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    Clinical Trial Results:
    A Phase III, Randomised, Parallel Group, Multi-Centre Study in Recurrent Glioblastoma Patients to Compare the Efficacy of Cediranib (AZD2171) Monotherapy and the Combination of Cediranib with Lomustine to the Efficacy of Lomustine Alone

    Summary
    EudraCT number
    2007-000383-24
    Trial protocol
    DE   FR   NL   BE   CZ   AT   GB  
    Global end of trial date
    26 Sep 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    D8480C00055
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    132 Hills Road, Cambridge, United Kingdom, CB2 1PG
    Public contact
    Tsveta Milenkova, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Tsveta Milenkova, AstraZeneca, ClinicalTrialTransparency@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
    25 Apr 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the relative efficacy of cediranib (either in monotherapy or in combination with oral lomustine) compared to oral lomustine alone by assessment of PFS as assessed by independent radiographic review.
    Protection of trial subjects
    Due to delayed bone marrow suppression, blood counts were monitored weekly for at least 6 weeks after a dose. Doses subsequent to the initial dose were adjusted according to the haematologic response of the subject to the preceding dose.A repeat course of lomustine would not be given until circulating blood elements have returned to acceptable levels. This usually occurs within 6 weeks. Lomustine could've been dose reduced a maximum of 2 times. Administration of antiemetics was recommended to treat and prevent nausea and vomiting according to standard of care. Additionally, the dose of lomustine could be split over 3 days if necessary. For AZD2171 dose interruptions should have been used as the first approach to managing toxicity and dose reduction could be considered. A management plan was provided to offer guidance on how to make toxicity. Two dose reductions for AZD2171 was permitted during the study. No re-escalation of dose was permitted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Oct 2008
    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
    Australia: 34
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 41
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Netherlands: 44
    Country: Number of subjects enrolled
    United Kingdom: 61
    Country: Number of subjects enrolled
    United States: 135
    Worldwide total number of subjects
    423
    EEA total number of subjects
    228
    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)
    342
    From 65 to 84 years
    81
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    In total, 423 patients from 71 centres in 10 countries (Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Netherlands, UK, and US) were enrolled into this study. The first patient was enrolled on 8 October 2008 and the last patient was enrolled on 2 September 2009.

    Pre-assignment
    Screening details
    Of the 423 patients enrolled, 325 were randomised, and 315 of those randomised received at least 1 dose of study treatment. Of the 10 patients who were randomised but did not receive study treatment, all had discontinued the study before 25 April 2010.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    The treatment groups are double blind for the lomustine containing arms and the 30 mg alone arm is unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cediranib 30 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    AZD2171
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the monotherapy arm received 1 x 30 mg tablet orally, once daily

    Arm title
    Cediranib 20 mg + lomustine
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Cediranib and lomustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients took 1 x 20 mg cediranib tablet once daily. Lomustine was administered orally at baseline and every 6 weeks thereafter at a dose of 110 mg/m2. The 110 mg/m2 dose was the starting dose, but lomustine was capped at a total maximum dose of 240 mg

    Arm title
    Placebo + lomustine
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo and lomustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients took 1 x 20 mg matched cediranib placebo tablet orally, once daily. Lomustine was administered orally at baseline and every 6 weeks thereafter at a dose of 110 mg/m2. The 110 mg/m2 dose was the starting dose, but lomustine was capped at a total maximum dose of 240 mg

    Number of subjects in period 1 [1]
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Started
    131
    129
    65
    Completed
    13
    18
    7
    Not completed
    118
    111
    58
         Protocol deviation
    -
    4
    -
         Other
    2
    1
    -
         Adverse event
    19
    22
    10
         Voluntary discontinuation by subject
    8
    6
    4
         Condition under investigation worsened
    89
    78
    44
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 423 patients enrolled, 325 were randomised,whereas out of these patients enrolled 98 failed screening and didn’t actually enter the study. Therefore only 325 patients were randomised to a treatment and thus “started” treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cediranib 30 mg
    Reporting group description
    -

    Reporting group title
    Cediranib 20 mg + lomustine
    Reporting group description
    -

    Reporting group title
    Placebo + lomustine
    Reporting group description
    -

    Reporting group values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine Total
    Number of subjects
    131 129 65 325
    Age Categorical
    Units: Subjects
        ≥18 to <65 years
    109 108 55 272
        ≥65 to <75 years
    18 20 8 46
        ≥75 years
    4 1 2 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    53.4 ± 11.8 53.7 ± 10.8 52 ± 13.1 -
    Gender Categorical
    Units: Subjects
        Female
    46 44 24 114
        Male
    85 85 41 211
    Race
    Units: Subjects
        White
    127 123 63 313
        Black or African American
    3 1 1 5
        Asian
    0 3 0 3
        American Indian or Alaska Native
    1 1 0 2
        Other
    0 1 1 2
    Karnofsky Performance Status
    Units: Subjects
        KPS 30
    0 1 0 1
        KPS 60
    0 0 1 1
        KPS 70
    33 27 10 70
        KPS 80
    32 35 13 80
        KPS 90
    38 44 27 109
        KPS 100
    27 22 13 62
        Missing
    1 0 1 2
    Resection for recurrent disease
    Units: Subjects
        Resection
    50 49 24 123
        No resection
    81 80 41 202
    Baseline steroid use
    Units: Subjects
        Steroid use
    64 71 26 161
        No steroid use
    67 58 39 164
    Baseline LDH
    Units: Subjects
        ≤1.5 x ULN
    122 125 63 310
        >1.5 x ULN
    2 0 0 2
        Missing
    7 4 2 13
    Baseline VEGF-A
    Units: Subjects
        ≥98 pg/mL
    45 44 13 102
        <98 pg/mL
    65 62 45 172
        Missing
    21 23 7 51
    Time from last radiotherapy to randomisation
    Units: Subjects
        0 to ≤3 months
    2 4 0 6
        3 months to ≤6 months
    32 29 16 77
        6 months to ≤12 months
    52 42 27 121
        >12 months
    45 54 22 121
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    81.5 ± 16.9 81.2 ± 15.3 79.8 ± 15.3 -
    BMI
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    26.8 ± 5 26.9 ± 4.2 26.8 ± 4.2 -

    End points

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    End points reporting groups
    Reporting group title
    Cediranib 30 mg
    Reporting group description
    -

    Reporting group title
    Cediranib 20 mg + lomustine
    Reporting group description
    -

    Reporting group title
    Placebo + lomustine
    Reporting group description
    -

    Primary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    Primary assessment of PFS will be made on the basis of axial T1-weighted contrast enhanced MRI from independent radiographic review. Supportive assessment of PFS will be made on the basis of axial T1-weighted contrast enhanced MRI from site review (ie, investigator review) and on the basis of combination of axial T1-weighted contrast enhanced MRI and T2-weighted/fluid attenuated inversion recovery (FLAIR) MRI from independent radiographic review
    End point type
    Primary
    End point timeframe
    The primary analysis is scheduled to occur after 230 PFS events. The data cut off was 25 April 2010.
    End point values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Number of subjects analysed
    131
    129
    65
    Units: Days
        median (inter-quartile range (Q1-Q3))
    92 (80 to 128)
    125 (83 to 201)
    82 (42 to 168)
    Statistical analysis title
    PFS based on central review T1
    Statistical analysis description
    Cediranib 30mg compared to placebo + lomustine
    Comparison groups
    Placebo + lomustine v Cediranib 30 mg
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.8992 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.5
    Notes
    [1] - Hazard Ratio and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years). Hazard Ratio <1 favours cediranib.
    [2] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 )
    Statistical analysis title
    PFS based on central review T1
    Statistical analysis description
    Cediranib 20mg and lomustine compared to placebo and lomustine
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.1624 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.08
    Notes
    [3] - Hazard Ratio and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years). Hazard Ratio <1 favours cediranib.
    [4] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 )
    Statistical analysis title
    Sensitivity of PFS
    Statistical analysis description
    PFS based on the earlier of site and central review, T1. Cediranib 30mg compared to Placebo and lomustine
    Comparison groups
    Cediranib 30 mg v Placebo + lomustine
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.538 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.34
    Notes
    [5] - Hazard Ratio and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years). Hazard Ratio <1 favours cediranib.
    [6] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65)
    Statistical analysis title
    Sensitivity of PFS
    Statistical analysis description
    PFS based on the earlier of site and central review, T1. Cediranib 20mg and lomustine compared to Placebo and lomustine
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.03 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.99
    Notes
    [7] - Hazard Ratio and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years). Hazard Ratio <1 favours cediranib.
    [8] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65)

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    The final OS was scheduled to take place after 270 deaths. At the time of the primary there was already a high maturity of the data (197 death events). Based on predictive power calculations there was a 0.01% chance of a positive outcome at the final analysis it was decided to not do the final OS analysis. The OS will be calculated as the interval from the date of randomization to the date of patient death (any cause). Patients who have not died at the time of the analysis, who are lost to follow-up or who withdraw consent will be censored at the last date the patient was known to be alive.
    End point type
    Secondary
    End point timeframe
    The OS was analysed at the same time as the primary objective (PFS).
    End point values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Number of subjects analysed
    131
    129
    65 [9]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    8 (4.1 to 14.5)
    9.4 (6.2 to 14.5)
    9.8 (4.9 to 9999)
    Notes
    [9] - Median 9.8 with Inter-Quartile Range of 4.9 to NC.
    Statistical analysis title
    Overall survival
    Statistical analysis description
    Cediranib 30mg compared to placebo and lomustine
    Comparison groups
    Cediranib 30 mg v Placebo + lomustine
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.1002 [11]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    2.13
    Notes
    [10] - Hazard Ratio and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years). Hazard Ratio <1 favours cediranib.
    [11] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65)
    Statistical analysis title
    Overall survival
    Statistical analysis description
    Cediranib 20mg and lomustine compared to placebo and lomustine
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.4985 [13]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.72
    Notes
    [12] - Hazard Ratio and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years). Hazard Ratio <1 favours cediranib.
    [13] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65)

    Secondary: Best objective response

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    End point title
    Best objective response
    End point description
    An individual visit response of PR is defined as a greater than or equal to 50% reduction in the sum of the products of the largest perpendicular diameters of contrast enhancement for all lesions compared to baseline as long as the steroid dose has not been increased within the previous 10 days and no new lesions are present. An individual visit response of CR is defined as the complete disappearance of all tumor on MRI scan.
    End point type
    Secondary
    End point timeframe
    Analysis performed at the same time as the primary analysis.
    End point values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Number of subjects analysed
    118 [14]
    122 [15]
    56 [16]
    Units: Patients
        Complete response
    1
    2
    0
        Partial response
    17
    19
    5
        Stable disease
    44
    57
    21
        Unconfirmed confirmed response
    0
    1
    0
        Unconfirmed partial response
    32
    9
    2
        Progressive disease
    10
    19
    23
        Non-evaluable
    14
    14
    5
    Notes
    [14] - Patients with measurable disease at baseline
    [15] - Patients with measurable disease at baseline
    [16] - Patients with measurable disease at baseline
    Statistical analysis title
    Best objective response
    Statistical analysis description
    Analysis of best objective response based on central review T1. Cediranib 30mg compared to placebo and lomustine
    Comparison groups
    Cediranib 30 mg v Placebo + lomustine
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    < 0.2486 [18]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    5.9
    Notes
    [17] - A responder is a patient with best confirmed PR or CR. Odds ratio, p-value, and CI estimated from logistic regression model with factors for treatment, surgical resection (yes/no prior to enrolment), and age (≤65 vs. >65 years). Odds ratio >1 favours cediranib.
    [18] - P-value estimated from logistic regression model with factors for treatment, surgical resection (yes/no prior to enrolment), and age (≤65 vs. >65 years)
    Statistical analysis title
    Best objective response
    Statistical analysis description
    Analysis of best objective response based on central review T1. Cediranib 20mg and lomustine compared to placebo and lomustine
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.1522 [20]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    6.7
    Notes
    [19] - A responder is a patient with best confirmed PR or CR. Odds ratio, p-value, and CI estimated from logistic regression model with factors for treatment, surgical resection (yes/no prior to enrolment), and age (≤65 vs. >65 years). Odds ratio >1 favours cediranib
    [20] - P-value estimated from logistic regression model with factors for treatment, surgical resection (yes/no prior to enrolment), and age (≤65 vs. >65 years).

    Secondary: Alive and progression-free at 6 months

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    End point title
    Alive and progression-free at 6 months
    End point description
    A patient will be defined as having progressed by 6 months, defined as 24 weeks (±10 days), if he/she has a progression event within 6 months of randomization, as assessed by independent review on axial T1-weighted contrast enhanced MRI only.
    End point type
    Secondary
    End point timeframe
    Analysis performed at the same time as the primary analysis.
    End point values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Number of subjects analysed
    131
    129
    65
    Units: Alive + progression-free at 6 months (%)
        number (not applicable)
    16.23
    34.53
    24.51
    Statistical analysis title
    APF6
    Statistical analysis description
    HR, CI, and p-value estimated from the methods of Hosmer and Lemeshow 1999 and Whitehead 1989. APF6 Alive and progression-free at 6 months (defined as 24 weeks after randomisation).
    Comparison groups
    Cediranib 30 mg v Placebo + lomustine
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    < 0.272 [22]
    Method
    Hosmer and Lemeshow 1999
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.92
    Notes
    [21] - Cediranib 30mg compared to Placebo and lomustine
    [22] - P-value estimated from the methods of Hosmer and Lemeshow 1999 and Whitehead 1989. APF6 Alive and progression-free at 6 months (defined as 24 weeks after randomisation).
    Statistical analysis title
    APF6
    Statistical analysis description
    HR, CI, and p-value estimated from the methods of Hosmer and Lemeshow 1999 and Whitehead 1989. APF6 Alive and progression-free at 6 months (defined as 24 weeks after randomisation).
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    < 0.107 [24]
    Method
    Hosmer and Lemeshow 1999
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    1.08
    Notes
    [23] - Cediranib 20mg and lomustine compared to placebo and lomustine
    [24] - P-value estimated from the methods of Hosmer and Lemeshow 1999 and Whitehead 1989. APF6 Alive and progression-free at 6 months (defined as 24 weeks after randomisation).

    Secondary: Average daily steroid dosage change from baseline until progression

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    End point title
    Average daily steroid dosage change from baseline until progression
    End point description
    Percent change in average daily steroid dosage from baseline will be derived for patients who were receiving steroids at baseline. The mean steroid dosage prior to treatment will be considered as the patient’s baseline. The percent change in average daily steroid dosage from baseline is calculated by following formula: PC = (md – bm)/bm*100; where PC is the percent change in average daily steroid dosage from baseline; md the mean daily steroid dosage recorded from the first day of therapy to progression; and bm the baseline mean. The mean will be calculated from all non-missing values. The number of steroid-free days is calculated as the number of steroid-free days from baseline to progression.
    End point type
    Secondary
    End point timeframe
    At the time of the primary analysis.
    End point values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Number of subjects analysed
    131
    129
    65
    Units: Number of steroid-free days
    arithmetic mean (standard deviation)
        Use of steroids at baseline
    15.9 ± 34.71
    21.5 ± 44.43
    18 ± 52.64
        No use of steroids at baseline
    130.3 ± 126.08
    140.7 ± 92.5
    143.1 ± 130.08
    Statistical analysis title
    % change from baseline in mean daily steroid dose
    Statistical analysis description
    Analysis using baseline-scaled ratio: post-baseline value/baseline value. This ratio was log-transformed prior to analysis and then exponentiated after analysis.
    Comparison groups
    Cediranib 30 mg v Placebo + lomustine
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    < 0.006
    Method
    Mixed models analysis
    Parameter type
    Ratio of glsmeans
    Point estimate
    -30.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -45.73
         upper limit
    -10.08
    Notes
    [25] - Cediranib 30mg compared to placebo and lomustine % change in mean daily steroid dose from baseline to progression (based on central review T1, or death) or study discontinuation (whichever was earlier).
    Statistical analysis title
    % change from baseline in mean daily steroid dose
    Statistical analysis description
    Analysis using baseline-scaled ratio: post-baseline value/baseline value. This ratio was log-transformed prior to analysis and then exponentiated after analysis.
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    < 0.012
    Method
    Mixed models analysis
    Parameter type
    Ratio of glsmeans
    Point estimate
    -27.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -43.54
         upper limit
    -0.73
    Notes
    [26] - Cediranib 20mg and lomustine compared to placebo and lomustine. % change in mean daily steroid dose from baseline to progression (based on central review T1, or death) or study discontinuation (whichever was earlier).

    Secondary: Time to deterioration of the neurological status of patients

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    End point title
    Time to deterioration of the neurological status of patients
    End point description
    End point type
    Secondary
    End point timeframe
    .
    End point values
    Cediranib 30 mg Cediranib 20 mg + lomustine Placebo + lomustine
    Number of subjects analysed
    131
    129
    65 [27]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    126 (77 to 224)
    170 (84 to 336)
    111 (44 to 999999)
    Notes
    [27] - Median 111 with Inter-Quartile Range of 44 to NC.
    Statistical analysis title
    Time to deterioration of neurological status
    Statistical analysis description
    HR and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years).
    Comparison groups
    Cediranib 30 mg v Placebo + lomustine
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    < 0.5731 [29]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.22
    Notes
    [28] - Radiological progression not considered an event (censored). Hazard Ratio <1 favours cediranib. Cediranib 30mg compared to placebo and lomustine
    [29] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years)
    Statistical analysis title
    Time to deterioration of neurological status
    Statistical analysis description
    HR and confidence interval estimated from a Cox-Proportional Hazards model including the factors surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years).
    Comparison groups
    Cediranib 20 mg + lomustine v Placebo + lomustine
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    < 0.0091 [31]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    0.95
    Notes
    [30] - Radiological progression not considered an event (censored). Hazard Ratio <1 favours cediranib.
    [31] - P-value estimated from Log-Rank test stratified by surgical resection (yes/no prior to enrolment) and age (≤65 vs. >65 years).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    ced 20 mg +lom 110 mg/m2
    Reporting group description
    ced 20 mg +lom 110 mg/m2

    Reporting group title
    pla 20 mg +lom 110 mg/m2
    Reporting group description
    pla 20 mg +lom 110 mg/m2

    Reporting group title
    cediranib 30 mg
    Reporting group description
    cediranib 30 mg

    Serious adverse events
    ced 20 mg +lom 110 mg/m2 pla 20 mg +lom 110 mg/m2 cediranib 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 123 (36.59%)
    26 / 64 (40.63%)
    55 / 128 (42.97%)
         number of deaths (all causes)
    73
    33
    85
         number of deaths resulting from adverse events
    1
    0
    0
    Vascular disorders
    DEEP VEIN THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 123 (3.25%)
    1 / 64 (1.56%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PHLEBITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Immune system disorders
    HYPERSENSITIVITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    FATIGUE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GAIT DISTURBANCE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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 PHYSICAL HEALTH DETERIORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 64 (1.56%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    AGGRESSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANXIETY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONFUSIONAL STATE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERSONALITY CHANGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    Reproductive system and breast disorders
    MENORRHAGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    CONCUSSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    FEEDING TUBE COMPLICATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEAD INJURY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    JOINT DISLOCATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         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 disorders
    ACUTE MYOCARDIAL INFARCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    ANGINA UNSTABLE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    TACHYCARDIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 123 (2.44%)
    0 / 64 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 64 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    5 / 123 (4.07%)
    0 / 64 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    THROMBOCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 123 (6.50%)
    2 / 64 (3.13%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    8 / 8
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    PNEUMOTHORAX
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    6 / 123 (4.88%)
    3 / 64 (4.69%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    ATAXIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL CYST
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    CEREBRAL HAEMATOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    CEREBRAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    2 / 64 (3.13%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL VENOUS THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    COMPLEX PARTIAL SEIZURES
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONVULSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 123 (2.44%)
    2 / 64 (3.13%)
    11 / 128 (8.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENCEPHALOPATHY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    GRAND MAL CONVULSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 64 (1.56%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEMIPARESIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYDROCEPHALUS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 64 (0.00%)
    0 / 128 (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
    INTRACRANIAL PRESSURE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    ISCHAEMIC CEREBRAL INFARCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    ISCHAEMIC STROKE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUROLOGICAL DECOMPENSATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUROLOGICAL SYMPTOM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    2 / 64 (3.13%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PARTIAL SEIZURES
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    2 / 64 (3.13%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL MOTOR NEUROPATHY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    SINUS HEADACHE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    SOMNOLENCE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPEECH DISORDER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    DIARRHOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 64 (1.56%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPHAGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 64 (0.00%)
    0 / 128 (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
    RECTAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL PERFORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 64 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    HEPATIC STEATOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    Skin and subcutaneous tissue disorders
    RASH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    SKIN DISORDER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 64 (1.56%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MOBILITY DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCLE HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOPOROSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    Endocrine disorders
    ADDISON'S DISEASE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    HYPOTHYROIDISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    HYPERGLYCAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    2 / 64 (3.13%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 64 (0.00%)
    0 / 128 (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
    BRONCHOPNEUMONIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CELLULITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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 OPHTHALMIC
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 64 (0.00%)
    0 / 128 (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
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 123 (2.44%)
    0 / 64 (0.00%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL ABSCESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 64 (1.56%)
    0 / 128 (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
    WOUND INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ced 20 mg +lom 110 mg/m2 pla 20 mg +lom 110 mg/m2 cediranib 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 123 (97.56%)
    61 / 64 (95.31%)
    124 / 128 (96.88%)
    Vascular disorders
    HYPERTENSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    57 / 123 (46.34%)
    4 / 64 (6.25%)
    64 / 128 (50.00%)
         occurrences all number
    74
    4
    85
    General disorders and administration site conditions
    ASTHENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    12 / 123 (9.76%)
    5 / 64 (7.81%)
    5 / 128 (3.91%)
         occurrences all number
    12
    7
    5
    FATIGUE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    72 / 123 (58.54%)
    30 / 64 (46.88%)
    65 / 128 (50.78%)
         occurrences all number
    89
    44
    86
    OEDEMA PERIPHERAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    16 / 123 (13.01%)
    8 / 64 (12.50%)
    17 / 128 (13.28%)
         occurrences all number
    18
    10
    20
    Psychiatric disorders
    AGITATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    2 / 64 (3.13%)
    8 / 128 (6.25%)
         occurrences all number
    1
    2
    8
    ANXIETY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 123 (7.32%)
    3 / 64 (4.69%)
    5 / 128 (3.91%)
         occurrences all number
    9
    3
    5
    CONFUSIONAL STATE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    6 / 123 (4.88%)
    1 / 64 (1.56%)
    10 / 128 (7.81%)
         occurrences all number
    6
    1
    11
    DEPRESSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    3 / 64 (4.69%)
    7 / 128 (5.47%)
         occurrences all number
    11
    3
    7
    INSOMNIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 123 (7.32%)
    8 / 64 (12.50%)
    9 / 128 (7.03%)
         occurrences all number
    9
    9
    10
    Injury, poisoning and procedural complications
    CONTUSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    2 / 64 (3.13%)
    7 / 128 (5.47%)
         occurrences all number
    12
    3
    8
    FALL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    6 / 123 (4.88%)
    5 / 64 (7.81%)
    5 / 128 (3.91%)
         occurrences all number
    7
    10
    5
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    13 / 123 (10.57%)
    2 / 64 (3.13%)
    4 / 128 (3.13%)
         occurrences all number
    17
    2
    4
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 123 (7.32%)
    1 / 64 (1.56%)
    2 / 128 (1.56%)
         occurrences all number
    11
    1
    2
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    13 / 123 (10.57%)
    2 / 64 (3.13%)
    2 / 128 (1.56%)
         occurrences all number
    16
    2
    2
    PLATELET COUNT DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    21 / 123 (17.07%)
    9 / 64 (14.06%)
    3 / 128 (2.34%)
         occurrences all number
    25
    12
    3
    WEIGHT DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    14 / 123 (11.38%)
    0 / 64 (0.00%)
    6 / 128 (4.69%)
         occurrences all number
    15
    0
    7
    WHITE BLOOD CELL COUNT DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    15 / 123 (12.20%)
    7 / 64 (10.94%)
    0 / 128 (0.00%)
         occurrences all number
    23
    7
    0
    Blood and lymphatic system disorders
    ANAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    1 / 64 (1.56%)
    1 / 128 (0.78%)
         occurrences all number
    18
    1
    1
    LEUKOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    25 / 123 (20.33%)
    11 / 64 (17.19%)
    2 / 128 (1.56%)
         occurrences all number
    47
    14
    2
    LYMPHOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 123 (6.50%)
    8 / 64 (12.50%)
    6 / 128 (4.69%)
         occurrences all number
    11
    9
    7
    NEUTROPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    28 / 123 (22.76%)
    8 / 64 (12.50%)
    2 / 128 (1.56%)
         occurrences all number
    44
    10
    2
    THROMBOCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    69 / 123 (56.10%)
    28 / 64 (43.75%)
    6 / 128 (4.69%)
         occurrences all number
    123
    35
    6
    Respiratory, thoracic and mediastinal disorders
    COUGH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    16 / 123 (13.01%)
    5 / 64 (7.81%)
    13 / 128 (10.16%)
         occurrences all number
    17
    6
    16
    DYSPHONIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    36 / 123 (29.27%)
    6 / 64 (9.38%)
    39 / 128 (30.47%)
         occurrences all number
    37
    7
    41
    DYSPNOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    1 / 64 (1.56%)
    7 / 128 (5.47%)
         occurrences all number
    10
    2
    10
    EPISTAXIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    11 / 123 (8.94%)
    2 / 64 (3.13%)
    3 / 128 (2.34%)
         occurrences all number
    18
    2
    4
    Nervous system disorders
    APHASIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 123 (3.25%)
    3 / 64 (4.69%)
    12 / 128 (9.38%)
         occurrences all number
    4
    4
    14
    CONVULSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 123 (7.32%)
    7 / 64 (10.94%)
    17 / 128 (13.28%)
         occurrences all number
    10
    9
    21
    DIZZINESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 123 (5.69%)
    4 / 64 (6.25%)
    13 / 128 (10.16%)
         occurrences all number
    8
    4
    14
    HEADACHE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    40 / 123 (32.52%)
    24 / 64 (37.50%)
    35 / 128 (27.34%)
         occurrences all number
    65
    30
    47
    LETHARGY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 123 (5.69%)
    3 / 64 (4.69%)
    5 / 128 (3.91%)
         occurrences all number
    9
    4
    6
    HEMIPARESIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 123 (3.25%)
    5 / 64 (7.81%)
    4 / 128 (3.13%)
         occurrences all number
    4
    5
    4
    Eye disorders
    VISION BLURRED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    6 / 123 (4.88%)
    4 / 64 (6.25%)
    5 / 128 (3.91%)
         occurrences all number
    6
    5
    5
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    11 / 123 (8.94%)
    2 / 64 (3.13%)
    7 / 128 (5.47%)
         occurrences all number
    11
    2
    7
    ABDOMINAL PAIN UPPER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 123 (5.69%)
    4 / 64 (6.25%)
    5 / 128 (3.91%)
         occurrences all number
    8
    4
    7
    CONSTIPATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    26 / 123 (21.14%)
    16 / 64 (25.00%)
    26 / 128 (20.31%)
         occurrences all number
    30
    17
    42
    DIARRHOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    87 / 123 (70.73%)
    11 / 64 (17.19%)
    91 / 128 (71.09%)
         occurrences all number
    253
    18
    219
    DRY MOUTH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 123 (5.69%)
    1 / 64 (1.56%)
    5 / 128 (3.91%)
         occurrences all number
    7
    1
    5
    FAECAL INCONTINENCE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 64 (0.00%)
    7 / 128 (5.47%)
         occurrences all number
    0
    0
    7
    NAUSEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    36 / 123 (29.27%)
    22 / 64 (34.38%)
    26 / 128 (20.31%)
         occurrences all number
    65
    31
    39
    ORAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    5 / 123 (4.07%)
    4 / 64 (6.25%)
    8 / 128 (6.25%)
         occurrences all number
    12
    6
    14
    STOMATITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 123 (2.44%)
    2 / 64 (3.13%)
    14 / 128 (10.94%)
         occurrences all number
    3
    2
    17
    VOMITING
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    25 / 123 (20.33%)
    7 / 64 (10.94%)
    10 / 128 (7.81%)
         occurrences all number
    36
    10
    17
    Renal and urinary disorders
    POLYURIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 123 (0.00%)
    4 / 64 (6.25%)
    1 / 128 (0.78%)
         occurrences all number
    0
    4
    1
    URINARY INCONTINENCE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 123 (3.25%)
    1 / 64 (1.56%)
    10 / 128 (7.81%)
         occurrences all number
    5
    1
    13
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 123 (7.32%)
    2 / 64 (3.13%)
    11 / 128 (8.59%)
         occurrences all number
    9
    2
    15
    DRY SKIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    6 / 123 (4.88%)
    3 / 64 (4.69%)
    7 / 128 (5.47%)
         occurrences all number
    6
    3
    8
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 123 (0.81%)
    2 / 64 (3.13%)
    9 / 128 (7.03%)
         occurrences all number
    1
    2
    9
    PETECHIAE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 123 (5.69%)
    0 / 64 (0.00%)
    4 / 128 (3.13%)
         occurrences all number
    9
    0
    4
    PRURITUS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    5 / 123 (4.07%)
    4 / 64 (6.25%)
    5 / 128 (3.91%)
         occurrences all number
    6
    4
    5
    RASH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    1 / 64 (1.56%)
    13 / 128 (10.16%)
         occurrences all number
    15
    1
    14
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 123 (6.50%)
    1 / 64 (1.56%)
    8 / 128 (6.25%)
         occurrences all number
    10
    1
    10
    BACK PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    7 / 64 (10.94%)
    7 / 128 (5.47%)
         occurrences all number
    13
    7
    7
    MUSCLE SPASMS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 123 (5.69%)
    3 / 64 (4.69%)
    2 / 128 (1.56%)
         occurrences all number
    8
    3
    2
    MUSCULAR WEAKNESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 123 (6.50%)
    6 / 64 (9.38%)
    10 / 128 (7.81%)
         occurrences all number
    8
    6
    11
    PAIN IN EXTREMITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    12 / 123 (9.76%)
    4 / 64 (6.25%)
    4 / 128 (3.13%)
         occurrences all number
    14
    4
    4
    Endocrine disorders
    HYPOTHYROIDISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    10 / 123 (8.13%)
    0 / 64 (0.00%)
    24 / 128 (18.75%)
         occurrences all number
    11
    0
    24
    Metabolism and nutrition disorders
    DECREASED APPETITE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    28 / 123 (22.76%)
    4 / 64 (6.25%)
    16 / 128 (12.50%)
         occurrences all number
    33
    4
    19
    Infections and infestations
    URINARY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 123 (6.50%)
    2 / 64 (3.13%)
    5 / 128 (3.91%)
         occurrences all number
    9
    2
    5
    UPPER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 123 (7.32%)
    3 / 64 (4.69%)
    6 / 128 (4.69%)
         occurrences all number
    9
    3
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2010
    Following the primary analysis of PFS and analysis of the secondary endpoints, the following changes were implemented: On approval of this amendment, treatment was unblinded, and patients who were still receiving cediranib were given the option, in consultation with their physician, to continue on treatment while deriving clinical benefit. Follow-up for OS ceased. Patients who had discontinued study treatment and were being followed for OS were to be discontinued from the study. End of study definition was changed to the last visit of the last patient for any protocol-related activity.

    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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