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    Clinical Trial Results:
    A Phase 2 Randomized Open-label Study of MEDI-551 in Adults With Relapsed or Refractory DLBCL

    Summary
    EudraCT number
    2011-002565-38
    Trial protocol
    DE   CZ   ES   HU   IT   PL  
    Global end of trial date
    17 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Feb 2018
    First version publication date
    21 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CD-ON-MEDI-551-1088
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01453205
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, United States, MD 20878
    Public contact
    AstraZeneca, AstraZeneca Clinical Study Information Center,, +1 18772409479, information.center@astrazenca.com
    Scientific contact
    AstraZeneca, AstraZeneca Clinical Study Information Center,, +1 18772409479, information.center@astrazeneca.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
    17 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the overall response rate (ORR), including partial response (PR) and complete response (CR), of participants treated with MEDI-551 when used in combination with ifosfamide-carboplatin-etoposide (ICE) or dexamethasone-cytarabine-cisplatin (DHAP) versus rituximab in combination with ICE or DHAP in participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice and applicable regulatory requirements. Participants signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 84
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Turkey: 7
    Worldwide total number of subjects
    187
    EEA total number of subjects
    73
    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)
    138
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted from 27Feb2012 to 17Jun2016.

    Pre-assignment
    Screening details
    A total of 256 participants were screened, of which 187 participants were randomized in the study.

    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
    Rituximab+ ICE/DHAP
    Arm description
    Participants received Rituximab in combination with ifosfamide + carboplatin + etoposide (ICE) or dexamethasone + cisplatin + cytarabine (DHAP) for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). Rituximab (375 mg/m^2) was administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of rituximab, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of rituximab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab (375 mg/m^2) was administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle.

    Arm title
    MEDI-551 2 mg/kg + ICE/DHAP
    Arm description
    Participants received MEDI-551 (2 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (2 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI-551 2 mg/kg
    Investigational medicinal product code
    Other name
    Inebilizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI-551 (2 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle.

    Arm title
    MEDI-551 4 mg/kg + ICE/DHAP
    Arm description
    Participants received MEDI-551 (4 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (4 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI-551 4 mg/kg
    Investigational medicinal product code
    Other name
    Inebilizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI-551 (4 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle.

    Number of subjects in period 1
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Started
    80
    52
    55
    Completed
    0
    0
    1
    Not completed
    80
    52
    54
         Adverse event, serious fatal
    24
    22
    18
         Unspecified
    45
    27
    35
         Consent withdrawn by subject
    8
    3
    -
         Lost to follow-up
    3
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab+ ICE/DHAP
    Reporting group description
    Participants received Rituximab in combination with ifosfamide + carboplatin + etoposide (ICE) or dexamethasone + cisplatin + cytarabine (DHAP) for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). Rituximab (375 mg/m^2) was administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of rituximab, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of rituximab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group title
    MEDI-551 2 mg/kg + ICE/DHAP
    Reporting group description
    Participants received MEDI-551 (2 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (2 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group title
    MEDI-551 4 mg/kg + ICE/DHAP
    Reporting group description
    Participants received MEDI-551 (4 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (4 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP Total
    Number of subjects
    80 52 55 187
    Age Categorical
    Units: Subjects
        < 65 YEARS
    60 35 43 138
        >= 65 YEARS
    20 17 12 49
    Age Continuous
    Units: YEARS
        arithmetic mean (standard deviation)
    56.4 ± 12.3 56.9 ± 11.4 55.9 ± 11.6 -
    Gender, Male/Female
    Units: Subjects
        Female
    35 19 24 78
        Male
    45 33 31 109
    Subject analysis sets

    Subject analysis set title
    MEDI-551
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were received MEDI-551 2 mg/kg or 4 mg/kg by IV infusion. Recommended MEDI-551 dose was selected based on the DMC reviews. As there is no data available for the 107 participants presented for the endpoint accepted dose of MEDI-551, I have included the arbitrary value of '99999' for Age continuous field (arithmetic mean and the standard deviation).

    Subject analysis sets values
    MEDI-551
    Number of subjects
    107
    Age Categorical
    Units: Subjects
        < 65 YEARS
        >= 65 YEARS
    Age Continuous
    Units: YEARS
        arithmetic mean (standard deviation)
    56.4 ± 11.8
    Gender, Male/Female
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Rituximab+ ICE/DHAP
    Reporting group description
    Participants received Rituximab in combination with ifosfamide + carboplatin + etoposide (ICE) or dexamethasone + cisplatin + cytarabine (DHAP) for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). Rituximab (375 mg/m^2) was administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of rituximab, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of rituximab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group title
    MEDI-551 2 mg/kg + ICE/DHAP
    Reporting group description
    Participants received MEDI-551 (2 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (2 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group title
    MEDI-551 4 mg/kg + ICE/DHAP
    Reporting group description
    Participants received MEDI-551 (4 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (4 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Subject analysis set title
    MEDI-551
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were received MEDI-551 2 mg/kg or 4 mg/kg by IV infusion. Recommended MEDI-551 dose was selected based on the DMC reviews. As there is no data available for the 107 participants presented for the endpoint accepted dose of MEDI-551, I have included the arbitrary value of '99999' for Age continuous field (arithmetic mean and the standard deviation).

    Primary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    Objective Response Rate, defined as the proportion of participants with a best response of complete response (disappearance of all evidence of disease) or partial response (regression of measurable disease and no new sites) according to the International Working Group criteria. The analysis for this end point was based on Intent-To-Treat (ITT) population, which included all participants who were randomized into the study.
    End point type
    Primary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    80
    52
    55
    Units: Percentage of participants
        number (confidence interval 95%)
    47.5 (36.2 to 59.0)
    46.2 (32.2 to 60.5)
    43.6 (30.3 to 57.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Rituximab+ ICE/DHAP v MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.5543
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    Progression-free survival (PFS) is defined as the time from randomization until the first documentation of disease progression or death due to any cause, whichever occurs first. PFS (months) = (Date of PD/death or censoring – Date of randomization + 1) / (365.25/12). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    80
    52
    55
    Units: months
        median (full range (min-max))
    6.1 (0.0 to 39.2)
    6.6 (0.0 to 31.3)
    7.7 (0 to 14.8)
    Statistical analysis title
    Rituximab vs Inebilizumab 4 mg/kg
    Comparison groups
    Rituximab+ ICE/DHAP v MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8567
    Method
    Logrank
    Confidence interval

    Secondary: Event-Free Survival (EFS)

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    End point title
    Event-Free Survival (EFS)
    End point description
    Event-Free Survival (EFS) is defined as the time from randomization until the first documentation of EFS events which include disease progression, initiation of alternative antitumor treatment or death due to any cause, whichever occurs first. EFS (months) = (Date of EFS or censoring – Date of randomization + 1) / (365.25/12). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    80
    52
    55
    Units: months
        median (full range (min-max))
    4.7 (0.0 to 39.2)
    4.2 (0.0 to 31.3)
    5.9 (0.0 to 14.8)
    Statistical analysis title
    Rituximab vs Inebilizumab 4 mg/kg
    Comparison groups
    Rituximab+ ICE/DHAP v MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.7412
    Method
    Logrank
    Confidence interval

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival defined as the time from randomization until death due to any cause. OS (months) = (Date of death or censoring – Date of randomization + 1) / (365.25/12). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study. '99999' indicates value was not estimable.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    80
    52
    55
    Units: months
        median (confidence interval 95%)
    99999 (15.6 to 99999)
    99999 (14.2 to 99999)
    23.0 (12.8 to 99999)
    Statistical analysis title
    Rituximab vs Inebilizumab 4 mg/kg
    Comparison groups
    Rituximab+ ICE/DHAP v MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.9996
    Method
    Logrank
    Confidence interval

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    Time to Progression (TTP) defined as the time from randomization until the first documentation of disease progression. TTP (months) = (Date of PD or censoring – Date of randomization + 1) / (365.25/12). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    80
    52
    55
    Units: months
        median (full range (min-max))
    4.9 (0.0 to 11.1)
    4.2 (0.0 to 31.3)
    5.9 (0.0 to 14.0)
    Statistical analysis title
    Rituximab vs Inebilizumab 4 mg/kg
    Comparison groups
    Rituximab+ ICE/DHAP v MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1686
    Method
    Logrank
    Confidence interval

    Secondary: Time to Response (TTR)

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    End point title
    Time to Response (TTR)
    End point description
    Time to response (TTR) defined as the time from randomization until the first documentation of disease response. Only participants who have achieved objective response (confirmed CR or confirmed PR) assessed by investigator were evaluated for TTR. TTR (months) = (Date of first disease response – Date of randomization + 1) / (365.25/12). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    42
    32
    30
    Units: months
        median (full range (min-max))
    1.7 (0.9 to 3.8)
    2.3 (1.5 to 3.4)
    2.3 (1.6 to 6.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DR)

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    End point title
    Duration of Response (DR)
    End point description
    Duration of Response (DR) defined as time from start of first documented objective response (confirmed Complete Response [CR] or confirmed Partial Response [PR]) to first documented disease progression. Only participants who have achieved objective response assessed by investigator were evaluated. DR calculated as (months) = (Date of PD or censoring – Date of first disease response + 1)/ (365.25/12). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study. '99999' indicates value was not estimable.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    42
    32
    30
    Units: months
        median (confidence interval 95%)
    99999 (4.9 to 99999)
    7.1 (4.1 to 99999)
    7.9 (4.6 to 12.2)
    No statistical analyses for this end point

    Secondary: Number of Participants with Best Overall Response Assessed by Blinded Independent Central Review (BICR)

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    End point title
    Number of Participants with Best Overall Response Assessed by Blinded Independent Central Review (BICR)
    End point description
    The best overall response was calculated, based upon the disease assessments recorded during the study visits, and summarized with the number of participants for the following categories: complete response (CR), partial response (PR), stable disease (SD), progessive disease (PD), and not evaluable (NE). The analysis for this end point was based on ITT population, which included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    80
    52
    55
    Units: Number of particpants
        COMPLETE RESPONSE (CR)
    20
    6
    12
        PARTIAL RESPONSE (PR)
    18
    18
    12
        STABLE DISEASE (SD)
    17
    12
    14
        PROGRESSIVE DISEASE (PD)
    5
    5
    5
        UNKNOWN
    20
    11
    12
    No statistical analyses for this end point

    Secondary: Acceptable Dose of MEDI-551

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    End point title
    Acceptable Dose of MEDI-551
    End point description
    Acceptable dose for MEDI-551 was evaluated based on the benefit-risk analysis. The analysis for this end point was based on all participants who were randomized into the study and received MEDI-551.
    End point type
    Secondary
    End point timeframe
    After the administration of the first dose of MEDI-551(7 days before the Cycle 1) to last dose of MEDI-551 (Cycle 3 Day 1) (each cycle of 21 days)
    End point values
    MEDI-551
    Number of subjects analysed
    107
    Units: milligram per kilogram (mg/kg)
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An Adverse Event (AE) is any unfavourable and unintended signs, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. SAE is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 90 days after the end of treatment (EOT). The analysis for this end point was based on safety population, which included all participants who received any study treatment.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    79
    52
    54
    Units: Number of participants
        TEAEs
    78
    51
    52
        TESAEs
    33
    25
    27
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Hematology/Coagulation Laboratory Results

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Hematology/Coagulation Laboratory Results
    End point description
    An abnormal laboratory finding that was judged by the investigator to be medically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of inebilizumab, or events absent at baseline that emerged after administration of inebilizumab, for the period extending to 90 days after the EOT. The analysis for this end point was based on safety population, which included all participants who received any study treatment.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    79
    52
    54
    Units: Number of participants
        Anaemia
    47
    32
    33
        Febrile neutropenia
    16
    9
    12
        Granulocytopenia
    3
    0
    2
        Leukopenia
    9
    6
    10
        Lymphopenia
    4
    2
    3
        Neutropenia
    30
    15
    20
        Pancytopenia
    2
    0
    3
        Thromobocytopenia
    49
    24
    29
        Activated partial thromboplastin time prolonged
    0
    2
    0
        Blood immunoglobulin g decreased
    0
    1
    0
        Blood immunoglobulin m decreased
    0
    1
    0
        Haemoglobin decreased
    0
    1
    0
        Immunoglobulins decreased
    0
    1
    0
        Lymphocyte count decreased
    9
    4
    3
        Neutrophil count decreased
    7
    6
    8
        Platelet count decreased
    12
    8
    10
        Platelet count increased
    0
    1
    0
        White blood cell count decreased
    6
    5
    6
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Chemistry Laboratory Results (include Urinalysis)

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Chemistry Laboratory Results (include Urinalysis)
    End point description
    An abnormal laboratory findings that was judged by the investigator to be medically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of inebilizumab, or events absent at baseline that emerged after administration of inebilizumab, for the period extending to 90 days after the end of study treatment. The analysis for this end point was based on safety population, which included all participants who received any study treatment.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    79
    52
    54
    Units: Number of participants
        Hyperbilirubinaemia
    1
    0
    0
        Hypernatraemia
    3
    1
    1
        Hyperphosphataemia
    0
    0
    2
        Hypertriglyerideaemia
    1
    0
    0
        Hyperuricaemia
    5
    4
    1
        Hypoalbuminaemia
    3
    4
    3
        Hypocalcaemia
    11
    6
    7
        Hypoglycaemia
    1
    1
    1
        Hypokalaemia
    24
    13
    14
        Hypomagnesaemia
    17
    6
    11
        Hyponatraemia
    8
    2
    2
        Hypophosphataemia
    4
    3
    3
        Hypoproteinaemia
    0
    0
    1
        Alanine aminotransferase increased
    7
    2
    4
        Aspartate aminotransferase increased
    5
    2
    6
        Blood alkaline phosphatase increased
    2
    0
    1
        Blood bicarbonate decreased
    1
    0
    0
        Blood bilirubin increased
    1
    1
    1
        Blood chloride increased
    0
    1
    0
        Blood creatinine increased
    10
    5
    7
        Blood lactate dehydrogenase increased
    2
    1
    1
        Blood magnesium decreased
    2
    0
    0
        Blood potassium decreased
    2
    0
    0
        Blood uric acid decreased
    0
    1
    0
        Blood uric acid increased
    1
    1
    0
        Gamma-glutamyltransferase increased
    9
    3
    3
        Hepatic enzyme increased
    1
    0
    1
        Protein total decreased
    0
    1
    1
        Transaminases increased
    1
    2
    0
        Dysuria
    2
    1
    3
        Hematuria
    2
    3
    0
        Glucose urine present
    0
    1
    1
        Proteinuria
    0
    1
    1
        Urine sodium increased
    0
    0
    1
        Calcium deficiency
    0
    0
    1
        Electrolyte imbalance
    2
    0
    0
        Hypercalcaemia
    2
    1
    0
        Hyperglycaemia
    12
    9
    2
        Hyperkalaemia
    2
    2
    1
        Hypermagnesaemia
    3
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and ECG Abnormalities

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and ECG Abnormalities
    End point description
    Vital signs included parameters such as heart rate, blood pressure, temperature, and respiratory rate. An abnormal vital signs and ECG findings that was judged by the investigator to be medically significant was reported an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of inebilizumab, or events absent at baseline that emerged after administration of inebilizumab, for the period extending to 90 days after the end of study treatment. The analysis for this end point was based on safety population, which included all participants who received any study treatment.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    End point values
    Rituximab+ ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    79
    52
    54
    Units: Number of participants
        Arrhythmia
    0
    0
    2
        Atrial fibrillation
    1
    1
    2
        Bradycardia
    3
    1
    2
        Extrasystoles
    0
    1
    0
        Palpitations
    2
    1
    0
        Sinus arrhythmia
    0
    0
    1
        Sinus bradycardia
    1
    2
    1
        Systolic dysfunction
    0
    0
    1
        Tachycardia
    3
    1
    2
        Pyrexia
    17
    14
    11
        Blood pressure increased
    0
    0
    1
        Carbon dioxide decreased
    1
    0
    0
        Electrocardiogram abnormal
    0
    0
    1
        Electrocardiogram QT prolonged
    0
    2
    2
        Heart rate irregular
    1
    0
    0
        Weight decreased
    0
    1
    1
        Weight increased
    1
    0
    1
        Dyspnoea
    11
    7
    8
        Dyspnoea exertional
    0
    3
    1
        Hypertension
    5
    2
    3
        Hypotension
    10
    4
    8
    No statistical analyses for this end point

    Secondary: Number of Participants who Developed Detectable MEDI-551 Anti-drug Antibodies

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    End point title
    Number of Participants who Developed Detectable MEDI-551 Anti-drug Antibodies [1]
    End point description
    A participant was considered ADA-positive across the study if they had a positive reading (titer of 50 or higher) at any time point during the study. The analysis for this end point was based on safety population, which included all participants who received any study treatment.
    End point type
    Secondary
    End point timeframe
    7 days before the start of Cycle 1, Day 1 of each subsequent Cycle, EOT, and post EOT on Days 30, 60, 90 and 270 (up to 36 months from the randomization of last participant)
    Notes
    [1] - 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: This end point is related to MEDI-551. Therefore, it is applicable for “MEDI-551 2 mg/kg + ICE/DHAP” and “MEDI-551 4 mg/kg + ICE/DHAP” arms only.
    End point values
    MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    52
    54
    Units: Number of participants
    1
    0
    No statistical analyses for this end point

    Secondary: Mean Serum Concentration of MEDI-551

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    End point title
    Mean Serum Concentration of MEDI-551 [2]
    End point description
    The mean serum concentration of MEDI-551 were observed. Participants who received MEDI-551 were analysed for this end point. Here, "n" is number of participants analysed at this time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day -7 Post dose, pre-dose and postdose on Day 1, post-dose on Days 4, 8, 15 of Cycle 1, pre-dose and postdose on Day 1 of Cycle 2 and Cycle 3
    Notes
    [2] - 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: This end point is related to MEDI-551. Therefore, it is applicable for “MEDI-551 2 mg/kg + ICE/DHAP” and “MEDI-551 4 mg/kg + ICE/DHAP” arms only.
    End point values
    MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    52
    54
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day-7 Post Dose (n= 46, 50)
    47.0 ± 23.7
    83.8 ± 21.9
        Cycle 1 Day 1 Pre Dose (n= 46, 52)
    16.7 ± 5.81
    33.1 ± 16.3
        Cycle 1 Day 1 Post Dose (n= 46, 51)
    64.8 ± 26.4
    116 ± 41.3
        Cycle 1 Day 4 (n= 43, 45)
    38.8 ± 14.6
    71.9 ± 23.0
        Cycle 1 Day 8 (n= 44, 48)
    30.6 ± 9.69
    69.3 ± 25.1
        Cycle 1 Day 15 (n= 40, 43)
    19.4 ± 6.19
    44.7 ± 25.0
        Cycle 2 Day 1 Pre Dose (n= 40, 44)
    15.0 ± 5.45
    30.9 ± 14.3
        Cycle 2 Day 1 Post Dose (n= 40, 43)
    52.3 ± 18.7
    112 ± 32.6
        Cycle 3 Day 1 Pre Dose (n= 26, 26)
    14.0 ± 6.50
    36.4 ± 18.7
        Cycle 3 Day 1 Post Dose (n= 25, 25)
    52.4 ± 16.9
    116 ± 30.9
    No statistical analyses for this end point

    Secondary: Half-life (T1/2) of MEDI-551

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    End point title
    Half-life (T1/2) of MEDI-551 [3]
    End point description
    Terminal elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the serum. Participants who received MEDI-551 were analysed for this end point. Here, "n" is number of participants analysed at this time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and EOT (Day 21 of Cycle 3 [each cycle of 21 days] or earlier cycles if treatment stopped before Cycle 3)
    Notes
    [3] - 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: This end point is related to MEDI-551. Therefore, it is applicable for “MEDI-551 2 mg/kg + ICE/DHAP” and “MEDI-551 4 mg/kg + ICE/DHAP” arms only.
    End point values
    MEDI-551 2 mg/kg + ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP
    Number of subjects analysed
    52
    54
    Units: Day
    arithmetic mean (standard deviation)
        Cycle 1 n= (36, 43)
    14.4 ± 5.09
    16.5 ± 10.5
        End of Treatment n= (9,17)
    18.9 ± 4.34
    20.2 ± 5.73
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From treatment administration (Day1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
    Adverse event reporting additional description
    AE were reported for safety population, which included all participants who received any study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Rituximab+ ICE/DHAP
    Reporting group description
    Participants received Rituximab in combination with ifosfamide + carboplatin + etoposide (ICE) or dexamethasone + cisplatin + cytarabine (DHAP) for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). Rituximab (375 mg/m^2) was administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of rituximab, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of rituximab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group title
    MEDI-551 4 mg/kg + ICE/DHAP
    Reporting group description
    Participants received MEDI-551 (4 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (4 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of Inebilizumab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Reporting group title
    MEDI-551 2 mg/kg + ICE/DHAP
    Reporting group description
    Participants received MEDI-551 (2 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and were followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (2 mg/kg) was administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of Inebilizumab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.

    Serious adverse events
    Rituximab+ ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 79 (41.77%)
    27 / 54 (50.00%)
    25 / 52 (48.08%)
         number of deaths (all causes)
    24
    18
    22
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Central nervous system lymphoma
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Tumour haemorrhage
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 54 (3.70%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal inflammation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 54 (3.70%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    11 / 79 (13.92%)
    9 / 54 (16.67%)
    8 / 52 (15.38%)
         occurrences causally related to treatment / all
    8 / 11
    10 / 10
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 54 (5.56%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    6 / 7
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Coma hepatic
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 54 (3.70%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 54 (3.70%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis viral
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 54 (7.41%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 3
    5 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Rituximab+ ICE/DHAP MEDI-551 4 mg/kg + ICE/DHAP MEDI-551 2 mg/kg + ICE/DHAP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 79 (98.73%)
    52 / 54 (96.30%)
    49 / 52 (94.23%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 54 (5.56%)
    2 / 52 (3.85%)
         occurrences all number
    9
    10
    2
    Hypotension
         subjects affected / exposed
    10 / 79 (12.66%)
    8 / 54 (14.81%)
    3 / 52 (5.77%)
         occurrences all number
    12
    9
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 79 (11.39%)
    11 / 54 (20.37%)
    12 / 52 (23.08%)
         occurrences all number
    12
    15
    21
    Chills
         subjects affected / exposed
    6 / 79 (7.59%)
    2 / 54 (3.70%)
    1 / 52 (1.92%)
         occurrences all number
    9
    2
    1
    Fatigue
         subjects affected / exposed
    22 / 79 (27.85%)
    15 / 54 (27.78%)
    20 / 52 (38.46%)
         occurrences all number
    32
    20
    33
    Mucosal inflammation
         subjects affected / exposed
    7 / 79 (8.86%)
    3 / 54 (5.56%)
    3 / 52 (5.77%)
         occurrences all number
    7
    5
    3
    Oedema
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 54 (3.70%)
    1 / 52 (1.92%)
         occurrences all number
    6
    2
    2
    Pyrexia
         subjects affected / exposed
    17 / 79 (21.52%)
    9 / 54 (16.67%)
    12 / 52 (23.08%)
         occurrences all number
    24
    10
    16
    Oedema peripheral
         subjects affected / exposed
    10 / 79 (12.66%)
    5 / 54 (9.26%)
    6 / 52 (11.54%)
         occurrences all number
    12
    7
    9
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 54 (5.56%)
    1 / 52 (1.92%)
         occurrences all number
    3
    4
    1
    Anxiety
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 54 (3.70%)
    5 / 52 (9.62%)
         occurrences all number
    8
    2
    5
    Insomnia
         subjects affected / exposed
    8 / 79 (10.13%)
    8 / 54 (14.81%)
    4 / 52 (7.69%)
         occurrences all number
    9
    8
    4
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    11 / 79 (13.92%)
    6 / 54 (11.11%)
    7 / 52 (13.46%)
         occurrences all number
    32
    6
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 79 (8.86%)
    4 / 54 (7.41%)
    2 / 52 (3.85%)
         occurrences all number
    13
    7
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 79 (6.33%)
    6 / 54 (11.11%)
    2 / 52 (3.85%)
         occurrences all number
    11
    13
    2
    Blood creatinine increased
         subjects affected / exposed
    10 / 79 (12.66%)
    7 / 54 (12.96%)
    5 / 52 (9.62%)
         occurrences all number
    17
    17
    8
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    2
    1
    1
    Electrocardiogram qt prolonged
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 54 (3.70%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 79 (11.39%)
    3 / 54 (5.56%)
    3 / 52 (5.77%)
         occurrences all number
    15
    4
    8
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 79 (11.39%)
    3 / 54 (5.56%)
    4 / 52 (7.69%)
         occurrences all number
    27
    7
    13
    Neutrophil count decreased
         subjects affected / exposed
    7 / 79 (8.86%)
    8 / 54 (14.81%)
    5 / 52 (9.62%)
         occurrences all number
    8
    16
    8
    Platelet count decreased
         subjects affected / exposed
    12 / 79 (15.19%)
    10 / 54 (18.52%)
    8 / 52 (15.38%)
         occurrences all number
    31
    23
    38
    White blood cell count decreased
         subjects affected / exposed
    6 / 79 (7.59%)
    6 / 54 (11.11%)
    4 / 52 (7.69%)
         occurrences all number
    13
    22
    9
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 54 (3.70%)
    1 / 52 (1.92%)
         occurrences all number
    1
    2
    1
    Bradycardia
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 54 (3.70%)
    1 / 52 (1.92%)
         occurrences all number
    3
    2
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    1
    1
    3
    Tachycardia
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 54 (3.70%)
    1 / 52 (1.92%)
         occurrences all number
    3
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 79 (12.66%)
    8 / 54 (14.81%)
    9 / 52 (17.31%)
         occurrences all number
    12
    8
    12
    Dyspnoea
         subjects affected / exposed
    11 / 79 (13.92%)
    7 / 54 (12.96%)
    7 / 52 (13.46%)
         occurrences all number
    15
    8
    11
    Dyspnoea exertional
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 54 (1.85%)
    3 / 52 (5.77%)
         occurrences all number
    0
    2
    3
    Epistaxis
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 54 (1.85%)
    3 / 52 (5.77%)
         occurrences all number
    5
    1
    5
    Hiccups
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 54 (3.70%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    3
    Oropharyngeal pain
         subjects affected / exposed
    6 / 79 (7.59%)
    4 / 54 (7.41%)
    0 / 52 (0.00%)
         occurrences all number
    7
    4
    0
    Pleural effusion
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences all number
    5
    2
    0
    Pulmonary embolism
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences all number
    2
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    6
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    47 / 79 (59.49%)
    33 / 54 (61.11%)
    32 / 52 (61.54%)
         occurrences all number
    113
    111
    87
    Granulocytopenia
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences all number
    5
    4
    0
    Febrile neutropenia
         subjects affected / exposed
    6 / 79 (7.59%)
    3 / 54 (5.56%)
    2 / 52 (3.85%)
         occurrences all number
    6
    4
    2
    Leukopenia
         subjects affected / exposed
    8 / 79 (10.13%)
    10 / 54 (18.52%)
    6 / 52 (11.54%)
         occurrences all number
    10
    31
    8
    Lymphopenia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 54 (5.56%)
    2 / 52 (3.85%)
         occurrences all number
    22
    4
    18
    Neutropenia
         subjects affected / exposed
    27 / 79 (34.18%)
    18 / 54 (33.33%)
    15 / 52 (28.85%)
         occurrences all number
    50
    45
    30
    Thrombocytopenia
         subjects affected / exposed
    47 / 79 (59.49%)
    28 / 54 (51.85%)
    24 / 52 (46.15%)
         occurrences all number
    172
    114
    71
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 79 (13.92%)
    7 / 54 (12.96%)
    8 / 52 (15.38%)
         occurrences all number
    12
    9
    10
    Dysgeusia
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 54 (5.56%)
    5 / 52 (9.62%)
         occurrences all number
    3
    3
    5
    Headache
         subjects affected / exposed
    14 / 79 (17.72%)
    8 / 54 (14.81%)
    7 / 52 (13.46%)
         occurrences all number
    19
    10
    7
    Neuropathy peripheral
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 54 (3.70%)
    2 / 52 (3.85%)
         occurrences all number
    5
    3
    2
    Presyncope
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    1
    Syncope
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 54 (3.70%)
    2 / 52 (3.85%)
         occurrences all number
    3
    2
    2
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    4
    0
    1
    Vision blurred
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    2
    1
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 54 (5.56%)
    0 / 52 (0.00%)
         occurrences all number
    4
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 54 (3.70%)
    6 / 52 (11.54%)
         occurrences all number
    5
    3
    9
    Abdominal pain upper
         subjects affected / exposed
    5 / 79 (6.33%)
    4 / 54 (7.41%)
    2 / 52 (3.85%)
         occurrences all number
    5
    4
    2
    Constipation
         subjects affected / exposed
    23 / 79 (29.11%)
    18 / 54 (33.33%)
    17 / 52 (32.69%)
         occurrences all number
    38
    27
    23
    Diarrhoea
         subjects affected / exposed
    19 / 79 (24.05%)
    13 / 54 (24.07%)
    15 / 52 (28.85%)
         occurrences all number
    26
    16
    17
    Dry mouth
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    4
    0
    1
    Dyspepsia
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    4
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 79 (7.59%)
    5 / 54 (9.26%)
    0 / 52 (0.00%)
         occurrences all number
    8
    5
    0
    Haemorrhoids
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    4
    1
    2
    Nausea
         subjects affected / exposed
    43 / 79 (54.43%)
    25 / 54 (46.30%)
    23 / 52 (44.23%)
         occurrences all number
    75
    42
    45
    Oral pain
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences all number
    2
    2
    0
    Stomatitis
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 54 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    5
    0
    2
    Vomiting
         subjects affected / exposed
    26 / 79 (32.91%)
    14 / 54 (25.93%)
    14 / 52 (26.92%)
         occurrences all number
    37
    21
    28
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 54 (7.41%)
    3 / 52 (5.77%)
         occurrences all number
    4
    5
    5
    Dysuria
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 54 (5.56%)
    1 / 52 (1.92%)
         occurrences all number
    2
    3
    3
    Haematuria
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    3
    0
    3
    Pollakiuria
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    4
    0
    2
    Renal failure
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences all number
    4
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 79 (7.59%)
    8 / 54 (14.81%)
    5 / 52 (9.62%)
         occurrences all number
    7
    8
    7
    Night sweats
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 54 (7.41%)
    1 / 52 (1.92%)
         occurrences all number
    3
    4
    1
    Petechiae
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    5
    1
    2
    Pruritus
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    1
    Rash
         subjects affected / exposed
    3 / 79 (3.80%)
    6 / 54 (11.11%)
    0 / 52 (0.00%)
         occurrences all number
    4
    8
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 54 (1.85%)
    4 / 52 (7.69%)
         occurrences all number
    4
    2
    5
    Back pain
         subjects affected / exposed
    12 / 79 (15.19%)
    4 / 54 (7.41%)
    2 / 52 (3.85%)
         occurrences all number
    15
    4
    2
    Bone pain
         subjects affected / exposed
    7 / 79 (8.86%)
    7 / 54 (12.96%)
    8 / 52 (15.38%)
         occurrences all number
    8
    9
    9
    Muscle spasms
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    4
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 54 (5.56%)
    4 / 52 (7.69%)
         occurrences all number
    1
    3
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 54 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    4
    0
    2
    Myalgia
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 54 (1.85%)
    4 / 52 (7.69%)
         occurrences all number
    7
    1
    8
    Neck pain
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    3
    0
    3
    Pain in extremity
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    6
    1
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 79 (15.19%)
    8 / 54 (14.81%)
    7 / 52 (13.46%)
         occurrences all number
    14
    11
    7
    Dehydration
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    0
    3
    Fluid overload
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    2
    1
    1
    Hyperglycaemia
         subjects affected / exposed
    12 / 79 (15.19%)
    2 / 54 (3.70%)
    8 / 52 (15.38%)
         occurrences all number
    23
    4
    22
    Hyperkalaemia
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    2
    1
    2
    Hypermagnesaemia
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 54 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    5
    0
    2
    Hypernatraemia
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    1
    Hyperuricaemia
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 54 (1.85%)
    4 / 52 (7.69%)
         occurrences all number
    6
    1
    5
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 54 (5.56%)
    4 / 52 (7.69%)
         occurrences all number
    3
    3
    4
    Hypocalcaemia
         subjects affected / exposed
    11 / 79 (13.92%)
    7 / 54 (12.96%)
    6 / 52 (11.54%)
         occurrences all number
    31
    8
    9
    Hypokalaemia
         subjects affected / exposed
    24 / 79 (30.38%)
    14 / 54 (25.93%)
    13 / 52 (25.00%)
         occurrences all number
    50
    28
    23
    Hypomagnesaemia
         subjects affected / exposed
    17 / 79 (21.52%)
    11 / 54 (20.37%)
    6 / 52 (11.54%)
         occurrences all number
    37
    19
    10
    Hyponatraemia
         subjects affected / exposed
    8 / 79 (10.13%)
    2 / 54 (3.70%)
    2 / 52 (3.85%)
         occurrences all number
    11
    2
    3
    Hypophosphataemia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 54 (5.56%)
    3 / 52 (5.77%)
         occurrences all number
    10
    3
    4
    Tumour lysis syndrome
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
         occurrences all number
    3
    1
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    1
    1
    2
    Oral herpes
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 54 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    5
    0
    2
    Pneumonia
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 54 (3.70%)
    0 / 52 (0.00%)
         occurrences all number
    2
    2
    0
    Rhinitis
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 54 (1.85%)
    2 / 52 (3.85%)
         occurrences all number
    2
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 54 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    0
    3
    Urinary tract infection
         subjects affected / exposed
    7 / 79 (8.86%)
    3 / 54 (5.56%)
    3 / 52 (5.77%)
         occurrences all number
    10
    3
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2013
    The Protocol was amended to update the exploratory objectives; Randomization plan and schedule of data monitoring committee (DMC) reviews updated; Number of study centers was increased from 50 to 106; Russia, and Israel were added; and Australia was removed, reflecting current strategy for enrolling the study. The choice of ifosfamide-carboplatin-etoposide (ICE) or dexamethasone-cytarabine-cisplatin (DHAP) as the chemotherapy regimen was made for each participant by the investigator as per institutional standard of care; Study-stopping criteria updated; Updated inclusion and exclusion criteria, withdrawal criteria, and specified replacement of participants criteria. Rituximab was added to ICE and DHAP. Updated treatment assignment and treatment regimen to improve study design. Added information related to MEDI-551 preparation and administration, dose modification for toxicity management, and concomitant medication to improve participants safety. The scheduled of procedures was updated.
    11 Mar 2014
    The minimum dose of methylprednisolone was administered before the first infusion of MEDI-551 was changed from 50 mg to 60 mg (or its equivalent), as this is the standard dose for this purpose; Three additional exploratory objectives were added; The total number of participants to be enrolled was increased from 170 to 180; Inclusion Criteria, exclusion Criteria, withdrawal Criteria, dose modification for toxicity management, permitted concomitant medications, schedule of study procedures were updated.
    06 Mar 2015
    Previous evaluations of “Full-body fluorodeoxyglucose-positron emission tomography (FDG-PET) scan and chest, abdomen, pelvis, and neck CT scan, unless participant discontinued for progressive disease (PD), tumor measurements, and disease response evaluation” at End of Treatment (+ 14 Days) and Day 60 Post EOT (+/- 7 Days) were changed to evaluation of “Chest, abdomen, pelvis, and neck CT scan, unless participant discontinued for PD” at End of Treatment and Day 90 Post EOT (+/- 14 Days) and evaluation of “Full-body FDG-PET scan (or CT-Pet scan)” at End of Treatment (+ 14 Days). The evaluation of Full-body FDG-PET scan was deleted from Long-term safety evaluations.

    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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