCTADAD (indication for SCT)
    End point type
    Secondary
    End point timeframe
    Before the start of OCTADAD
    End point values
    		 Secondary - MRD response in MR patients before OCTADAD
    Number of subjects analysed
    24
    Units: Number of patients
        MRD before OCTADAD/HSCT ≥ 5x10-4
    0
    No statistical analyses for this end point

    Secondary: cCR/CR and 6 months post-induction EFS and long term EFS and OS

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    End point title
    		 cCR/CR and 6 months post-induction EFS and long term EFS and OS
    End point description
    cCR/CR and 6 months post-induction EFS and the long-term EFS and OS
    End point type
    Secondary
    End point timeframe
    From enrollment until 31 August 2022
    End point values
    		 Secondary - cCR/CR and post-induction EFS/long term EFS/OS
    Number of subjects analysed
    30
    Units: Number of events
        Relapse
    4
        Death
    2
        Progressive disease
    0
        Secondary malignancy
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of blinatumomab till start of chemotherapy according to protocol IB.
    Adverse event reporting additional description
    As for the Interfant-06 study, AEs occurring in each treatment phase are reported with the Toxicity Form. During blinatumomab until start protocol IB all AEs grades are reported with the exception of non-reportable AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    (S)AEs from start of blinatumomab until start of protocol IB
    Reporting group description
    		 Patients who had the same adverse event multiple times were counted once, and the highest grade is reported. If a patient had episodes in different adverse event categories, it is counted in each category. CTCAE denotes Common Terminology Criteria for Adverse Events. Only AEs with CTCAE grade >= 3 are mentioned here. Fever of grade 1 occurred twice in one patient.

    Serious adverse events
    		 (S)AEs from start of blinatumomab until start of protocol IB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 30 (30.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
    Additional description: Grade 3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
    Additional description: Grade 1
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
    Additional description: Grade 3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Line infection
    Additional description: Grade 3
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper Respiratory infection
    Additional description: Grade 4
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
    Additional description: Grade 3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 (S)AEs from start of blinatumomab until start of protocol IB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 30 (53.33%)
    Vascular disorders
    Hypertension
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    10
    Febrile neutropenia
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Decreased neutrophil count
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Decreased white-cell count
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    Hepatobiliary disorders
    Increased alanine aminotransferase level
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Increased γ-glutamyltransferase level
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Infections and infestations
    Pharyngitis
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypoproteinemia
    Additional description: Adverse events of CTCAE grade ≥3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2019
    Protocol amendment no. 1: Editorial changes and changes for clarification; Corrections and changes in contact details; Change in Principal investigator(s) DCOG (NL) and Sponsor representative; Additional information about blinatumomab approvals for new indication; Change of estimated study duration and timelines; Correction of exclusion criteria before start (-d3) of blinatumomab; Correction MRD measurement.
    09 Apr 2021
    Amendment no. 2: Investigator's Brochure with relevant RSI update

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37099340
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