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    Clinical Trial Results:
    A Randomized, Open-label, Controlled Phase 3 Trial to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With High-risk First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)

    Summary
    EudraCT number
    		 2014-002476-92
    Trial protocol
    		 DE   CZ   BE   IT   SE   PT   DK   AT   GB   PL   ES   FR   NL   Outside EU/EEA   GR   NO   HU   RO  
    Global end of trial date
    21 Nov 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Jun 2023
    First version publication date
    19 May 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    20120215
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02393859
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
    Scientific contact
    Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000574-PIP02-12
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy.
    Protection of trial subjects
    The study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice and applicable national or regional regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 7
    Worldwide total number of subjects
    111
    EEA total number of subjects
    97
    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)
    3
    Children (2-11 years)
    88
    Adolescents (12-17 years)
    20
    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
    		 This study was conducted at 48 centers across 13 countries (Europe, Australia, Israel). The first participant was enrolled on 10 November 2015. The last participant enrolled on 30 August 2019. The primary completion date was 17 July 2019 and the study completion date was 21 November 2022.

    Pre-assignment
    Screening details
    		 After a 3-week screening period, participants were enrolled and randomized 1:1 into 1 of 2 treatment groups: High Risk Consolidation 3 (HC3) chemotherapy or blinatumomab. Randomization was stratified by age and bone marrow/minimal residual disease (MRD) status.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HC3 Chemotherapy
    Arm description
    		 One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SOC chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use, Intramuscular use
    Dosage and administration details
    The standard intensive consolidation chemotherapy course HC3 included dexamethasone (10 mg/m^2/day IV on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and PEG-asparaginase (1000 U/m^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).

    Arm title
    		 Blinatumomab
    Arm description
    		 One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blinatumomab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Blinatumomab was administered as CIVI at a constant daily flow rate of 15 µg/m^2/day over 4 weeks (1 cycle).

    Number of subjects in period 1
    		HC3 Chemotherapy Blinatumomab
    Started
    57
    54
    Participants Treated
    52
    54
    Primary analysis population
    54
    54
    Final analysis population
    57
    54
    Completed
    16
    33
    Not completed
    41
    21
         Adverse event, serious fatal
    27
    10
         Consent withdrawn by subject
    11
    6
         Decision by Sponsor
    2
    4
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HC3 Chemotherapy
    Reporting group description
    		 One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).

    Reporting group title
    Blinatumomab
    Reporting group description
    		 One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI).

    Reporting group values
    		 HC3 Chemotherapy Blinatumomab Total
    Number of subjects
    		 57 54 111
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.6 ( 4.3 ) 7.3 ( 4.4 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 34 24 58
        Male
    		 23 30 53
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 1 4
        Not Hispanic or Latino
    		 54 53 107
        Unknown or Not Reported
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 46 50 96
        Other, Not Specified
    		 5 3 8
        Asian
    		 3 1 4
        Black or African American
    		 3 0 3
    Stratification Factor: Marrow/Minimal Residual Disease (MRD)
    M1: representative bone marrow aspirate or biopsy with blasts < 5%, with satisfactory cellularity and with regenerating hematopoiesis; M2: Representative bone marrow aspirate or biopsy with ≥ 5% and < 25% blasts; MRD=minimal residual disease levels ≥ 10^-3 or < 10^-3, by polymerase chain reaction (PCR) or flow cytometry.
    Units: Subjects
        M1 Marrow + MRD level ≥ 10^-3
    		 17 15 32
        M1 Marrow + MRD level < 10^-3
    		 36 35 71
        M2 Marrow
    		 4 4 8
    Stratification Factor: Age Category
    Units: Subjects
        1 to 9 years
    		 41 39 80
        Other (< 1 year and > 9 years)
    		 16 15 31

    End points

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    End points reporting groups
    Reporting group title
    HC3 Chemotherapy
    Reporting group description
    		 One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).

    Reporting group title
    Blinatumomab
    Reporting group description
    		 One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI).

    Subject analysis set title
    HC3 Chemotherapy (Primary Analysis)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in the full analysis set at the primary completion date randomized to HC3 chemotherapy. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).

    Subject analysis set title
    Blinatumomab (Primary Analysis)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in the full analysis set at the primary completion date randomized to blinatumomab

    Primary: Kaplan Meier Estimate: EFS (Primary Analysis)

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    End point title
    		 Kaplan Meier Estimate: EFS (Primary Analysis)
    End point description
    EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with investigational product (IP) or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: M1 marrow, peripheral blood without blasts, absence of extramedullary leukemic involvement. Full analysis set (FAS): randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (primary analysis population). 99999 = data was not estimable.
    End point type
    Primary
    End point timeframe
    As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.
    End point values
    		 HC3 Chemotherapy (Primary Analysis) Blinatumomab (Primary Analysis)
    Number of subjects analysed
    54
    54
    Units: months
        median (confidence interval 95%)
    7.4 (4.5 to 12.7)
    99999 (12.0 to 99999)
    Statistical analysis title
    		 Stratified log-rank test
    Comparison groups
    HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Stratified log-rank test
    Confidence interval
    Notes
    [1] - Normal score = -11.54 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.)
    [2] - Stratification factors were: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2).
    Statistical analysis title
    		 Stratified HR with time-dependent covariate
    Statistical analysis description
    Cox proportional hazard model including time from randomization to allogeneic hematopoietic stem cell transplant. Stratification factors: age and marrow/MRD status. (HR <1.0=lower average event rate and longer EFS for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Stratified HR
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.64
    Statistical analysis title
    		 Unstratified HR
    Statistical analysis description
    Cox proportional hazard model. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Unstratified HR
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.7
    Statistical analysis title
    		 Unstratified log-rank test
    Comparison groups
    HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.001
    Method
    		 Unstratified log-rank test
    Confidence interval
    Notes
    [3] - Normal score: -11.16. (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.)
    Statistical analysis title
    		 Stratified hazard ratio (HR)
    Statistical analysis description
    Cox proportional hazard model. Stratification factors were: age and marrow/MRD status. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy (Primary Analysis) v Blinatumomab (Primary Analysis)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Stratified HR
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.66

    Primary: Kaplan Meier Estimate: EFS (Final Analysis)

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    End point title
    		 Kaplan Meier Estimate: EFS (Final Analysis)
    End point description
    EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a CR, failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with IP or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: M1 marrow, peripheral blood without blasts, absence of extramedullary leukemic involvement. FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (final analysis population). 99999 = data was not estimable.
    End point type
    Primary
    End point timeframe
    At final analysis, overall median follow-up time for EFS was 51.9 months.
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    57
    54
    Units: months
        median (confidence interval 95%)
    7.8 (5.8 to 13.4)
    99999 (24.8 to 99999)
    Statistical analysis title
    		 Stratified log-rank test
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001 [5]
    Method
    		 Stratified log-rank test
    Confidence interval
    Notes
    [4] - Normal score: -13.90 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.)
    [5] - Stratification factors were: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2).
    Statistical analysis title
    		 Unstratified log-rank test
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 Unstratified log-rank test
    Confidence interval
    Notes
    [6] - Normal score: -13.61 (A normal score < 0 indicates fewer than expected events for Blinatumomab relative to HC3 and therefore a longer event free survival time.)
    Statistical analysis title
    		 Unstratified HR
    Statistical analysis description
    Cox proportional hazard model. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Unstratified HR
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.65
    Statistical analysis title
    		 Stratified HR with time-dependent covariate
    Statistical analysis description
    Cox proportional hazard model including time from randomization to allogeneic hematopoietic stem cell transplant. Stratification factors: age and marrow/MRD status. (HR <1.0=lower average event rate and longer EFS for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Stratified HR
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.59
    Statistical analysis title
    		 Stratified HR
    Statistical analysis description
    Cox proportional hazard model. Stratification factors were: age and marrow/MRD status. (HR < 1.0 indicates a lower average event rate and a longer EFS for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Stratified HR
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.61

    Secondary: Kaplan Meier Estimate: Overall Survival (OS)

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    End point title
    		 Kaplan Meier Estimate: Overall Survival (OS)
    End point description
    OS was calculated from time of randomization until death due to any cause. Participants still alive were censored at the date they were last known to be alive. FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received. 99999 = data was not estimable.
    End point type
    Secondary
    End point timeframe
    At final analysis, overall median follow-up time for OS was 55.2 months.
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    57
    54
    Units: months
        median (confidence interval 95%)
    25.6 (17.5 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Stratified log-rank test
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.001 [8]
    Method
    		 Stratified log-rank test
    Confidence interval
    Notes
    [7] - Normal score: -10.14 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.)
    [8] - Stratification factors were: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2).
    Statistical analysis title
    		 Unstratified HR
    Statistical analysis description
    Cox proportional hazard model. (HR < 1.0 indicates a lower average event rate and a longer survival for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Unstratified HR
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.65
    Statistical analysis title
    		 Stratified HR
    Statistical analysis description
    Cox proportional hazard model. Stratification factors were: age and marrow/MRD status. (HR < 1.0 indicates a lower average event rate and a longer survival for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Stratified HR
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.66
    Statistical analysis title
    		 Unstratified log-rank test
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001
    Method
    		 Unstratified log-rank test
    Confidence interval
    Notes
    [9] - Normal score: -10.32 (A normal score < 0 indicates fewer than expected events for blinatumomab relative to HC3 and therefore a longer event-free survival time.)

    Secondary: Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation

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    End point title
    		 Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation
    End point description
    At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. MRD response was defined as MRD level < 10^-4, by polymerase chain reaction (PCR) or flow cytometry, at the end of treatment (Cycle 1 Day 29) with study drug. Participants who were part of the MRD Evaluable Set and were missing the end of treatment (Cycle 1 Day 29) assessment for a respective MRD assessment method were considered not to have achieved a response. MRD Evaluable Set: participants for whom an evaluable baseline MRD marker can be found with either of the MRD assessment methods of PCR or flow cytometry.
    End point type
    Secondary
    End point timeframe
    Up to End of Treatment (Cycle 1, Day 29)
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    56
    54
    Units: percentage of participants
    number (confidence interval 95%)
        MRD Response by PCR (N=49; 49)
    53.1 (38.3 to 67.5)
    93.9 (83.1 to 98.7)
        MRD Response by Flow Cytometry (N=55; 54)
    60.0 (45.9 to 73.0)
    92.6 (82.1 to 97.9)
    Statistical analysis title
    		 MRD response by flow cytometry
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [10] - Cochran-Mantel-Haenszel test adjusting for the stratification factors: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10-3 vs M1 with MRD level ≥ 10-3 vs M2).
    Statistical analysis title
    		 MRD response by PCR
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [11] - Cochran-Mantel-Haenszel test adjusting for the stratification factors: age (1 to 9 years vs other [< 1 year and > 9 years]), and marrow/MRD status (M1 with MRD level < 10^-3 vs M1 with MRD level ≥ 10^-3 vs M2).

    Secondary: Cumulative Incidence of Relapse (CIR)

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    End point title
    		 Cumulative Incidence of Relapse (CIR)
    End point description
    CIR estimate, presented as median months to relapse, calculated from date of achievement of first CR, using the cumulative incidence method (Fine JP, Gray RJ:1999). Deaths prior to relapse not considered related to an otherwise undocumented relapse were treated as a competing risk. Participants still alive without a date of relapse were censored at the time of last follow-up. Relapse=presence of ≥1 of the following: isolated bone marrow relapse (M3 marrow [representative bone marrow aspirate or biopsy with ≥25% blasts] in the absence of extramedullary involvement), combined bone marrow relapse (M2 or M3 marrow and ≥1 extramedullary manifestation of acute lymphoblastic leukemia), central nervous system extramedullary relapse, testicular extramedullary relapse, extramedullary relapse at other sites. FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received. 99999 = data was not estimable.
    End point type
    Secondary
    End point timeframe
    At final analysis, the overall maximum follow-up time was 82.0 months.
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    57
    54
    Units: months
        median (confidence interval 95%)
    7.9 (5.8 to 18.6)
    99999 (99999 to 99999)
    Statistical analysis title
    		 HR
    Statistical analysis description
    The subdistribution HR estimates are obtained from the subdistribution Cox model. (HR < 1.0 indicates a lower average event rate and a longer relapse-free time for blinatumomab relative to HC3.)
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.52
    Statistical analysis title
    		 Stratified HR
    Statistical analysis description
    The subdistribution HR estimates are obtained from the subdistribution Cox model. (HR < 1.0 indicates a lower average event rate and a longer relapse-free time for blinatumomab relative to HC3.) Stratification factors are age and marrow/MRD status.
    Comparison groups
    HC3 Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Stratified HR
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.48

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)
    End point description
    Adverse event (AE): any untoward medical occurrence. Serious AE: an AE meeting at least 1 of the following serious criteria: fatal; life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Severity was graded according to the Common Terminology Criteria for AEs (CTCAE) version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Investigational product (IP) in the HC3 arm refers to dexamethasone, methotrexate, daunorubicin, erwinase, ifosfamide, asparaginase, and vincristine, and in the blinatumomab arm refers to blinatumomab. Treatment-related refers to the assessment of a relationship between IP and the event. Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received.
    End point type
    Secondary
    End point timeframe
    From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    52
    54
    Units: participants
        TEAEs
    50
    54
        TEAEs Grade ≥ 3
    43
    33
        Serious TEAEs
    24
    15
        Fatal TEAEs
    0
    0
        TEAEs Leading to Discontinuation of IP
    0
    2
        TEAEs Leading to Interruption of IP
    2
    6
        TRAEs
    41
    45
        TRAEs Grade ≥ 3
    33
    9
        Serious TRAEs
    15
    9
        Fatal TRAEs
    0
    0
        TRAEs Leading to Discontinuation of IP
    0
    2
        TRAEs Leading to Interruption of IP
    2
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With TEAEs of Interest

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    End point title
    		 Number of Participants With TEAEs of Interest
    End point description
    TEAEs of interest included capillary leak syndrome (CLS), cytokine release syndrome (CRS), decreased immunoglobulins (DI), elevated liver enzymes (ELE), embolic and thrombotic events (ETE), infections (INF), infusion reactions without considering duration (IRWCD), medication errors (ME), neurologic events (NE), neutropenia and febrile neutropenia (NFN), pancreatitis (PNC), tumor lysis syndrome, leukoencephalopathy, immunogenicity. Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received.
    End point type
    Secondary
    End point timeframe
    From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    52
    54
    Units: participants
        CLS Events
    1
    0
        CLS Events Grade ≥ 3
    1
    0
        Serious CLS Events
    1
    0
        Fatal CLS Events
    0
    0
        CLS Events Leading to Discontinuation of IP
    0
    0
        CLS Events Leading to Interruption of IP
    0
    0
        CRS Events
    1
    2
        CRS Events Grade ≥ 3
    0
    0
        Serious CRS Events
    0
    0
        Fatal CRS Events
    0
    0
        CRS Events Leading to Discontinuation of IP
    0
    0
        CRS Events Leading to Interruption of IP
    0
    0
        DI Events
    6
    9
        DI Events Grade ≥ 3
    1
    1
        Serious DI Events
    0
    1
        Fatal DI Events
    0
    0
        DI Events Leading to Discontinuation of IP
    0
    0
        DI Events Leading to Interruption of IP
    0
    0
        ELE Events
    15
    7
        ELE Events Grade ≥ 3
    9
    3
        Serious ELE Events
    1
    0
        Fatal ELE Events
    0
    0
        ELE Events Leading to Discontinuation of IP
    0
    0
        ELE Events Leading to Interruption of IP
    0
    0
        ETE Events
    0
    4
        ETE Events Grade ≥ 3
    0
    2
        Serious ETE Events
    0
    0
        Fatal ETE Events
    0
    0
        ETE Events Leading to Discontinuation of IP
    0
    0
        ETE Events Leading to Interruption of IP
    0
    0
        INF Events
    18
    25
        INF Events Grade ≥ 3
    6
    11
        Serious INF events
    6
    4
        Fatal INF Events
    0
    0
        IFN Events Leading to Discontinuation of IP
    0
    0
        IFN Events Leading to Interruption of IP
    0
    0
        IRWCD Events
    4
    37
        IRWCD Events Grade ≥ 3
    0
    2
        Serious IRWCD Events
    0
    1
        Fatal IRWCD Events
    0
    0
        IRWCD Events Leading to Discontinuation of IP
    0
    0
        IRWCD Events Leading to Interruption of IP
    0
    0
        ME Events
    0
    1
        ME Events Grade ≥ 3
    0
    0
        Serious ME Events
    0
    1
        Fatal ME Events
    0
    0
        ME Events Leading to Discontinuation of IP
    0
    0
        ME Events Leading to Interruption of IP
    0
    1
        NE Events
    15
    26
        NE Events Grade ≥ 3
    1
    3
        Serious NE Events
    1
    5
        Fatal NE Events
    0
    0
        NE Events Leading to Discontinuation of IP
    0
    2
        NE Events Leading to Interruption of IP
    1
    3
        NFN events
    28
    12
        NFN Events Grade ≥ 3
    27
    11
        Serious NFN Events
    12
    0
        Fatal NFN Events
    0
    0
        NFN Events Leading to Discontinuation of IP
    0
    0
        NFN Events Leading to Interruption of IP
    0
    0
        PNC Events
    1
    0
        PNC Events Grade ≥ 3
    1
    0
        Serious PNC Events
    1
    0
        Fatal PNC Events
    0
    0
        PNC Events Leading to Discontinuation of IP
    0
    0
        PNC Events Leading to Interruption of IP
    0
    0
        Tumour Lysis Syndrome Events
    0
    0
        Leukoencephalopathy Events
    0
    0
        Immunogenicity Events
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values

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    End point title
    		 Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values
    End point description
    Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Increases (↑) or decreases (↓) in laboratory value grades (Gr) from baseline (BL) to worst postbaseline (→ PB) grade are presented. NA=not available. Safety Analysis Set: who received protocol-specified therapy analyzed according to the treatment they received.
    End point type
    Secondary
    End point timeframe
    Up to Day 29 (± 2 days)
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    52
    54
    Units: participants
        Potassium ↑ BL Gr 0 → PB Gr 3
    0
    1
        Potassium ↓ BL Gr 0 → PB Gr 3
    4
    5
        Potassium ↓ BL Gr 0 → PB Gr 4
    1
    1
        Albumin ↓ BL Gr 0 → PB Gr 3
    0
    1
        Calcium ↓ BL Gr 0 → PB Gr 4
    1
    1
        Alanine Aminotransferase ↑ BL Gr 0 → PB Gr 3
    1
    0
        Alanine Aminotransferase ↑ BL Gr 1 → PB Gr 3
    9
    5
        Aspartate Aminotransferase ↑ BL Gr NA → PB Gr 3
    1
    0
        Aspartate Aminotransferase ↑ BL Gr 0 → PB Gr 3
    2
    0
        Aspartate Aminotransferase ↑ BL Gr 1 → PB Gr 3
    5
    1
        Aspartate Aminotransferase ↑ BL Gr 1 → PB Gr 4
    1
    0
        Gamma-Glutamyl Transferase ↑ BL Gr NA → PB Gr 3
    0
    1
        Gamma-Glutamyl Transferase ↑ BL Gr 0 → PB Gr 3
    3
    4
        Gamma-Glutamyl Transferase ↑ BL Gr 1 → PB Gr 3
    6
    2
        Gamma-Glutamyl Transferase ↑ BL Gr 1 → PB Gr 4
    0
    3
        Amylase ↑ BL Gr 0 → PB Gr 3
    1
    1
        Amylase ↑ BL Gr 0 → PB Gr 4
    1
    0
        Amylase ↑ BL Gr 1 → PB Gr 3
    0
    1
        Lipase ↑ BL Gr 0 → PB Gr 3
    3
    2
        Lipase ↑ BL Gr 0 → PB Gr 4
    1
    2
        Bilirubin ↑ BL Gr 0 → PB Gr 3
    2
    1
        Bilirubin ↑ BL Gr 0 → PB Gr 4
    1
    0
        Creatinine ↑ BL Gr NA → PB Gr 3
    0
    2
        Hemoglobin ↓ BL Gr 0 → PB Gr 3
    1
    0
        Hemoglobin ↓ BL Gr 1 → PB Gr 3
    4
    1
        Platelets ↓ BL Gr 0 → PB Gr 3
    7
    6
        Platelets ↓ BL Gr 0 → PB Gr 4
    13
    6
        Platelets ↓ BL Gr 1 → PB Gr 3
    1
    2
        Platelets ↓ BL Gr 1 → PB Gr 4
    8
    2
        Leukocytes ↓ BL Gr 0 → PB Gr 3
    2
    0
        Leukocytes ↓ BL Gr 0 → PB Gr 4
    4
    0
        Leukocytes ↓ BL Gr 1 → PB Gr 3
    4
    4
        Leukocytes ↓ BL Gr 1 → PB Gr 4
    7
    1
        Neutrophils ↓ BL Gr 0 → PB Gr 3
    4
    11
        Neutrophils ↓ BL Gr 0 → PB Gr 4
    23
    3
        Lymphocytes ↑ BL Gr 0 → PB Gr 3
    0
    1
        Lymphocytes ↓ BL Gr 0 → PB Gr 3
    1
    3
        Lymphocytes ↓ BL Gr 0 → PB Gr 4
    1
    1
        Lymphocytes ↓ BL Gr 1 → PB Gr 3
    0
    1
        Lymphocytes ↓ BL Gr 1 → PB Gr 4
    1
    2
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)

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    End point title
    		 Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)
    End point description
    The analysis of 100-day mortality after alloHSCT was assessed for participants who received an alloHSCT while in remission and did not receive any additional anti-leukemic treatment. 100-day mortality after alloHSCT was calculated relative to the date of alloHSCT. The 100-day mortality rate after alloHSCT was defined as the percentage of participants having died up to 100 days after alloHSCT, estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive were censored at the date they were last known to be alive. HSCT Analysis Set: participants who underwent an HSCT while in remission without any other anti-leukemic therapy.
    End point type
    Secondary
    End point timeframe
    From the date of alloHSCT until death/censor date; median follow up time was 1742.0 days for blinatumomab and 1619.0 days for HC3.
    End point values
    		 HC3 Chemotherapy Blinatumomab
    Number of subjects analysed
    39
    51
    Units: percentage of participants
        number (confidence interval 95%)
    5.1 (1.3 to 19.0)
    3.9 (1.0 to 14.8)
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only)

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    End point title
    		 Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only) [12]
    End point description
    Participants receiving blinatumomab had blood samples analyzed for binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. Participants who were binding antibody-positive or neutralizing antibody-positive post-baseline with a negative or no result at baseline are presented. Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received. Participants in the blinatumumab arm with a post-baseline result.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 29
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The secondary endpoint assessed anti-blinatumomab antibodies in participants assigned to the blinatumomab arm only.
    End point values
    		 Blinatumomab
    Number of subjects analysed
    52
    Units: participants
        Binding Antibody Positive
    0
        Neutralizing Antibody Positive
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Concentration of Blinatumomab at Steady State (Css) (Blinatumomab arm only)

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    End point title
    		 Pharmacokinetics: Concentration of Blinatumomab at Steady State (Css) (Blinatumomab arm only) [13]
    End point description
    Pharmacokinetic (PK) Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected.
    End point type
    Secondary
    End point timeframe
    Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The secondary endpoint assessed blinatumomab pharmacokinetics in participants assigned to the blinatumomab arm only.
    End point values
    		 Blinatumomab
    Number of subjects analysed
    45
    Units: pg/mL
        arithmetic mean (standard deviation)
    884 ( 969 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Clearance (CL) of Blinatumomab (Blinatumomab arm only)

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    End point title
    		 Pharmacokinetics: Clearance (CL) of Blinatumomab (Blinatumomab arm only) [14]
    End point description
    PK Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected
    End point type
    Secondary
    End point timeframe
    Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The secondary endpoint assessed blinatumomab pharmacokinetics in participants assigned to the blinatumomab arm only.
    End point values
    		 Blinatumomab
    Number of subjects analysed
    45
    Units: L/hr/m^2
        arithmetic mean (standard deviation)
    1.14 ( 0.836 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality is reported from randomization through the end of study; the median overall follow-up time was 55.2 months. Treatment-emergent adverse events are reported from first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
    Adverse event reporting additional description
    All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Blinatumomab
    Reporting group description
    		 One 4-week cycle of blinatumomab 15 μg/m^2/day as a continuous intravenous infusion (CIVI).

    Reporting group title
    HC3 Chemotherapy
    Reporting group description
    		 One week of treatment with HC3 followed by 3 weeks of no treatment.

    Serious adverse events
    		 Blinatumomab HC3 Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 54 (27.78%)
    24 / 52 (46.15%)
         number of deaths (all causes)
    11
    27
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B precursor type acute leukaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Capillary leak syndrome
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter placement
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Engraftment syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neurological examination abnormal
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood immunoglobulin G decreased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 54 (0.00%)
    9 / 52 (17.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal cellulitis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngotracheitis obstructive
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Blinatumomab HC3 Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 54 (100.00%)
    48 / 52 (92.31%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 54 (11.11%)
    4 / 52 (7.69%)
         occurrences all number
    6
    5
    Hypertension
         subjects affected / exposed
    7 / 54 (12.96%)
    4 / 52 (7.69%)
         occurrences all number
    9
    4
    Haematoma
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    43 / 54 (79.63%)
    10 / 52 (19.23%)
         occurrences all number
    69
    12
    Pain
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Mucosal inflammation
         subjects affected / exposed
    9 / 54 (16.67%)
    4 / 52 (7.69%)
         occurrences all number
    10
    4
    Fatigue
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 52 (3.85%)
         occurrences all number
    3
    2
    Immune system disorders
    Immunodeficiency
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 52 (0.00%)
         occurrences all number
    6
    0
    Hypogammaglobulinaemia
         subjects affected / exposed
    6 / 54 (11.11%)
    2 / 52 (3.85%)
         occurrences all number
    7
    2
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 52 (5.77%)
         occurrences all number
    2
    4
    Epistaxis
         subjects affected / exposed
    5 / 54 (9.26%)
    7 / 52 (13.46%)
         occurrences all number
    6
    8
    Cough
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 52 (1.92%)
         occurrences all number
    5
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 52 (1.92%)
         occurrences all number
    5
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 54 (7.41%)
    7 / 52 (13.46%)
         occurrences all number
    6
    19
    White blood cell count decreased
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 52 (1.92%)
         occurrences all number
    7
    4
    Platelet count decreased
         subjects affected / exposed
    7 / 54 (12.96%)
    8 / 52 (15.38%)
         occurrences all number
    9
    17
    Neutrophil count decreased
         subjects affected / exposed
    5 / 54 (9.26%)
    2 / 52 (3.85%)
         occurrences all number
    8
    4
    Fluid balance positive
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 52 (5.77%)
         occurrences all number
    4
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 54 (3.70%)
    5 / 52 (9.62%)
         occurrences all number
    3
    11
    Antithrombin III decreased
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 52 (5.77%)
         occurrences all number
    2
    6
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    2 / 54 (3.70%)
    4 / 52 (7.69%)
         occurrences all number
    2
    4
    Nervous system disorders
    Tremor
         subjects affected / exposed
    5 / 54 (9.26%)
    0 / 52 (0.00%)
         occurrences all number
    5
    0
    Headache
         subjects affected / exposed
    20 / 54 (37.04%)
    8 / 52 (15.38%)
         occurrences all number
    28
    13
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 54 (5.56%)
    4 / 52 (7.69%)
         occurrences all number
    3
    5
    Anaemia
         subjects affected / exposed
    13 / 54 (24.07%)
    24 / 52 (46.15%)
         occurrences all number
    16
    46
    Leukopenia
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    7
    Thrombocytopenia
         subjects affected / exposed
    4 / 54 (7.41%)
    11 / 52 (21.15%)
         occurrences all number
    9
    18
    Neutropenia
         subjects affected / exposed
    5 / 54 (9.26%)
    13 / 52 (25.00%)
         occurrences all number
    8
    18
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 54 (42.59%)
    9 / 52 (17.31%)
         occurrences all number
    37
    9
    Diarrhoea
         subjects affected / exposed
    12 / 54 (22.22%)
    9 / 52 (17.31%)
         occurrences all number
    17
    11
    Constipation
         subjects affected / exposed
    5 / 54 (9.26%)
    7 / 52 (13.46%)
         occurrences all number
    9
    9
    Abdominal pain upper
         subjects affected / exposed
    4 / 54 (7.41%)
    4 / 52 (7.69%)
         occurrences all number
    5
    4
    Abdominal pain
         subjects affected / exposed
    7 / 54 (12.96%)
    11 / 52 (21.15%)
         occurrences all number
    9
    16
    Anal inflammation
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 52 (3.85%)
         occurrences all number
    4
    2
    Vomiting
         subjects affected / exposed
    17 / 54 (31.48%)
    11 / 52 (21.15%)
         occurrences all number
    27
    16
    Stomatitis
         subjects affected / exposed
    11 / 54 (20.37%)
    27 / 52 (51.92%)
         occurrences all number
    11
    44
    Oral pain
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 52 (5.77%)
         occurrences all number
    1
    4
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    4 / 52 (7.69%)
         occurrences all number
    1
    7
    Hepatotoxicity
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0
    Rash
         subjects affected / exposed
    7 / 54 (12.96%)
    5 / 52 (9.62%)
         occurrences all number
    9
    5
    Pruritus
         subjects affected / exposed
    6 / 54 (11.11%)
    5 / 52 (9.62%)
         occurrences all number
    7
    5
    Petechiae
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 52 (1.92%)
         occurrences all number
    4
    1
    Erythema
         subjects affected / exposed
    6 / 54 (11.11%)
    2 / 52 (3.85%)
         occurrences all number
    6
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 54 (5.56%)
    5 / 52 (9.62%)
         occurrences all number
    3
    5
    Arthralgia
         subjects affected / exposed
    0 / 54 (0.00%)
    4 / 52 (7.69%)
         occurrences all number
    0
    4
    Pain in extremity
         subjects affected / exposed
    2 / 54 (3.70%)
    5 / 52 (9.62%)
         occurrences all number
    2
    5
    Infections and infestations
    Paronychia
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0
    Rhinitis
         subjects affected / exposed
    1 / 54 (1.85%)
    5 / 52 (9.62%)
         occurrences all number
    1
    5
    Nasopharyngitis
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    6 / 54 (11.11%)
    5 / 52 (9.62%)
         occurrences all number
    6
    6
    Hypervolaemia
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0
    Decreased appetite
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2015
    - modified exclusion criteria to clarify that participants with abnormal serum creatinine were to be excluded from the study - added measures to prevent and/or minimize pain and discomfort during blood draws - added measures to minimize the blood volumes drawn during the study
    29 Sep 2015
    - added prophylactic intrathecal hydrocortisone as an alternative to prednisolone to allow the United Kingdom and Australia to participate in the study - changed distribution of sites participating in the study (New Zealand was removed) - changed the time period for administration of intrathecal prophylaxis to align with best medical practice for the standard of care arm - added "cumulative incidence of relapse" to secondary endpoints - clarified that MRD aliquots for PCR and/or flow cytometry that were to be collected at screening, Day 15 (blinatumomab arm only), and at Day 29 were to be analyzed at a central lab defined by the sponsor - updated pregnancy, contraception, and lactation requirements to align with current risk and discomforts language
    19 Apr 2016
    - added "population PK analysis" as a secondary endpoint - corrected the time frame for administration of intrathecal prophylaxis as premedication in the HC3 arm - changed treatment-free interval from 2 weeks to 1 week when defining a cycle in the adaptive design - updated the number of sites from 60 to 75 - in inclusion criteria, added a requirement for historical samples for central analysis of MRD - updated exclusion criteria to clarify that for participants with total bilirubin < 1.5 mg/dL, measurement of direct bilirubin was not required, and to remove exclusion of other investigational procedures during study contact - clarified that maximum daily dose of blinatumomab was not to exceed 28 µg/day - clarified criteria for discontinuation of blinatumomab - updated laboratory analyte listing - updated language for pregnancy and lactation reporting
    11 Jul 2017
    - added text to "evaluate PK of blinatumomab" to the secondary objectives. Previously, this was an endpoint that was not listed as an objective - secondary endpoints for population PK analysis were clarified - clarified that not all participants were to proceed to transplant if M1 marrow occurred after consolidation (reasons not to proceed to transplant may include issues such as donor not available, infection, organ function issues) - updated number of study centers from 75 to 82 - updated the definition of primary completion to include the premature conclusion of the study - updated inclusion criteria to remove definition of M2 marrow and to exclude central nervous system relapse participants from having to supply material requested for central lab MRD analysis - updated exclusion criteria to change direct bilirubin values to total bilirubin and increased the acceptable level of total bilirubin for study entry, to indicate that other exclusion criteria do not have to resolve to ≤ grade 2 for study participation and to clarify that asparaginase reactions were not an exclusion criterion - clarified that the screening period could be extended by up to 7 days for bone marrow count recovery and/or scheduling of bone marrow collection only - clarified that anticonvulsant treatment needed to be started before resumption of the cycle after a seizure had interrupted the blinatumomab infusion - clarified that blinatumomab should only be discontinued in case of blinatumomab-related relevant neurologic events - added allergic reactions as a complication that occurs with asparaginase - clarified the concomitant medications that needed to be collected - clarified the timing of intrathecal chemotherapy and that it could have been administered before signing consent as long as it was administered within 7 days prior to treatment start
    05 Dec 2017
    - adaptation was removed from the protocol to align with the Pediatric Investigation Plan amendment - inclusion criterion updated to clarify what cases were exempt from supplying material from relapse for PCR central lab analysis - the section on excluded treatments and/or procedures during the study period was updated to exclude participants who received additional cycles of the study drugs (HC3 or blinatumomab) after the treatment cycle was completed until an event occurred - long-term follow-up for participants was changed from 36 months after alloHSCT to until the last participant enrolled on the study was 36 months after alloHSCT to allow longer follow-up data on the participants to be collected while the study was open - primary completion and end of study language was updated
    01 Nov 2019
    - added an exploratory endpoint - updated the number of study centers from 82 to 113 - updated adverse event guidance
    23 Dec 2021
    - clarified that adverse events associated with key safety parameter should be reported for the duration of the study with the exception of those related to other anti-cancer therapies occurring post blinatumomab treatment could be excluded - updated language to clarify that serious adverse events suspected to be related to blinatumomab that the investigator became aware of were to be reported to Amgen within 24 hours of awareness during the long-term follow-up phase - changed the contraception period, avoidance of pregnancy, breast feeding, and sperm donation period from 6 months to 48 hours - updated the language for reporting procedures for adverse events and serious adverse events - clarified that only adverse events and serious adverse events were to be reported if there was harm from overdose - updated the serious adverse event reporting, pregnancy, and lactation form in the appendices
    01 Aug 2022
    - updated contraception duration - clarified that where there was a potential overlap of contraceptive duration requirements due to different treatments, the most conservative contraceptive duration requirement was to be followed - overdose language was updated to inform that for HC3 chemotherapy or concomitant medications, overdose was not to be reported as an adverse event/serious adverse event unless it was an intentional overdose

    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
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