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    Clinical Trial Results:
    A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE® Antibody Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (TOWER Study)

    Summary
    EudraCT number
    2013-000536-10
    Trial protocol
    IT   CZ   DE   BE   IE   AT   GB   ES   FR   GR   PL   BG  
    Global end of trial date
    14 Mar 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Mar 2018
    First version publication date
    09 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    00103311
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02013167
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    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
    Final
    Date of interim/final analysis
    14 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of blinatumomab on overall survival when compared to standard of care (SOC) chemotherapy.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The regulations or guidelines were applicable to all regions where the study was conducted and in accordance with the ethical principles set forth in the Declaration of Helsinki. All study centers complied with local regulations. The study and all amendments were reviewed by an independent ethics committee (IEC)/institutional review board (IRB) at each center.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Turkey: 28
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    United States: 46
    Country: Number of subjects enrolled
    Austria: 7
    Worldwide total number of subjects
    405
    EEA total number of subjects
    227
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    357
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 101 centers in 21 countries in Asia, Australia, Europe, and Latin and North America. The first participant was enrolled on 03 January 2014 and was treated on 06 January 2014. The last participant enrolled on 25 September 2015.

    Pre-assignment
    Screening details
    Participants were randomized in a 2:1 ratio to either blinatumomab or standard of care (SOC) chemotherapy regimens. Randomization was stratified by age (< 35 years vs ≥ 35 years), prior salvage therapy (yes vs no), and prior allogeneic hematopoietic stem cell transplantation (HSCT) (yes vs no) as assessed at the time of consent.

    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
    Standard of Care Chemotherapy
    Arm description
    Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh*/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive SOC therapy for an additional 12 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    Standard of Care Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • FLAG (fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor) ± anthracycline-based regimen (e.g. idarubicin 10 mg/m² days 1 & 3; fludarabine 30 mg/m² days 1-5; cytarabine arabinoside 2 g/m² days 1-5). Patients > 60 years: Idarubicin 5 mg/m² day 1 & 3; fludarabine 20 mg/m² day 1-5; cytarabine arabinoside 1 g/m² day 1-5 • HiDAC (high-dose cytarabine arabinoside) - based regimen ≥1 g/m²/day ± anthracycline and/or in combination with other drugs such as native Escherichia coli asparaginase, polyethylene glycol linked to asparaginase (PEG-asparaginase), vinca alkaloids, steroids, etoposide or alkylating agents • High-dose methotrexate-based regimen (HDMTX; 500 mg/m² to 3 g/m² infused up to 24 hours) in combination with native E. coli asparaginase, PEG-asparaginase, vinca alkaloids, steroids, etoposide or alkylating agents. • Clofarabine as a single agent as recommended in the prescribing information or clofarabine-based regimens with 20 mg/m²/day for up to 5 days.

    Arm title
    Blinatumomab
    Arm description
    Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh*/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Blinatumomab
    Investigational medicinal product code
    MT103
    Other name
    Blincyto® AMG 103 MT103
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Blinatumomab is administered as a continuous intravenous infusion (CIV).

    Number of subjects in period 1
    Standard of Care Chemotherapy Blinatumomab
    Started
    134
    271
    Received Treatment
    109
    267
    Completed
    0
    0
    Not completed
    134
    271
         Death
    88
    178
         Decision by sponsor
    31
    77
         Consent withdrawn by subject
    15
    15
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard of Care Chemotherapy
    Reporting group description
    Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh*/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive SOC therapy for an additional 12 months.

    Reporting group title
    Blinatumomab
    Reporting group description
    Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh*/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.

    Reporting group values
    Standard of Care Chemotherapy Blinatumomab Total
    Number of subjects
    134 271 405
    Age Categorical
    Units: Subjects
        < 35 years
    60 124 184
        35 to 54 years
    33 80 113
        55 to 64 years
    26 34 60
        ≥ 65 years
    15 33 48
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.1 ± 17.3 40.8 ± 17.1 -
    Gender Categorical
    Units: Subjects
        Female
    57 109 166
        Male
    77 162 239
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    11 26 37
        Not Hispanic or Latino
    122 243 365
        Unknown
    1 2 3
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 4 5
        Asian
    9 19 28
        Native Hawaiian or Other Pacific Islander
    1 1 2
        Black or African American
    3 5 8
        White
    112 228 340
        Multiple
    0 2 2
        Other
    8 12 20
    Age Stratification at Randomization
    Units: Subjects
        < 35 years
    60 123 183
        ≥ 35 years
    74 148 222
    Prior Salvage Therapy Stratification at Randomization
    Units: Subjects
        Yes
    80 164 244
        No
    54 107 161
    Prior Allogeneic Hematopoietic Stem Cell Transplant (HCST)
    Units: Subjects
        Yes
    46 94 140
        No
    88 177 265
    Standard of Care Chemotherapy Regimen Received
    FLAG = fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor (filgrastim); HiDAC = high-dose cytarabine arabinoside
    Units: Subjects
        FLAG ± anthracycline
    56 0 56
        High-dose methotrexate
    30 0 30
        Clofarabine
    26 0 26
        HIDAC
    22 0 22
        Not applicable
    0 271 271

    End points

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    End points reporting groups
    Reporting group title
    Standard of Care Chemotherapy
    Reporting group description
    Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh*/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive SOC therapy for an additional 12 months.

    Reporting group title
    Blinatumomab
    Reporting group description
    Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh*/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.

    Primary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival (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.
    End point type
    Primary
    End point timeframe
    From randomization until end of study (14 March 2017); median observation time was 13.6 months in the SOC group and 15.7 months in the blinatumomab group.
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    134
    271
    Units: months
        median (confidence interval 95%)
    4.0 (2.9 to 5.5)
    7.7 (5.6 to 9.6)
    Statistical analysis title
    Primary Analysis of Overall Survival
    Statistical analysis description
    A 2-sided stratified log-rank test, stratified by the randomization factors, was used to determine if overall survival was superior in the blinatumomab arm compared to SOC chemotherapy arm. A hazard ratio with a 95% CI was estimated from a stratified Cox proportional hazard model. A hazard ratio < 1.0 indicates a lower average event rate and longer survival time for blinatumomab relative to SOC chemotherapy.
    Comparison groups
    Standard of Care Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.052 [1]
    Method
    Stratified Log Rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1
    Notes
    [1] - Stratified by age (< 35 years; ≥ 35 years), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no).

    Secondary: Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation

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    End point title
    Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation
    End point description
    Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete Remission (CR) was defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1,000/μl. CR must have occurred within 12 weeks of the first dose of therapy.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    134
    271
    Units: percentage of participants
        number (confidence interval 95%)
    15.7 (10.0 to 23.0)
    33.6 (28.0 to 39.5)
    Statistical analysis title
    PrimaryAnalysis of Complete Remission
    Comparison groups
    Standard of Care Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment Difference
    Point estimate
    17.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.6
         upper limit
    26.2
    Notes
    [2] - Adjusted for the stratification factors: age (< 35 vs. ≥ 35), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no).

    Secondary: Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) Within 12 Weeks of Treatment Initiation

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    End point title
    Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) Within 12 Weeks of Treatment Initiation
    End point description
    Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/μl, and ANC > 1,000/μl. Complete Remission with partial hematological recovery (CRh*) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Complete remission with incomplete hematological recovery (CRi) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1000 (but not both).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    134
    271
    Units: percentage of participants
        number (confidence interval 95%)
    24.6 (17.6 to 32.8)
    43.9 (37.9 to 50.0)
    Statistical analysis title
    Primary Analysis of CR/CRh*/CRi
    Comparison groups
    Standard of Care Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment Difference
    Point estimate
    19.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.9
         upper limit
    28.7
    Notes
    [3] - Adjusted for the stratification factors: age (< 35 vs. ≥ 35), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no).

    Secondary: Event Free Survival (EFS) Rate at 6 Months

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    End point title
    Event Free Survival (EFS) Rate at 6 Months
    End point description
    Event free survival was defined as the time from randomization until a documented relapse after achieving CR/CRh*/CRi or death, whichever occurred first. Participants who failed to achieve a CR/CRh*/CRi within 12 weeks of treatment initiation were considered as non-responders and assigned an EFS duration of 1 day. Participants still alive and relapse-free were censored on their last disease assessment date. A relapse event was any one of the following: • Hematological relapse: proportion of blasts in bone marrow >5% or blasts in peripheral blood after documented CR or CRh* or CRi • Progressive disease: An increase from baseline of at least 25% of bone marrow blasts or an absolute increase of at least 5,000 cells/μL in the number of circulating leukemia cells • Extramedullary relapse: extramedullary lesion that is new or increased by 50% from nadir as assessed by Cheson criteria. The Kaplan-Meier estimate of EFS at 6 months is reported.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    134
    271
    Units: percentage of participants
        number (confidence interval 95%)
    13.3 (8.0 to 19.9)
    31.4 (25.8 to 37.1)
    Statistical analysis title
    Primary Analysis of Event-free Survival
    Statistical analysis description
    The hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer survival for Blinatumomab relative to SOC Chemotherapy.
    Comparison groups
    Standard of Care Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    Stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    0.73
    Notes
    [4] - Stratified by age (< 35 years; ≥ 35 years), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no).

    Secondary: Duration of Complete Remission

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    End point title
    Duration of Complete Remission
    End point description
    Duration of complete remission, calculated only for participants who achieved a CR, was calculated from the date a CR was first achieved until the earliest date of a disease assessment indicating a relapse event or death, whichever occurred first. Participants who did not have a relapse event were censored on their last disease assessment date.
    End point type
    Secondary
    End point timeframe
    Up to the end of study (14 March 2017); median observation time was 10.8 months in the SOC group and 15.3 months in the blinatumomab group.
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    21 [5]
    91 [6]
    Units: months
        median (confidence interval 95%)
    7.8 (2.2 to 19.0)
    8.9 (6.0 to 10.7)
    Notes
    [5] - Participants with a best response of complete remission within 12 weeks of treatment initiation.
    [6] - Participants with a best response of complete remission within 12 weeks of treatment initiation.
    No statistical analyses for this end point

    Secondary: Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi)

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    End point title
    Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi)
    End point description
    Duration of CR/CRh*/CRi, calculated only for participants who achieved a CR/CRh*/CRi, was calculated from the date a CR/CRh*/CRi was first achieved until the earliest date of a disease assessment indicating a relapse event or death, whichever occurred first. Participants who did not have a relapse event were censored on their last disease assessment date.
    End point type
    Secondary
    End point timeframe
    Up to the end of study (14 March 2017); median observation time was 10.8 months in the SOC group and 15.3 months in the blinatumomab group.
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    33 [7]
    119 [8]
    Units: months
        median (confidence interval 95%)
    5.4 (1.8 to 19.0)
    8.8 (6.0 to 10.2)
    Notes
    [7] - Participants with a best response of CR/CRh*/CRi within 12 weeks of treatment initiation.
    [8] - Participants with a best response of CR/CRh*/CRi within 12 weeks of treatment initiation.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation

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    End point title
    Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation
    End point description
    Bone marrow samples were evaluated for MRD remission by a central laboratory. MRD remission was defined as the occurrence of an MRD level below 10^-4 measured by quantitative reverse transcription polymerase chain reaction (PCR) or flow cytometry.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    134
    271
    Units: percentage of participants
        number (confidence interval 95%)
    14.2 (8.8 to 21.3)
    29.9 (24.5 to 35.7)
    Statistical analysis title
    Primary Analysis of MRD Response
    Comparison groups
    Standard of Care Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment Difference
    Point estimate
    15.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.7
         upper limit
    23.7
    Notes
    [9] - Stratified by age (<35 vs. ≥ 35), prior salvage therapy (yes vs. no), and prior alloHSCT (yes vs. no)

    Secondary: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

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    End point title
    Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to the end of study; maximum time on study was 26 months.
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    134
    271
    Units: percentage of participants
        number (confidence interval 95%)
    23.9 (16.9 to 32.0)
    24.7 (19.7 to 30.3)
    Statistical analysis title
    Analysis of Postbaseline alloHSCT
    Comparison groups
    Standard of Care Chemotherapy v Blinatumomab
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment Difference
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    9.7
    Notes
    [10] - Stratified by age (< 35 years; ≥ 35 years), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no).

    Secondary: Number of Participants With Adverse Events

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    End point title
    Number of Participants With Adverse Events
    End point description
    Adverse events (AEs) were graded for severity according to the CTCAE version 4.0, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to blinatumomab based on response to the question: Is there a reasonable possibility that the event may have been caused by blinatumomab or other protocol-specified therapies/procedures?
    End point type
    Secondary
    End point timeframe
    From first dose of protocol-specified therapy until 30 days after the last dose; median duration of treatment was 5 days in the SOC group and 70 days in the blinatumomab group.
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    109 [11]
    267 [12]
    Units: participants
        Any adverse event
    108
    263
        AE grade ≥ 2
    106
    256
        AE grade ≥ 3
    100
    231
        AE grade ≥ 4
    67
    135
        Serious adverse events
    49
    168
        AEs leading to interruption of study drug
    6
    72
        AEs leading to discontinuation of study drug
    10
    42
        Life-threatening adverse events
    27
    56
        Fatal adverse events
    20
    52
        Treatment-related adverse events
    92
    214
        Treatment-related AE grade ≥ 2
    89
    195
        Treatment-related AE grade ≥ 3
    78
    144
        Treatment-related AE grade ≥ 4
    51
    59
        Serious treatment-related adverse events
    34
    76
        TRAEs leading to interruption of study drug
    6
    55
        TRAEs leading to discontinuation of study drug
    8
    23
        Treatment-related life-threatening adverse events
    17
    21
        Treatment-related fatal adverse events
    8
    8
    Notes
    [11] - Partipants who received protocol-specified therapy
    [12] - Partipants who received protocol-specified therapy
    No statistical analyses for this end point

    Secondary: 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant

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    End point title
    100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
    End point description
    The analysis of 100-day mortality after allogeneic HSCT was assessed for participants who achieved a best response of CR/CRh*CTi within 12 weeks of treatment initiation, who received an allogeneic HSCT and did not receive any additional anticancer treatment before the transplant. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. "99999" indicates data not estimable.
    End point type
    Secondary
    End point timeframe
    100 days, from the date of allogeneic HSCT until the end of study
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    12 [13]
    42 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (-99999 to 99999)
    12.3 (5.3 to 27.1)
    Notes
    [13] - Subjects with CR/CRh*/CRi within 12 weeks of treatment & no other anticancer therapy before alloHSCT
    [14] - Subjects with CR/CRh*/CRi within 12 weeks of treatment & no other anticancer therapy before alloHSCT
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-blinatumomab Antibodies

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    End point title
    Number of Participants With Anti-blinatumomab Antibodies [15]
    End point description
    Anti-blinatumomab binding antibodies were evaluated using a validated electrochemiluminescence (ECL)-based assay (binding assay). Samples positive for binding were analyzed using a cell-based bioassay to determine if the detected antibodies had neutralizing properties (neutralizing assay).
    End point type
    Secondary
    End point timeframe
    Samples were collected on day 29 at the end of cycle 2 and 30 days after the last dose of blinatumomab (median duration of treatment was 70 days).
    Notes
    [15] - 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: Analysis was only conducted in participants who received blinatumomab.
    End point values
    Blinatumomab
    Number of subjects analysed
    171 [16]
    Units: participants
        Binding antibody positive
    5
        Neutralizing antibody positive
    3
    Notes
    [16] - Participants who received blinatumomab with available post-baseline antibody data.
    No statistical analyses for this end point

    Secondary: Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death

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    End point title
    Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death
    End point description
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is a 30-item questionnaire that assesses the health related quality of life of cancer patients. The EORTC QLQ-C30 consists of a global health status/quality of life (QoL) scale, 5 functional scales, 3 symptom scales, and 6 single items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life durig the past week on a scale from 1 (very poor) to 7 (excellent). The scale score was derived as the sum of each score and transformed to a scale from 0 to 100 where higher scores represent a high QoL. Time to a ≥10-point decrease from baseline GHS/QoL or death, whichever came first, was calculated from baseline. Participants still alive and without a 10-point decrease in GHS/QoL EORTC QLQ-C30 were censored on their last EORTC QLQ-C30 assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 04 January 2016; EORTC QLQ-C30 was assessed on day 1, 8, 15, and 29 during cycle 1; days 1, 15, and 29 in cycle 2 and each consolidation cycle, and 30-days following the last dose of drug treatment.
    End point values
    Standard of Care Chemotherapy Blinatumomab
    Number of subjects analysed
    95 [17]
    247 [18]
    Units: months
        median (confidence interval 95%)
    1.0 (0.5 to 1.5)
    1.7 (1.1 to 3.6)
    Notes
    [17] - Subjects with non-missing baseline and at least 1 postbaseline result of any QLQ-C30 scales/item
    [18] - Subjects with non-missing baseline and at least 1 postbaseline result of any QLQ-C30 scales/item
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of protocol-specified therapy until 30 days after the last dose; median duration of treatment was 5 days in the SOC group and 70 days in the blinatumomab group.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Standard of Care Chemotherapy
    Reporting group description
    Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh*/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive SOC therapy for an additional 12 months.

    Reporting group title
    Blinatumomab
    Reporting group description
    Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh*/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.

    Serious adverse events
    Standard of Care Chemotherapy Blinatumomab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 109 (44.95%)
    168 / 267 (62.92%)
         number of deaths (all causes)
    78
    180
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic occlusion
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 109 (1.83%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter placement
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chloroma
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemic infiltration extramedullary
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemic infiltration pulmonary
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease in skin
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 109 (0.00%)
    7 / 267 (2.62%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in liver
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Discomfort
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 109 (0.92%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Hyperthermia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 109 (0.92%)
    16 / 267 (5.99%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mental status changes
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 109 (0.00%)
    8 / 267 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CSF cell count abnormal
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pericardial effusion
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Epistaxis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 109 (0.92%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 109 (1.83%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Histiocytosis haematophagic
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    12 / 109 (11.01%)
    24 / 267 (8.99%)
         occurrences causally related to treatment / all
    11 / 12
    12 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperleukocytosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukopenia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 109 (1.83%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 109 (0.92%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    0 / 109 (0.00%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 109 (1.83%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hemianopia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoaesthesia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intention tremor
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 109 (1.83%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Hydronephrosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         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 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 109 (0.00%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess fungal
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 109 (2.75%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bacterial sepsis
         subjects affected / exposed
    2 / 109 (1.83%)
    6 / 267 (2.25%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Brain abscess
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 109 (0.92%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Catheter site infection
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system abscess
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Citrobacter infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         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 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Citrobacter sepsis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    2 / 109 (1.83%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 109 (0.92%)
    6 / 267 (2.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis enteroviral
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Fungaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Fungal infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fusarium infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatosplenic candidiasis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection in an immunocompromised host
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mastoiditis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucormycosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    1 / 109 (0.92%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Osteomyelitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 109 (1.83%)
    10 / 267 (3.75%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Otitis media acute
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    2 / 109 (1.83%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 109 (0.92%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 109 (0.92%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 109 (6.42%)
    13 / 267 (4.87%)
         occurrences causally related to treatment / all
    5 / 9
    3 / 13
         deaths causally related to treatment / all
    2 / 4
    2 / 8
    Rhinovirus infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    3 / 109 (2.75%)
    8 / 267 (3.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 6
    Sinusitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         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
    1 / 109 (0.92%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Standard of Care Chemotherapy Blinatumomab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 109 (97.25%)
    251 / 267 (94.01%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    11 / 109 (10.09%)
    33 / 267 (12.36%)
         occurrences all number
    16
    38
    Hypertension
         subjects affected / exposed
    9 / 109 (8.26%)
    18 / 267 (6.74%)
         occurrences all number
    9
    20
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 109 (0.00%)
    35 / 267 (13.11%)
         occurrences all number
    0
    42
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 109 (0.92%)
    19 / 267 (7.12%)
         occurrences all number
    1
    31
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    12 / 109 (11.01%)
    20 / 267 (7.49%)
         occurrences all number
    16
    24
    Chest pain
         subjects affected / exposed
    6 / 109 (5.50%)
    6 / 267 (2.25%)
         occurrences all number
    6
    7
    Asthenia
         subjects affected / exposed
    11 / 109 (10.09%)
    20 / 267 (7.49%)
         occurrences all number
    15
    32
    Mucosal inflammation
         subjects affected / exposed
    14 / 109 (12.84%)
    9 / 267 (3.37%)
         occurrences all number
    15
    10
    Fatigue
         subjects affected / exposed
    14 / 109 (12.84%)
    36 / 267 (13.48%)
         occurrences all number
    15
    52
    Oedema peripheral
         subjects affected / exposed
    16 / 109 (14.68%)
    39 / 267 (14.61%)
         occurrences all number
    20
    52
    Pain
         subjects affected / exposed
    6 / 109 (5.50%)
    16 / 267 (5.99%)
         occurrences all number
    6
    20
    Pyrexia
         subjects affected / exposed
    48 / 109 (44.04%)
    153 / 267 (57.30%)
         occurrences all number
    73
    326
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 109 (9.17%)
    31 / 267 (11.61%)
         occurrences all number
    12
    44
    Anxiety
         subjects affected / exposed
    6 / 109 (5.50%)
    14 / 267 (5.24%)
         occurrences all number
    6
    14
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 109 (9.17%)
    15 / 267 (5.62%)
         occurrences all number
    24
    31
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 109 (10.09%)
    24 / 267 (8.99%)
         occurrences all number
    35
    47
    Blood bilirubin increased
         subjects affected / exposed
    9 / 109 (8.26%)
    10 / 267 (3.75%)
         occurrences all number
    23
    19
    Platelet count decreased
         subjects affected / exposed
    13 / 109 (11.93%)
    18 / 267 (6.74%)
         occurrences all number
    72
    60
    Neutrophil count decreased
         subjects affected / exposed
    11 / 109 (10.09%)
    10 / 267 (3.75%)
         occurrences all number
    28
    23
    White blood cell count decreased
         subjects affected / exposed
    6 / 109 (5.50%)
    14 / 267 (5.24%)
         occurrences all number
    12
    38
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    10 / 109 (9.17%)
    18 / 267 (6.74%)
         occurrences all number
    10
    30
    Sinus tachycardia
         subjects affected / exposed
    6 / 109 (5.50%)
    15 / 267 (5.62%)
         occurrences all number
    8
    19
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    36 / 109 (33.03%)
    48 / 267 (17.98%)
         occurrences all number
    42
    55
    Anaemia
         subjects affected / exposed
    46 / 109 (42.20%)
    68 / 267 (25.47%)
         occurrences all number
    144
    222
    Thrombocytopenia
         subjects affected / exposed
    32 / 109 (29.36%)
    48 / 267 (17.98%)
         occurrences all number
    108
    114
    Neutropenia
         subjects affected / exposed
    31 / 109 (28.44%)
    51 / 267 (19.10%)
         occurrences all number
    50
    108
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 109 (5.50%)
    42 / 267 (15.73%)
         occurrences all number
    7
    52
    Dyspnoea
         subjects affected / exposed
    8 / 109 (7.34%)
    16 / 267 (5.99%)
         occurrences all number
    9
    17
    Epistaxis
         subjects affected / exposed
    9 / 109 (8.26%)
    16 / 267 (5.99%)
         occurrences all number
    10
    17
    Oropharyngeal pain
         subjects affected / exposed
    7 / 109 (6.42%)
    15 / 267 (5.62%)
         occurrences all number
    8
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 109 (7.34%)
    18 / 267 (6.74%)
         occurrences all number
    8
    20
    Headache
         subjects affected / exposed
    32 / 109 (29.36%)
    79 / 267 (29.59%)
         occurrences all number
    39
    106
    Somnolence
         subjects affected / exposed
    1 / 109 (0.92%)
    14 / 267 (5.24%)
         occurrences all number
    1
    20
    Tremor
         subjects affected / exposed
    0 / 109 (0.00%)
    26 / 267 (9.74%)
         occurrences all number
    0
    35
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 109 (17.43%)
    16 / 267 (5.99%)
         occurrences all number
    25
    19
    Constipation
         subjects affected / exposed
    28 / 109 (25.69%)
    35 / 267 (13.11%)
         occurrences all number
    34
    46
    Haemorrhoids
         subjects affected / exposed
    7 / 109 (6.42%)
    7 / 267 (2.62%)
         occurrences all number
    7
    7
    Dyspepsia
         subjects affected / exposed
    7 / 109 (6.42%)
    10 / 267 (3.75%)
         occurrences all number
    7
    11
    Diarrhoea
         subjects affected / exposed
    38 / 109 (34.86%)
    59 / 267 (22.10%)
         occurrences all number
    49
    75
    Nausea
         subjects affected / exposed
    46 / 109 (42.20%)
    51 / 267 (19.10%)
         occurrences all number
    69
    73
    Proctalgia
         subjects affected / exposed
    7 / 109 (6.42%)
    2 / 267 (0.75%)
         occurrences all number
    8
    2
    Stomatitis
         subjects affected / exposed
    14 / 109 (12.84%)
    17 / 267 (6.37%)
         occurrences all number
    16
    18
    Vomiting
         subjects affected / exposed
    26 / 109 (23.85%)
    33 / 267 (12.36%)
         occurrences all number
    40
    37
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 109 (5.50%)
    8 / 267 (3.00%)
         occurrences all number
    8
    8
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    6 / 109 (5.50%)
    7 / 267 (2.62%)
         occurrences all number
    6
    7
    Rash
         subjects affected / exposed
    13 / 109 (11.93%)
    20 / 267 (7.49%)
         occurrences all number
    15
    24
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 109 (9.17%)
    34 / 267 (12.73%)
         occurrences all number
    14
    40
    Arthralgia
         subjects affected / exposed
    5 / 109 (4.59%)
    17 / 267 (6.37%)
         occurrences all number
    5
    20
    Bone pain
         subjects affected / exposed
    8 / 109 (7.34%)
    29 / 267 (10.86%)
         occurrences all number
    9
    42
    Pain in extremity
         subjects affected / exposed
    8 / 109 (7.34%)
    25 / 267 (9.36%)
         occurrences all number
    8
    39
    Myalgia
         subjects affected / exposed
    6 / 109 (5.50%)
    19 / 267 (7.12%)
         occurrences all number
    7
    21
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 109 (13.76%)
    20 / 267 (7.49%)
         occurrences all number
    15
    24
    Hyperglycaemia
         subjects affected / exposed
    9 / 109 (8.26%)
    21 / 267 (7.87%)
         occurrences all number
    15
    29
    Hypoalbuminaemia
         subjects affected / exposed
    11 / 109 (10.09%)
    14 / 267 (5.24%)
         occurrences all number
    14
    27
    Hypomagnesaemia
         subjects affected / exposed
    18 / 109 (16.51%)
    28 / 267 (10.49%)
         occurrences all number
    20
    37
    Hypokalaemia
         subjects affected / exposed
    30 / 109 (27.52%)
    46 / 267 (17.23%)
         occurrences all number
    43
    78
    Hypocalcaemia
         subjects affected / exposed
    10 / 109 (9.17%)
    12 / 267 (4.49%)
         occurrences all number
    14
    14
    Hypophosphataemia
         subjects affected / exposed
    6 / 109 (5.50%)
    12 / 267 (4.49%)
         occurrences all number
    6
    20
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    6 / 109 (5.50%)
    3 / 267 (1.12%)
         occurrences all number
    7
    4
    Device related infection
         subjects affected / exposed
    5 / 109 (4.59%)
    14 / 267 (5.24%)
         occurrences all number
    5
    17
    Oral herpes
         subjects affected / exposed
    9 / 109 (8.26%)
    15 / 267 (5.62%)
         occurrences all number
    10
    16
    Pneumonia
         subjects affected / exposed
    14 / 109 (12.84%)
    7 / 267 (2.62%)
         occurrences all number
    16
    7
    Sinusitis
         subjects affected / exposed
    6 / 109 (5.50%)
    6 / 267 (2.25%)
         occurrences all number
    6
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 109 (0.00%)
    15 / 267 (5.62%)
         occurrences all number
    0
    17
    Urinary tract infection
         subjects affected / exposed
    2 / 109 (1.83%)
    15 / 267 (5.62%)
         occurrences all number
    2
    20
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 109 (0.92%)
    20 / 267 (7.49%)
         occurrences all number
    1
    29

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2014
    - Clarify timing, scope, and applicability of study procedures to treatment arms - Clarify criteria for discontinuation and withdrawal of blinatumomab-treated subjects, clarify terms and definitions used in protocol, clarify secondary endpoints and analyses, clarify study participation, clarify requirements for medical coverage and safety monitoring in an outpatient setting Increase the number of study centers globally - Provide updated information on packaging, presentation, dose modifications, and overdose (> 10%) of blinatumomab - Provide dose modification guidance for SOC chemotherapy regimen - Update Amgen publication policy guidelines and team contact information to facilitate the enrollment of subjects, entry criteria were modified to allow for the screening of serum for potential drugs of abuse in subjects receiving hemodialysis with no urine output and to remove the requirement of “no detectable viral RNA” for subjects known to have had hepatitis C
    10 Mar 2015
    - Clarify protocol-required procedures - Updates made to align with current Amgen protocol templates
    09 Sep 2015
    - Update pregnancy, lactation, and contraception requirements to align with blinatumomab core risk and discomfort language - Provide clarification on study design, and procedures for bone marrow aspirates, vital signs, and long-term follow-up
    20 Apr 2016
    - Update contraception timeframes to align with blinatumomab core risk and discomfort language - Update sponsor contact information and definition of adverse events to align with current protocol template language

    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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