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    Clinical Trial Results:
    An Open-label, Multicenter, Exploratory Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

    Summary
    EudraCT number
    		 2009-015989-62
    Trial protocol
    		 DE  
    Global end of trial date
    14 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2017
    First version publication date
    19 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0103206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01209286
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 01320
    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 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine whether the bispecific T-cell engager blinatumomab is effective, safe and tolerable in the treatment of patients with relapsed/refractory B-precursor ALL.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and country-specific national and local laws and regulations. The study protocol including amendments, informed consent form (ICF), and any accompanying material provided to the subject was reviewed and approved by the Independent Ethics Committee (IEC). A copy of the written approval of the protocol and the ICF were collected by Amgen before recruitment of any study subjects and shipment of Amgen investigational product commenced. Amgen notified the IEC of any deviations from the protocol or of any serious adverse events that occurred. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study. Subject informed consent was obtained in writing before enrollment into the study according to all applicable regulatory requirements. The written ICF was dated and signed by both the investigator (or designee) and the subject before any study-related procedure was initiated.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Oct 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    31
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was open to adult patients with relapsed / refractory B-precursor acute lymphoblastic leukemia (ALL). This study was conducted at 9 centers in Germany.

    Pre-assignment
    Screening details
    		 This study consisted of a core study of up to 33 weeks, efficacy follow-up until 24 months after treatment start and survival follow-up until 5 years after treatment start.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Blinatumomab 15 μg
    Arm description
    		 Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blinatumomab
    Investigational medicinal product code
    AMG 103
    Other name
    MT103, BLINCYTO™
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continuous intravenous infusion over four weeks per treatment cycle

    Arm title
    		 Blinatumomab 5/15 μg
    Arm description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blinatumomab
    Investigational medicinal product code
    AMG 103
    Other name
    MT103, BLINCYTO™
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continuous intravenous infusion over four weeks per treatment cycle

    Arm title
    		 Blinatumomab 5/15/30 μg
    Arm description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blinatumomab
    Investigational medicinal product code
    AMG 103
    Other name
    MT103, BLINCYTO™
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continuous intravenous infusion over four weeks per treatment cycle

    Number of subjects in period 1
    		Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg
    Started
    7
    23
    6
    Completed
    2
    13
    3
    Not completed
    5
    10
    3
         Physician decision
    -
    2
    -
         Adverse event, non-fatal
    4
    3
    1
         Other
    -
    1
    -
         Hematological Relapse After Remission
    -
    1
    1
         Remission Not Achieved in 2 Cycles
    1
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Blinatumomab 15 μg
    Reporting group description
    		 Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

    Reporting group title
    Blinatumomab 5/15 μg
    Reporting group description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment.

    Reporting group title
    Blinatumomab 5/15/30 μg
    Reporting group description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment.

    Reporting group values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Total
    Number of subjects
    		 7 23 6 36
    Age Categorical
    Units: Subjects
        <=60 years
    		 5 20 4 29
        > 60 years
    		 2 3 2 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.0 ( 21.5 ) 38.1 ( 16.7 ) 42.5 ( 23.2 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 3 9 2 14
        Male
    		 4 14 4 22
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 7 22 6 35
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Number of Prior Relapses
    Units: Subjects
        No relapes
    		 0 2 1 3
        1 relapse
    		 5 15 3 23
        2 relapses
    		 2 6 1 9
        3 relapses
    		 0 0 1 1
    Relapsed / refractory Status
    Units: Subjects
        Primary Refractory
    		 0 2 1 3
        Relapsed
    		 7 21 5 33
    Prior Allogeneic Hematopoietic Stem cell Transplantation (HSCT)
    Units: Subjects
        Yes, Sibling
    		 1 1 1 3
        Yes, Unrelated
    		 2 9 1 12
        Yes, Haploidentical (mother/father)
    		 0 0 0 0
        No prior allogeneic HSCT
    		 4 13 4 21

    End points

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    End points reporting groups
    Reporting group title
    Blinatumomab 15 μg
    Reporting group description
    		 Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

    Reporting group title
    Blinatumomab 5/15 μg
    Reporting group description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment.

    Reporting group title
    Blinatumomab 5/15/30 μg
    Reporting group description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment.

    Subject analysis set title
    Blinatumomab Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

    Subject analysis set title
    Blinatumomab 5 μg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants receiving blinatumomab 5 μg/m²/day.

    Subject analysis set title
    Blinatumomab 15 μg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants receiving blinatumomab 15 μg/m²/day.

    Subject analysis set title
    Blinatumomab 30 μg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants receiving blinatumomab 30 μg/m²/day.

    Primary: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

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    End point title
    		 Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment [1]
    End point description
    At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Response/Remission (CR): • Less than or equal to 5% blasts in the bone marrow • No evidence of circulating blasts or extramedullar disease • Full recovery of peripheral blood counts: ◦ Platelets > 100,000/μL ◦ Hemoglobin ≥ 11 g/dL ◦ Absolute neutrophil count (ANC) > 1,500/μL Complete Remission with only Partial Hematological Recovery (CRh*): • Less than or equal to 5% blasts in the bone marrow • No evidence of circulating blasts or extramedullar disease • Partial recovery of peripheral blood counts: ◦ Platelets > 50,000/μL ◦ Hemoglobin ≥ 7 g/dL ◦ ANC > 500/μL
    End point type
    Primary
    End point timeframe
    Within the first 2 cycles of treatment, 12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study efficacy objectives were evaluated using descriptive methods. Confirmatory analyses were not performed.
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: percentage of participants
        number (confidence interval 95%)
    71.4 (29.0 to 96.3)
    69.6 (47.1 to 86.8)
    66.7 (22.3 to 95.7)
    69.4 (51.9 to 83.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment

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    End point title
    		 Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment
    End point description
    At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete Response/Remission (CR) was defined by the following criteria: • Less than or equal to 5% blasts in the bone marrow • No evidence of circulating blasts or extramedullar disease • Full recovery of peripheral blood counts: ◦ Platelets > 100,000/μL ◦ Hemoglobin ≥ 11 g/dL ◦ Absolute neutrophil count (ANC) > 1,500/μL
    End point type
    Secondary
    End point timeframe
    Within the first 2 cycles of treatment, 12 weeks
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: percentage of participants
        number (confidence interval 95%)
    14.3 (0.4 to 57.9)
    43.5 (23.2 to 65.5)
    66.7 (22.3 to 95.7)
    41.7 (25.5 to 59.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

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    End point title
    		 Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
    End point description
    At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete remission with only partial hematological recovery (CRh*) was defined by the following criteria: • Less than or equal to 5% blasts in the bone marrow • No evidence of circulating blasts or extramedullar disease • Partial recovery of peripheral blood counts: ◦ Platelets > 50,000/μL ◦ Hemoglobin ≥ 7 g/dL ◦ ANC > 500/μL.
    End point type
    Secondary
    End point timeframe
    Within the first 2 cycles of treatment, 12 weeks
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: percentage of participants
        number (confidence interval 95%)
    57.1 (18.4 to 90.1)
    26.1 (10.2 to 48.4)
    0.0 (0.0 to 45.9)
    27.8 (14.2 to 45.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment

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    End point title
    		 Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment
    End point description
    At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Partial remission was defined by the following criteria: • Bone marrow blasts ≤ 25%
    End point type
    Secondary
    End point timeframe
    Within the first 2 cycles of treatment, 12 weeks
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 41.0)
    8.7 (1.1 to 28.0)
    0.0 (0.0 to 45.9)
    5.6 (0.7 to 18.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study

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    End point title
    		 Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study
    End point description
    A minimal residual disease (MRD) response is defined as MRD < 10^-4 blasts/nucleated cells based on polymerase chain reaction (PCR) evaluation of individual rearrangements of immunoglobulin or T cell receptor genes.
    End point type
    Secondary
    End point timeframe
    During the core study treatment period (up to 30 weeks).
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: percentage of participants
        number (confidence interval 95%)
    71.4 (29.0 to 96.3)
    73.9 (51.6 to 89.8)
    50.0 (11.8 to 88.2)
    69.4 (51.9 to 83.7)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab
    End point description
    The percentage of participants who underwent immediate allogeneic HSCT (defined as those in remission who undergo HSCT without receiving any other treatments) after having discontinued or completed the core study.
    End point type
    Secondary
    End point timeframe
    Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: percentage of participants
        number (not applicable)
    42.9
    60.9
    16.7
    50.0
    No statistical analyses for this end point

    Secondary: Time to Hematological Relapse

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    End point title
    		 Time to Hematological Relapse
    End point description
    Time to hematological relapse was measured for participants who achieved a CR or CRh* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their day of death. Hematological Relapse was defined as: • Proportion of blasts in bone marrow > 5% • Extramedullary relapse. Time to hematological relapse was analyzed by Kaplan-Meier methods. "99999" indicates data not estimable due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From remission during the core study until the end of follow-up period; median time on study was 404.5 days.
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    5
    16
    4
    25
    Units: days
        median (confidence interval 95%)
    240.0 (63.0 to 270.0)
    1535.0 (275.0 to 99999)
    373.0 (15.0 to 99999)
    352.0 (240.0 to 99999)
    No statistical analyses for this end point

    Secondary: Relapse-free Survival

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    End point title
    		 Relapse-free Survival
    End point description
    Relapse-free survival was measured only for participants who achieved a CR or CRh* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse-free survival was estimated using Kaplan-Meier methods. "99999" indicates data not estimable due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From remission during the core study until the end of follow-up period; median time on study was 404.5 days.
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    5
    16
    4
    25
    Units: days
        median (confidence interval 95%)
    137.0 (63.0 to 270.0)
    283.0 (226.0 to 1535.0)
    373.0 (15.0 to 99999)
    268.0 (175.0 to 403.0)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was measured for all subjects from the date of first infusion of blinatumomab until the date of death because of any cause. Subjects who did not die were censored on the last documented visit date. Overall survival was estimated using Kaplan-Meier methods. "99999" indicates data not estimable due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From first dose until the end of follow-up period; median time on study was 404.5 days.
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: days
        median (confidence interval 95%)
    269.0 (165.0 to 482.0)
    361.0 (258.0 to 973.0)
    584.0 (276.0 to 99999)
    396.0 (262.0 to 667.0)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events
    End point description
    Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 and according to the following: Grade I (mild); Grade 2 (moderate); Grade 3 (severe - significantly limits the patient's ability to perform routine activities despite symptomatic therapy; Grade 4 (life-threatening); Grade 5 (death). The investigator used medical judgment to determine if there was a causal relationship (ie, certain, probable, possible, unlikely, not related) between an adverse event and blinatumomab. A serious adverse event is any untoward medical occurrence or effect, that at any dose: resulted in death, was life-threatening, required or prolonged hospitalization, resulted in persistent or significant disability or incapacity, is a congenital anomaly or birth defect or is a medically important condition.
    End point type
    Secondary
    End point timeframe
    From the first infusion to 30 days after the last infusion in the core study or from the first retreatment cycle infusion to 30 days after the last retreatment cycle; Median treatment duration was 44, 56 and 75 days in each cohort respectively.
    End point values
    		 Blinatumomab 15 μg Blinatumomab 5/15 μg Blinatumomab 5/15/30 μg Blinatumomab Overall
    Number of subjects analysed
    7
    23
    6
    36
    Units: participants
        Any adverse event (AE)
    7
    23
    6
    36
        Adverse events of at least CTC grade 3
    7
    15
    5
    27
        Treatment-related adverse events
    7
    23
    6
    36
        Related adverse events of at least CTC grade 3
    7
    12
    4
    23
        Serious adverse events
    6
    14
    5
    25
        Serious adverse events of at least CTC grade 3
    6
    12
    4
    22
        Serious related adverse events
    4
    10
    4
    18
        AEs leading to interruption of blinatumomab
    3
    6
    3
    12
        AEs leading to discontinuation of blinatumomab
    4
    5
    1
    10
        AEs leading to death
    1
    4
    1
    6
    No statistical analyses for this end point

    Secondary: Steady State Blinatumomab Concentration

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    End point title
    		 Steady State Blinatumomab Concentration
    End point description
    The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the intravenous infusion was started for cycle 1 and cycle 2, respectively. Actual doses administered were used in the analysis. Concentrations below the limit of detection (3 pg/mL) were set to zero before data analysis and concentrations below the lower limit of quantitation (50 pg/mL) were excluded from analysis.
    End point type
    Secondary
    End point timeframe
    Samples were collected at predose and at 48 hours following start of infusion, when dose is escalated and on Days 8, 15, 22, and 29 of the first 2 cycles.
    End point values
    		 Blinatumomab 5 μg Blinatumomab 15 μg Blinatumomab 30 μg
    Number of subjects analysed
    31
    34
    5
    Units: pg/mL
        arithmetic mean (standard deviation)
    167 ( 66 )
    553 ( 238 )
    1180 ( 820 )
    No statistical analyses for this end point

    Secondary: Clearance of Blinatumomab

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    End point title
    		 Clearance of Blinatumomab
    End point description
    Clearance was calculated as R0/Css; where R0 is the infusion rate (μg/m²/hr) and Css is the steady state concentration.
    End point type
    Secondary
    End point timeframe
    Samples were collected at predose and at 48 hours following start of infusion, when dose is escalated and on Days 8, 15, 22, and 29 of the first 2 cycles.
    End point values
    		 Blinatumomab Overall
    Number of subjects analysed
    36
    Units: L/m²/hr
        arithmetic mean (standard deviation)
    1.34 ( 0.61 )
    No statistical analyses for this end point

    Secondary: Serum Cytokine Peak Levels

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    End point title
    		 Serum Cytokine Peak Levels
    End point description
    The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) is 125 pg/mL and the limit of detection (LOD) is 20 pg/mL. "99999" indicates values below detection level of the assay.
    End point type
    Secondary
    End point timeframe
    Samples were collected prior to treatment start (baseline), and at 2, 6, 24, and 48 hours after drug infusion start, and at these same time points when dose is escalated in each treatment cycle.
    End point values
    		 Blinatumomab Overall
    Number of subjects analysed
    36
    Units: pg/mL
    arithmetic mean (standard deviation)
        IL-6: Cycle 1 (N=35)
    2563 ( 5231 )
        IL-6: Cycle 2 (N=22)
    212 ( 477 )
        IL-6: Cycle 3 (N=11)
    21 ( 26 )
        IL-10: Cycle 1 (N=35)
    1302 ( 2563 )
        IL-10: Cycle 2 (N=22)
    351 ( 582 )
        IL-10: Cycle 3 (N=11)
    419 ( 730 )
        IFN-Ɣ: Cycle 1 (N=35)
    467 ( 1824 )
        IFN-Ɣ: Cycle 2 (N=22)
    25 ( 28 )
        IFN-Ɣ: Cycle 3 (N=11)
    99999 ( 99999 )
        IL-2: Cycle 1 (N=35)
    36 ( 49 )
        IL-2: Cycle 2 (N=22)
    99999 ( 99999 )
        IL-2: Cycle 3 (N=11)
    99999 ( 99999 )
        TNF-α: Cycle 1 (N=35)
    60 ( 122 )
        TNF-α: Cycle 2 (N=22)
    99999 ( 99999 )
        TNF-α: Cycle 3 (N=11)
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first infusion to 30 days after the last infusion in the core study or from the first retreatment cycle infusion to 30 days after the last retreatment cycle; Median treatment duration was 44, 56 and 75 days in each cohort respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Blinatumomab 15 µg/m²/day
    Reporting group description
    		 Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

    Reporting group title
    Blinatumomab 5/15 µg/m²/day
    Reporting group description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment.

    Reporting group title
    Blinatumomab 5/15/30 µg/m²/day
    Reporting group description
    		 Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment.

    Reporting group title
    Blinatumomab Overall
    Reporting group description
    		 All participants who received blinatumomab by continuous intravenous infusion during the study.

    Serious adverse events
    		 Blinatumomab 15 µg/m²/day Blinatumomab 5/15 µg/m²/day Blinatumomab 5/15/30 µg/m²/day Blinatumomab Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    14 / 23 (60.87%)
    5 / 6 (83.33%)
    25 / 36 (69.44%)
         number of deaths (all causes)
    7
    17
    4
    28
         number of deaths resulting from adverse events
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysgraphia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Cytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Candida sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Catheter site infection
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Febrile infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pulmonary sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Blinatumomab 15 µg/m²/day Blinatumomab 5/15 µg/m²/day Blinatumomab 5/15/30 µg/m²/day Blinatumomab Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    23 / 23 (100.00%)
    6 / 6 (100.00%)
    36 / 36 (100.00%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    4 / 36 (11.11%)
         occurrences all number
    2
    1
    1
    4
    Flushing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Hypertension
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 23 (21.74%)
    1 / 6 (16.67%)
    8 / 36 (22.22%)
         occurrences all number
    3
    7
    1
    11
    Hypotension
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    4 / 36 (11.11%)
         occurrences all number
    5
    0
    3
    8
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Catheter site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    0
    3
    Chest pain
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    2
    3
    0
    5
    Chills
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 23 (8.70%)
    3 / 6 (50.00%)
    7 / 36 (19.44%)
         occurrences all number
    2
    2
    7
    11
    Face oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    1
    2
    Fatigue
         subjects affected / exposed
    5 / 7 (71.43%)
    8 / 23 (34.78%)
    5 / 6 (83.33%)
    18 / 36 (50.00%)
         occurrences all number
    7
    10
    7
    24
    General physical health deterioration
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    2
    2
    Injection site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Localised oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    1
    2
    Mucosal inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 23 (8.70%)
    1 / 6 (16.67%)
    4 / 36 (11.11%)
         occurrences all number
    1
    3
    1
    5
    Oedema peripheral
         subjects affected / exposed
    6 / 7 (85.71%)
    5 / 23 (21.74%)
    3 / 6 (50.00%)
    14 / 36 (38.89%)
         occurrences all number
    8
    8
    6
    22
    Pyrexia
         subjects affected / exposed
    5 / 7 (71.43%)
    18 / 23 (78.26%)
    6 / 6 (100.00%)
    29 / 36 (80.56%)
         occurrences all number
    16
    36
    25
    77
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Graft versus host disease in skin
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 23 (21.74%)
    2 / 6 (33.33%)
    8 / 36 (22.22%)
         occurrences all number
    1
    5
    2
    8
    Dry throat
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    1
    2
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    2
    0
    4
    Epistaxis
         subjects affected / exposed
    2 / 7 (28.57%)
    6 / 23 (26.09%)
    1 / 6 (16.67%)
    9 / 36 (25.00%)
         occurrences all number
    2
    7
    2
    11
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Hyperventilation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Mediastinal haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    4
    0
    4
    Pleural effusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    0
    2
    Respiratory failure
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    1
    0
    3
    Rhinitis allergic
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    1
    2
    Depression
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Disorientation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Fear
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    1
    3
    0
    4
    Organic brain syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    2 / 6 (33.33%)
    4 / 36 (11.11%)
         occurrences all number
    0
    2
    2
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    4 / 36 (11.11%)
         occurrences all number
    2
    1
    1
    4
    Amylase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 23 (8.70%)
    1 / 6 (16.67%)
    5 / 36 (13.89%)
         occurrences all number
    2
    3
    1
    6
    Blood albumin decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Blood calcium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Blood fibrinogen increased
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 23 (17.39%)
    0 / 6 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    1
    4
    0
    5
    Blood immunoglobulin A decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 23 (17.39%)
    2 / 6 (33.33%)
    8 / 36 (22.22%)
         occurrences all number
    2
    4
    2
    8
    Blood immunoglobulin G decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 23 (13.04%)
    2 / 6 (33.33%)
    7 / 36 (19.44%)
         occurrences all number
    2
    3
    3
    8
    Blood immunoglobulin M decreased
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 23 (8.70%)
    2 / 6 (33.33%)
    7 / 36 (19.44%)
         occurrences all number
    3
    2
    2
    7
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    2
    4
    0
    6
    C-reactive protein increased
         subjects affected / exposed
    3 / 7 (42.86%)
    5 / 23 (21.74%)
    2 / 6 (33.33%)
    10 / 36 (27.78%)
         occurrences all number
    5
    6
    2
    13
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Fibrin D dimer increased
         subjects affected / exposed
    3 / 7 (42.86%)
    4 / 23 (17.39%)
    2 / 6 (33.33%)
    9 / 36 (25.00%)
         occurrences all number
    3
    4
    3
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    7 / 36 (19.44%)
         occurrences all number
    5
    3
    0
    8
    Immunoglobulins decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Lipase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    0
    2
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    1
    0
    3
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    1
    2
    Reticulocyte count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Vital capacity abnormal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 23 (8.70%)
    2 / 6 (33.33%)
    8 / 36 (22.22%)
         occurrences all number
    4
    2
    2
    8
    Weight increased
         subjects affected / exposed
    3 / 7 (42.86%)
    7 / 23 (30.43%)
    3 / 6 (50.00%)
    13 / 36 (36.11%)
         occurrences all number
    6
    7
    6
    19
    pH urine decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    2
    2
    0
    4
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Laceration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 23 (21.74%)
    2 / 6 (33.33%)
    9 / 36 (25.00%)
         occurrences all number
    2
    7
    2
    11
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    1
    0
    3
    Apraxia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Balance disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 23 (17.39%)
    0 / 6 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    1
    4
    0
    5
    Formication
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    11 / 23 (47.83%)
    4 / 6 (66.67%)
    17 / 36 (47.22%)
         occurrences all number
    5
    22
    6
    33
    Intention tremor
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences all number
    0
    2
    1
    3
    Neurotoxicity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 23 (13.04%)
    1 / 6 (16.67%)
    5 / 36 (13.89%)
         occurrences all number
    1
    4
    1
    6
    Polyneuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    0
    2
    Tremor
         subjects affected / exposed
    2 / 7 (28.57%)
    8 / 23 (34.78%)
    2 / 6 (33.33%)
    12 / 36 (33.33%)
         occurrences all number
    3
    11
    3
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Coagulopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    2
    0
    0
    2
    Leukopenia
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 23 (4.35%)
    2 / 6 (33.33%)
    6 / 36 (16.67%)
         occurrences all number
    4
    4
    4
    12
    Lymphopenia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    4
    0
    0
    4
    Monocytosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    0
    2
    Splenomegaly
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 23 (13.04%)
    1 / 6 (16.67%)
    7 / 36 (19.44%)
         occurrences all number
    3
    3
    1
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    2 / 6 (33.33%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    2
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences all number
    0
    2
    1
    3
    Eye pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Eyelid oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Lacrimation increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Periorbital oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    1
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    2 / 6 (33.33%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    2
    0
    3
    Anal incontinence
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Aphthous ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 23 (17.39%)
    2 / 6 (33.33%)
    7 / 36 (19.44%)
         occurrences all number
    2
    6
    2
    10
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
    6 / 23 (26.09%)
    3 / 6 (50.00%)
    12 / 36 (33.33%)
         occurrences all number
    5
    7
    3
    15
    Dry mouth
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 23 (0.00%)
    2 / 6 (33.33%)
    4 / 36 (11.11%)
         occurrences all number
    3
    0
    2
    5
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    3
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    1
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 23 (21.74%)
    2 / 6 (33.33%)
    8 / 36 (22.22%)
         occurrences all number
    1
    7
    3
    11
    Proctitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 23 (8.70%)
    2 / 6 (33.33%)
    5 / 36 (13.89%)
         occurrences all number
    3
    2
    3
    8
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Hepatotoxicity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Dry skin
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 23 (13.04%)
    1 / 6 (16.67%)
    5 / 36 (13.89%)
         occurrences all number
    1
    3
    1
    5
    Erythema
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    4 / 36 (11.11%)
         occurrences all number
    2
    1
    1
    4
    Hirsutism
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    0
    3
    Petechiae
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences all number
    3
    2
    3
    8
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    2
    0
    3
    Psoriasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    6 / 23 (26.09%)
    1 / 6 (16.67%)
    8 / 36 (22.22%)
         occurrences all number
    1
    10
    1
    12
    Rash generalised
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    2
    0
    0
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Incontinence
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    1
    2
    Proteinuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Urinary tract pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    3
    1
    0
    4
    Back pain
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 23 (13.04%)
    1 / 6 (16.67%)
    6 / 36 (16.67%)
         occurrences all number
    2
    3
    1
    6
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 23 (17.39%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    6
    0
    6
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    2 / 6 (33.33%)
    4 / 36 (11.11%)
         occurrences all number
    0
    3
    2
    5
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    4
    0
    4
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    3
    3
    Myopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    0
    3
    Neck pain
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    1
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 23 (21.74%)
    0 / 6 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    5
    0
    5
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Candida infection
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    4
    1
    0
    5
    Conjunctivitis
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    2
    2
    0
    4
    Cystitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences all number
    1
    1
    1
    3
    JC virus infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 23 (17.39%)
    2 / 6 (33.33%)
    7 / 36 (19.44%)
         occurrences all number
    1
    5
    2
    8
    Oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 23 (13.04%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    4
    0
    4
    Otitis media
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    1
    2
    Pneumonia fungal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    2
    0
    3
    Sinusitis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences all number
    2
    0
    1
    3
    Skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    2
    2
    Staphylococcal infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    0
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    3 / 36 (8.33%)
         occurrences all number
    1
    1
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    4
    0
    0
    4
    Hypokalaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 23 (13.04%)
    1 / 6 (16.67%)
    6 / 36 (16.67%)
         occurrences all number
    2
    3
    1
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2010
    - Reduce the highest dose explored in the study from 60 μg/m²/day to 30 μg/m²/day
    27 Jan 2011
    - Implementation of an interim cohort 2a with a lower initial dose of 5 μg/m²/day for the first week and with the maintenance dose of 15 μg/m²/day for the remaining 3 weeks of the first cycle on the basis of recommendation of the Data Monitoring Committee (DMC) - Implementation of possibility for re-treatment in case of medullary relapse after treatment start - Shortening of period for last dose of tyrosine kinase inhibitor and initiation of treatment with blinatumomab from 2 weeks to 72 hours - Exclusion of subjects with testicular involvement of acute lymphoblastic leukemia - Recommendation to obtain an additional bone marrow aspiration/biopsy on day 15 of the first treatment cycle - Outsourcing of analyses of lymphocyte subpopulation (cohorts 1 and 2a were performed at Amgen Research [Munich]); cohorts 2b and 3 analyses were outsourced to a central laboratory (Labor München Zentrum). Reduction of blood sampling time points and change of marker panel in connection with the change in laboratory.
    02 Sep 2011
    - Implementation of decisions made at investigator meeting (03 March 2011) and DMC meetings (08 March 2011 and 15 July 2011) concerning dose modification in case of relevant central nervous system (CNS) events and dosing in re-treatment cycles: - No dose increase to 30 μg/m²/day for subjects treated in cohort 2b who experience clinically-relevant CNS events at a dose of 15 μg/m²/day. - For subjects experiencing a clinically-relevant CNS event leading to treatment stop at a dose of 15 μg/m²/day, the infusion could be restarted at a constant dose of 5 μg/m²/day for the remaining treatment duration in the core study after a temporary interruption for up to 2 weeks. - Dosing in re-treatment cycles had to be the same as in cohort 3 (5 to 15 μg/m²/day). - Increase in the number of subjects for ethical and operational reasons: subjects who already were in the screening phase at the time the 25th potentially evaluable subject started treatment, had to be allowed to receive treatment as well. Therefore, an over running of subject recruitment up to a total of approximately 30 subjects could be possible.
    16 Feb 2012
    - Antifungal prophylaxis for subjects with active graft-versus-host disease in their medical history after allogeneic hematopoietic stem cell transplantation - Permanent discontinuation of blinatumomab in case of occurrence of ≥ 1 seizure - Prophylactic measures for subjects with a high risk for cytomegalovirus infection - Prophylactic anticonvulsant treatment for subjects who had a seizure - Diagnostic measures to exclude potential infectious causes after CNS events Common Terminology Criteria for Adverse Events grade ≥ 3

    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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