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    Clinical Trial Results:
    A Phase 2 Open-label Study of MEDI-551 and Bendamustine vs Rituximab and Bendamustine in Adults With Relapsed or Refractory CLL

    Summary
    EudraCT number
    2011-002566-21
    Trial protocol
    DE   BE   IT   PL  
    Global end of trial date
    08 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 May 2017
    First version publication date
    05 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CD-ON-MEDI-551-1019
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01466153
    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 Clinical Study Information Center, AstraZeneca, +1 1-877-240-9479, information.center@astrazenca.com
    Scientific contact
    AstraZeneca Clinical Study Information Center, AstraZeneca, +1 1-877-240-9479, information.center@astrazenca.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
    08 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the ORR, including CR and PR, in adult subjects with progressive CLL, including small lymphocytic lymphoma (SLL) treated with up to 6 cycles of MEDI-551 in combination with bendamustine versus rituximab in combination with bendamustine.
    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. Subjects 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
    07 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    159
    EEA total number of subjects
    87
    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)
    72
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 182 subjects were screened in this study, of which 159 subjects were randomized.

    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 + Bendamustine
    Arm description
    Rituximab was administered on Day 2 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.
    Arm type
    Active comparator

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Treanda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine infusion was administered as 70 mg/m^2 for all 6 cycles.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at the dose of 375 mg/m^2 for first cycle and then 500 mg/m^2 for subsequent cycles.

    Arm title
    MEDI-551 2 mg/kg + Bendamustine
    Arm description
    MEDI-551 2 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI-551
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI-551 infusion was administered as 2 mg/kg for all 6 cycles.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Treanda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine infusion was administered as 70 mg/m^2 for all 6 cycles.

    Arm title
    MEDI-551 4 mg/kg + Bendamustine
    Arm description
    MEDI-551 4 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Treanda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine infusion was administered as 70 mg/m^2 for all 6 cycles.

    Investigational medicinal product name
    MEDI-551
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI-551 infusion was administered as 4 mg/kg for all 6 cycles.

    Number of subjects in period 1
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Started
    62
    36
    61
    Completed
    33
    12
    36
    Not completed
    29
    24
    25
         Disease Progression
    2
    2
    -
         Withdrawal of Consent
    2
    -
    -
         Other-Unspecified
    6
    4
    2
         Investigator Discretion
    3
    2
    2
         Adverse event, non-fatal
    14
    13
    17
         Randomized-Not Treated
    2
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab + Bendamustine
    Reporting group description
    Rituximab was administered on Day 2 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.

    Reporting group title
    MEDI-551 2 mg/kg + Bendamustine
    Reporting group description
    MEDI-551 2 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.

    Reporting group title
    MEDI-551 4 mg/kg + Bendamustine
    Reporting group description
    MEDI-551 4 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.

    Reporting group values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine Total
    Number of subjects
    62 36 61 159
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    34 17 21 72
        From 65-84 years
    28 19 40 87
    Age Continuous
    Units: YEARS
        arithmetic mean (standard deviation)
    63.4 ± 8.8 65.1 ± 8.7 66.3 ± 8.9 -
    Gender, Male/Female
    Units: Subjects
        Female
    16 14 18 48
        Male
    46 22 43 111

    End points

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    End points reporting groups
    Reporting group title
    Rituximab + Bendamustine
    Reporting group description
    Rituximab was administered on Day 2 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.

    Reporting group title
    MEDI-551 2 mg/kg + Bendamustine
    Reporting group description
    MEDI-551 2 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.

    Reporting group title
    MEDI-551 4 mg/kg + Bendamustine
    Reporting group description
    MEDI-551 4 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.

    Primary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    ORR, defined as the proportion of subjects with complete response (CR) or partial response (PR) out of total number of subjects. Responses were assessed by using National Cancer Institute - Working Group guidelines on CLL. Intent-to-treat (ITT) population includes all subjects who are randomized into the study.
    End point type
    Primary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Percentage of Subjects
        number (confidence interval 95%)
    59.7 (46.4 to 71.9)
    52.8 (35.5 to 69.6)
    63.9 (50.6 to 75.8)
    Statistical analysis title
    Rituximab+bendamustine vs MEDI-551+bendamustine
    Comparison groups
    Rituximab + Bendamustine v MEDI-551 4 mg/kg + Bendamustine
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4475
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs)

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug (MEDI-551). A serious adverse event (SAE) was an AE resulting in any of these outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between use of study drug and Day 90 that were absent before treatment or that worsened relative to pre-treatment state. An AESIs was one of scientific and medical interest specific to understanding of study product and may have required close monitoring and rapid communication by investigator to the sponsor. Treatment emergent AESIs were collected from the time of dosing through Day 90 after the last dose of study drug. Hepatic function abnormality and infusion reactions resulting in discontinuation were considered as AESIs in this study. The safety population includes all subjects who received any investigational product.
    End point type
    Secondary
    End point timeframe
    From time of consent to 90 days post last dose
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    60
    33
    57
    Units: Subjects
        TEAEs
    58
    33
    57
        TESAEs
    19
    16
    19
        AESIs
    2
    4
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Clinical Laboratory Parameters Reported as AEs

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    End point title
    Number of Subjects With Abnormal Clinical Laboratory Parameters Reported as AEs
    End point description
    An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Laboratory evaluations (haematology, serum chemistry and urinalysis) of blood and urine samples were performed. The safety population includes all subjects who received any investigational product.
    End point type
    Secondary
    End point timeframe
    From time of consent to 90 days post last dose
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    60
    33
    57
    Units: Subjects
        Hyperbilirubinaemia
    0
    2
    1
        Hypercalcaemia
    1
    0
    0
        Hypercholesterolaemia
    1
    0
    1
        Hyperglycaemia
    4
    2
    1
        Hyperkalaemia
    2
    1
    2
        Hyperlipidaemia
    0
    1
    0
        Hypermagnesaemia
    1
    0
    0
        Hyperphosphataemia
    0
    1
    1
        Hypertriglyceridaemia
    1
    0
    0
        Hyperuricaemia
    3
    5
    2
        Hypoalbuminaemia
    2
    0
    2
        Hypocalcaemia
    3
    1
    1
        Hypokalaemia
    6
    1
    4
        Hypomagnesaemia
    2
    2
    1
        Hyponatraemia
    2
    1
    0
        Alanine Aminotransferase Increased
    1
    0
    3
        Aspartate Aminotransferase Increased
    1
    0
    3
        Blood Alkaline Phosphatase Increased
    1
    1
    2
        Blood Bilirubin Increased
    0
    1
    1
        Blood Cholesterol Decreased
    0
    0
    1
        Blood Creatinine Decreased
    1
    0
    0
        Blood Creatinine Increased
    1
    2
    1
        Blood Immunoglobulin G Decreased
    0
    0
    1
        Blood Lactate Dehydrogenase Increased
    4
    0
    0
        Blood Urea Increased
    1
    1
    0
        Gamma-Glutamyltransferase Increased
    1
    1
    2
        Hepatic enzyme Increased
    1
    0
    0
        Anaemia
    18
    7
    9
        Eosinophilia
    0
    0
    1
        Lymphopenia
    4
    3
    1
        Neutropenia
    28
    10
    19
        Thromobocytopenia
    12
    6
    10
        Activated Partial Thromboplastin Time Prolonged
    2
    0
    0
        Blood Fibrinogen Increased
    1
    0
    0
        Haemoglobin Decreased
    0
    1
    0
        Lymphocyte Count Decreased
    3
    0
    2
        Neutrophil Count Decreased
    9
    1
    3
        Platelet Count Decreased
    2
    2
    3
        Prothrombin Time Shortened
    1
    0
    0
        Haematuria
    0
    2
    1
        Proteinuria
    0
    1
    0
        White Blood Cells in Urine
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Vital Signs and Electrocardiogram Reported as AEs

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    End point title
    Number of Subjects With Abnormal Vital Signs and Electrocardiogram Reported as AEs
    End point description
    AEs observed in subjects with clinically significant ECG abnormalities were assessed. The safety population includes all subjects who received any investigational product.
    End point type
    Secondary
    End point timeframe
    From time of consent to 90 days post last dose
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    60
    33
    57
    Units: Subjects
        Atrial Fibrillation
    1
    2
    1
        Atrioventricular Block
    1
    0
    0
        Palpitations
    0
    0
    2
        Sinus Bradycardia
    1
    0
    0
        Sinus Tachycardia
    1
    0
    0
        Tachycardia
    2
    1
    1
        Pyrexia
    20
    11
    14
        Dyspnoea
    9
    2
    4
        Dyspnoea Exertional
    3
    1
    0
        Hypertension
    1
    0
    1
        Hypotension
    5
    2
    6
        Orthostatic Hypotension
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Complete Response Rate

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    End point title
    Complete Response Rate
    End point description
    Complete response was as per IWG was complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Intent-to-treat (ITT) population includes all subjects who are randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Percentage of Subjects
        number (confidence interval 95%)
    6.5 (1.8 to 15.7)
    5.6 (0.7 to 18.7)
    11.5 (4.7 to 22.2)
    Statistical analysis title
    Rituximab+bendamustine vs MEDI-551+bendamustine
    Comparison groups
    Rituximab + Bendamustine v MEDI-551 4 mg/kg + Bendamustine
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3206
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Minimal Residual Disease Negative Complete Response (CR) rate

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    End point title
    Minimal Residual Disease Negative Complete Response (CR) rate
    End point description
    The MRD-negative CR rate was defined as the percentage of subjects who achieved CR and became MRD-negative as determined by flow cytometry. CR as per International Working Group (IWG) was complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Intent-to-treat (ITT) population includes all subjects who are randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Percentage of Subjects
        number (confidence interval 95%)
    1.6 (0 to 8.7)
    5.6 (0.7 to 18.7)
    4.9 (1 to 13.7)
    Statistical analysis title
    Rituximab+bendamustine vs MEDI551+bendamustine
    Comparison groups
    Rituximab + Bendamustine v MEDI-551 4 mg/kg + Bendamustine
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.313
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response was evaluated using the Kaplan-Meier method. Intent-to-treat (ITT) population includes all subjects who are randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Months
        median (confidence interval 95%)
    2.1 (1.9 to 2.6)
    1.9 (1.7 to 2.9)
    2.1 (1.9 to 3.5)
    No statistical analyses for this end point

    Secondary: Time to Disease Progression (TTP)

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    End point title
    Time to Disease Progression (TTP)
    End point description
    TTP was defined as the time from onset of treatment with study drug until first evidence/diagnosis of progressive disease or – in the absence of any diagnosis of progressive disease – until the subject´s death. Intent-to-treat (ITT) population includes all subjects who are randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Months
        median (confidence interval 95%)
    15.4 (12 to 27.2)
    15 (5.8 to 23.3)
    16.1 (12.5 to 24)
    Statistical analysis title
    Rituximab+bendamustine vs MEDI-551+bendamustine
    Comparison groups
    Rituximab + Bendamustine v MEDI-551 4 mg/kg + Bendamustine
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9527
    Method
    Logrank
    Confidence interval

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was measured from the start of treatment with study drug until the first documentation of disease progression or death due to any cause, whichever occurred first. Kaplan-Meier method was used for evaluation. Intent-to-treat (ITT) population includes all subjects who are randomized into the study.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Months
        median (confidence interval 95%)
    14.8 (11.4 to 23.5)
    15 (5.8 to 22.1)
    16.1 (12.5 to 21.6)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was determined as the time from the start of treatment with study drug until death due to any cause. For subjects who were alive at the end of the study or lost to follow-up, OS was censored on the last date when the subject was known be alive. Kaplan-Meier method was used for evaluation. Intent-to-treat (ITT) population includes all subjects who are randomized into the study. In this section, 99999 represents that median was not reached and the upper and/or lower limit of the 95% confidence interval was not calculable because an insufficient number of subjects reached the event at the final time point for assessment.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    End point values
    Rituximab + Bendamustine MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    62
    36
    61
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (23.9 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects who developed detectable anti-drug antibodies (ADA)

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    End point title
    Number of Subjects who developed detectable anti-drug antibodies (ADA) [1]
    End point description
    A subject was considered ADA-positive across the study if they had a positive reading at any time point during the study. The safety population includes all subjects who received any investigational product. Subjects whom ADA samples were available were analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)
    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: ADA was analyzed only for 'MEDI-551 2 mg/kg + Bendamustine' and 'MEDI-551 4 mg/kg + Bendamustine' arms
    End point values
    MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    31
    57
    Units: Subjects
    4
    8
    No statistical analyses for this end point

    Secondary: Terminal Half life (t1/2) of MEDI-551

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    End point title
    Terminal Half life (t1/2) of MEDI-551 [2]
    End point description
    Terminal phase elimination half-life (T1/2) was the time required for half of the drug to be eliminated from the serum. The safety population includes all subjects who received any investigational product. Subjects whom PK samples were available were analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-infusion and 1 hour post infusion on Days 2 and 8, Days 15 and 22 of cycle 1
    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: ADA was analyzed only for 'MEDI-551 2 mg/kg + Bendamustine' and 'MEDI-551 4 mg/kg + Bendamustine' arms
    End point values
    MEDI-551 2 mg/kg + Bendamustine MEDI-551 4 mg/kg + Bendamustine
    Number of subjects analysed
    12
    38
    Units: Day
        arithmetic mean (standard deviation)
    17.2 ± 9.56
    22 ± 14.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration until 90 days after the last dose of study drug
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Rituximab + Bendamustine
    Reporting group description
    Rituximab was administered on Day 2 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.

    Reporting group title
    MEDI-551 4 mg/kg + Bendamustine
    Reporting group description
    MEDI-551 4 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.

    Reporting group title
    MEDI-551 2 mg/kg + Bendamustine
    Reporting group description
    MEDI-551 2 mg/kg was administered on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was administered on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.

    Serious adverse events
    Rituximab + Bendamustine MEDI-551 4 mg/kg + Bendamustine MEDI-551 2 mg/kg + Bendamustine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 60 (31.67%)
    19 / 57 (33.33%)
    16 / 33 (48.48%)
         number of deaths (all causes)
    3
    3
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Inflammation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Infusion related reaction
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 57 (8.77%)
    5 / 33 (15.15%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 14
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Atrioventricular block
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Cardiac failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Congenital, familial and genetic disorders
    Thyroglossal cyst
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Cough
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Epistaxis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Respiratory tract inflammation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Blood and lymphatic system disorders
    Abdominal lymphadenopathy
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Febrile neutropenia
         subjects affected / exposed
    6 / 60 (10.00%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Thrombocytopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Syncope
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Diarrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Nausea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Small intestinal obstruction
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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 / 60 (3.33%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Renal failure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Dehydration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (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
    Bronchitis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Pneumonia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    4 / 33 (12.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia viral
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Rhinovirus infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Sepsis
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Viral myocarditis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    0 / 33 (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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Rituximab + Bendamustine MEDI-551 4 mg/kg + Bendamustine MEDI-551 2 mg/kg + Bendamustine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 60 (96.67%)
    54 / 57 (94.74%)
    31 / 33 (93.94%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    7
    1
    3
    Hypotension
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 57 (10.53%)
    2 / 33 (6.06%)
         occurrences all number
    4
    7
    2
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    1
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    20 / 60 (33.33%)
    7 / 57 (12.28%)
    4 / 33 (12.12%)
         occurrences all number
    31
    17
    4
    Chest discomfort
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    2
    2
    0
    Chills
         subjects affected / exposed
    11 / 60 (18.33%)
    7 / 57 (12.28%)
    6 / 33 (18.18%)
         occurrences all number
    15
    10
    7
    Fatigue
         subjects affected / exposed
    18 / 60 (30.00%)
    20 / 57 (35.09%)
    14 / 33 (42.42%)
         occurrences all number
    38
    30
    19
    Oedema peripheral
         subjects affected / exposed
    3 / 60 (5.00%)
    7 / 57 (12.28%)
    2 / 33 (6.06%)
         occurrences all number
    4
    7
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    2
    2
    2
    Pyrexia
         subjects affected / exposed
    20 / 60 (33.33%)
    14 / 57 (24.56%)
    11 / 33 (33.33%)
         occurrences all number
    27
    23
    14
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 57 (7.02%)
    0 / 33 (0.00%)
         occurrences all number
    5
    5
    0
    Depression
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    3 / 33 (9.09%)
         occurrences all number
    2
    2
    3
    Insomnia
         subjects affected / exposed
    6 / 60 (10.00%)
    5 / 57 (8.77%)
    2 / 33 (6.06%)
         occurrences all number
    7
    5
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    0
    Infusion related reaction
         subjects affected / exposed
    14 / 60 (23.33%)
    37 / 57 (64.91%)
    21 / 33 (63.64%)
         occurrences all number
    25
    123
    64
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
         occurrences all number
    3
    4
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
         occurrences all number
    4
    4
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    3
    2
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    3
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    7
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    4
    2
    1
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    8
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    9 / 60 (15.00%)
    3 / 57 (5.26%)
    1 / 33 (3.03%)
         occurrences all number
    16
    6
    3
    Platelet count decreased
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    2
    Weight decreased
         subjects affected / exposed
    5 / 60 (8.33%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    6
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    3
    2
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    0
    2
    Tachycardia
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 60 (18.33%)
    19 / 57 (33.33%)
    5 / 33 (15.15%)
         occurrences all number
    13
    24
    9
    Dysphonia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    0
    2
    Dyspnoea
         subjects affected / exposed
    9 / 60 (15.00%)
    4 / 57 (7.02%)
    2 / 33 (6.06%)
         occurrences all number
    13
    5
    2
    Dyspnoea exertional
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    4
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    1
    Nasal congestion
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 57 (5.26%)
    1 / 33 (3.03%)
         occurrences all number
    4
    4
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    1
    Pleural effusion
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    2
    Pulmonary congestion
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    2
    2
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    2
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 57 (5.26%)
    1 / 33 (3.03%)
         occurrences all number
    3
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 60 (30.00%)
    9 / 57 (15.79%)
    7 / 33 (21.21%)
         occurrences all number
    64
    13
    20
    Febrile neutropenia
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    5
    1
    0
    Leukopenia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    26
    1
    0
    Lymphopenia
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 57 (1.75%)
    3 / 33 (9.09%)
         occurrences all number
    26
    5
    7
    Neutropenia
         subjects affected / exposed
    28 / 60 (46.67%)
    19 / 57 (33.33%)
    10 / 33 (30.30%)
         occurrences all number
    78
    58
    44
    Thrombocytopenia
         subjects affected / exposed
    12 / 60 (20.00%)
    10 / 57 (17.54%)
    5 / 33 (15.15%)
         occurrences all number
    76
    21
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 60 (8.33%)
    7 / 57 (12.28%)
    3 / 33 (9.09%)
         occurrences all number
    5
    10
    6
    Dysgeusia
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 57 (1.75%)
    3 / 33 (9.09%)
         occurrences all number
    7
    1
    3
    Headache
         subjects affected / exposed
    7 / 60 (11.67%)
    5 / 57 (8.77%)
    6 / 33 (18.18%)
         occurrences all number
    9
    6
    9
    Neuropathy peripheral
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    1
    Paraesthesia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    3
    2
    0
    Sciatica
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    0
    Restless legs syndrome
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    1
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    2
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    4
    1
    2
    Abdominal distension
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    2
    Abdominal pain
         subjects affected / exposed
    7 / 60 (11.67%)
    7 / 57 (12.28%)
    3 / 33 (9.09%)
         occurrences all number
    8
    15
    3
    Abdominal pain upper
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 57 (5.26%)
    1 / 33 (3.03%)
         occurrences all number
    6
    3
    1
    Constipation
         subjects affected / exposed
    20 / 60 (33.33%)
    10 / 57 (17.54%)
    9 / 33 (27.27%)
         occurrences all number
    23
    11
    11
    Diarrhoea
         subjects affected / exposed
    13 / 60 (21.67%)
    11 / 57 (19.30%)
    5 / 33 (15.15%)
         occurrences all number
    20
    15
    5
    Dyspepsia
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 57 (7.02%)
    2 / 33 (6.06%)
         occurrences all number
    1
    5
    2
    Flatulence
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    4
    2
    0
    Gingival pain
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    1
    Haemorrhoids
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    2
    1
    0
    Nausea
         subjects affected / exposed
    29 / 60 (48.33%)
    29 / 57 (50.88%)
    13 / 33 (39.39%)
         occurrences all number
    45
    47
    23
    Vomiting
         subjects affected / exposed
    13 / 60 (21.67%)
    7 / 57 (12.28%)
    7 / 33 (21.21%)
         occurrences all number
    14
    7
    8
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    5
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    2
    Pollakiuria
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    2
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    2
    Erythema
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 57 (10.53%)
    0 / 33 (0.00%)
         occurrences all number
    4
    6
    0
    Hyperhidrosis
         subjects affected / exposed
    7 / 60 (11.67%)
    2 / 57 (3.51%)
    3 / 33 (9.09%)
         occurrences all number
    7
    3
    3
    Night sweats
         subjects affected / exposed
    5 / 60 (8.33%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    6
    0
    1
    Pruritus
         subjects affected / exposed
    9 / 60 (15.00%)
    6 / 57 (10.53%)
    5 / 33 (15.15%)
         occurrences all number
    13
    6
    9
    Rash erythematous
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    0
    Rash
         subjects affected / exposed
    4 / 60 (6.67%)
    8 / 57 (14.04%)
    4 / 33 (12.12%)
         occurrences all number
    7
    10
    6
    Rash pruritic
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 60 (11.67%)
    4 / 57 (7.02%)
    1 / 33 (3.03%)
         occurrences all number
    7
    4
    1
    Back pain
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 57 (8.77%)
    4 / 33 (12.12%)
         occurrences all number
    5
    8
    4
    Bone pain
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 57 (8.77%)
    1 / 33 (3.03%)
         occurrences all number
    4
    9
    1
    Muscle spasms
         subjects affected / exposed
    5 / 60 (8.33%)
    7 / 57 (12.28%)
    1 / 33 (3.03%)
         occurrences all number
    9
    9
    1
    Muscular weakness
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    3
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 57 (3.51%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    2
    Myalgia
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 57 (7.02%)
    0 / 33 (0.00%)
         occurrences all number
    6
    5
    0
    Neck pain
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 57 (3.51%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    2
    Pain in extremity
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 57 (5.26%)
    2 / 33 (6.06%)
         occurrences all number
    4
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 60 (21.67%)
    6 / 57 (10.53%)
    4 / 33 (12.12%)
         occurrences all number
    17
    6
    4
    Dehydration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 57 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    1
    0
    3
    Hyperglycaemia
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    4
    1
    3
    Hyperkalaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
         occurrences all number
    2
    3
    1
    Hyperuricaemia
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 57 (3.51%)
    5 / 33 (15.15%)
         occurrences all number
    5
    2
    6
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
         occurrences all number
    3
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    1
    Hypokalaemia
         subjects affected / exposed
    6 / 60 (10.00%)
    4 / 57 (7.02%)
    1 / 33 (3.03%)
         occurrences all number
    7
    4
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    2 / 33 (6.06%)
         occurrences all number
    2
    1
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 57 (7.02%)
    3 / 33 (9.09%)
         occurrences all number
    4
    4
    4
    Conjunctivitis
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    2
    1
    0
    Lung infection
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 57 (7.02%)
    2 / 33 (6.06%)
         occurrences all number
    5
    5
    3
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 57 (7.02%)
    1 / 33 (3.03%)
         occurrences all number
    0
    5
    1
    Rhinitis
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 57 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    2
    0
    2
    Sinusitis
         subjects affected / exposed
    3 / 60 (5.00%)
    6 / 57 (10.53%)
    1 / 33 (3.03%)
         occurrences all number
    3
    6
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 57 (1.75%)
    3 / 33 (9.09%)
         occurrences all number
    4
    1
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
         occurrences all number
    8
    3
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jan 2012
    - The bendamustine dose used in another CLL study was corrected from 90 mg/m^2 to 70 mg/m^2 - Inclusion Criterion were revised from stating study subjects must be eligible for chemotherapy to stating that study subjects must be eligible for bendamustine/rituximab therapy to be included in the study - Inclusion Criterion for description of symptomatic disease was expanded to include enlarging adenopathy and increasing cytopenias. The additional indications were added in accordance with the diagnostic, treatment and response criteria in Hallek et al, 2008. - Exclusion Criterion for describing excluded prior therapies was removed to correctly state the intention of the sponsor to permit any prior therapy. - Exclusion Criterion was added to exclude any subject who had exposure to bendamustine within 180 days before study enrollment. There is a high likelihood that patients who have received bendamustine in the last 180 days are resistant to it; therefore it is unethical to provide the same therapy - The lists of acceptable treatments for infusion reactions and for pretreatment of subjects who experienced infusion reactions were revised. In addition to acetaminophen and antihistamines, corticosteroids are permitted. Steroids are considered standard, acceptable adjunctive treatments for infusion reactions. - The listed procedure of MEDI-551 PK sample was revised to list pre-dose and post-dose samples separately to emphasize that pre-dose and post-dose samples must be taken on Day 1 of each cycle and on Day 8 of Cycle 1. - The procedure of pregnancy test (urine β hCG) and in visit descriptions was revised to include the restriction to women of childbearing potential. This was done as an aid to the investigator staff and to avoid needless testing. - Information about the composition and operation of the study DMC was revised to reflect the current plan.
    07 Jul 2012
    Exploratory objective changed from, “To conduct exploratory pharmacogenomic analyses” to “To examine the association of FcγR polymorphisms with MEDI-551 treatment effects and complete elimination of minimal residual disease. Clarified primary endpoint ORR, is defined as the proportion of subjects with CR or PR according to the International Workshop on Chronic Lymphocytic Leukemia’s update of the National Cancer Institute - Working Group 1996 guidelines on CLL. The dosing section updated with Phase 1 protocol MI-CP204 results. Changes to inclusion criteria: Eligible subjects must have had a minimum of one course of chemotherapy with rituximab, because rituximab is considered the standard of care for CLL; Confirmation of CLL and presence of symptomatic disease defined in more detail; The definition of adequate hematological function criterion for absolute neutrophil count (ANC) was lowered from a minimum of 1,500/mm^3 to 1,000/mm^3; CLL is a disease that commonly presents with cytopenias resulting from disease-overloaded marrow with limited hematopoietic function; the majority of subjects present with ANC below 1500/mm3; Therefore, the ANC requirement has been lowered to permit increased access of study drug to subjects; Investigators are permitted to supplement subjects with GCSF at their discretion to minimize the duration of neutropenia so as to minimize the risk of infection; Serum creatinine limits modified to ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 60 mL/minute as determined by the Cockcroft-Gault equation to provide limits more appropriate to this population. Changes to exclusion criteria: Subjects suspected of having Richter’s transformation or high-grade disease, current pregnancy or lactation and history of yellow fever vaccination; cautions regarding potential of interaction of bendamustine with CYP1A2 inhibitors and inducers of CYP1A2 were added; the DMC’s plan for recommendation for the dose selected (2 mg/kg or 4 mg/kg) was clarified.
    09 May 2013
    -All subjects were given oral acetaminophen & diphenhydramine methylprednisolone IV 30-60 min prior to first infusion of MEDI-551 was added. -MEDI-551/rituximab on Day2 of Cycle1,followed by 2nd dose of bendamustine. -Prophylaxis before rituximab infusion was at investigator’s discretion added. -Potential risks of MEDI-551 were updated. 3 exploratory objectives were added -Inclusion Criteria •Recovered from any acute side effects resulting from previous anticancer therapy was removed. •Hemoglobin & platelet count lowered to ≥8g/dL & ≥50000/mm^3. Alternative hemoglobin level & platelet count were eliminated for simplify entry requirements. •Adequate organ function was revised: bilirubin level revised from <2mg/dL to <2×ULN, calculated creatinine clearance lowered to ≥50 mL/min. •Use of birth control after study drug was extend beyond 90 days. •Duration of contraception was modified to at least Day1 through 90 days after the last dose of study drug. -Exclusion Criteria •Was changed to History of Grade 4 anaphylactic reaction to any component of MEDI-551, rituximab/bendamustine formulations Grade of anaphylactic reaction was defined. •Exclusions related to hepatitis B&C was split into 2 exclusion criteria; Exclusion relates to hepatitis C. -Conditions were added to reasons for permanent discontinuation from study drug: •Grade 4 febrile neutropenia or sepsis, regardless of attribution & treatment arm. •Grade 3 or higher toxicity attributed to MEDI-551. •Delay in start of a cycle by greater than 7 days. •Grade 4 infusion reaction by MEDI-551. -Subjects received mandatory premedication before the first dose of MEDI-551 was restated. Other premedication was permitted as clinically indicated, or in accordance with institutional guidelines for administration of a MAb. -Prophylactic antibiotics allowed & recommended in subjects with medical history of recurrent or severe infections.” -The schedule of study procedures was updated -Futility analysis added.
    19 Oct 2015
    Details about Blinded central independent review was removed from rationale from “Study Design, dose and control group” as well as the section on Blinding. The following text was removed from the planned analysis section: “Two formal analyses are planned for the study. The first analysis will be performed once all subjects have discontinued from the study-specific chemoimmunotherapies. This will occur approximately 6 months post randomization of the last subject randomized into the study.”

    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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