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    Clinical Trial Results:
    A Phase II, Multi-centre, Open-Label, Parallel Group, Randomised Study To Compare the Efficacy of selumetinib (AZD6244, ARRY-142886). vs Temozolomide in Patients with Unresectable AJCC Stage 3 or 4 Malignant Melanoma

    Summary
    EudraCT number
    2006-001456-12
    Trial protocol
    GB   AT   DK   FR  
    Global end of trial date
    24 Jul 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    06 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D1532C00003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00338130
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom, SK10 4TG
    Public contact
    AstraZeneca, AstraZeneca, AZTrial_results_posting@AstraZeneca.com
    Scientific contact
    Selumetinib Global Clinical Lead, MD, AstraZeneca, AZTrial_results_posting@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
    20 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of selumetinib (AZD6244, ARRY-142886). versus TMZ in patients with unresectable AJCC Stage 3 or 4 malignant melanoma by evaluation of Progression Free Survival (PFS)
    Protection of trial subjects
    This study was performed in compliance with Good Clinical Practice, including the archiving of essential documents
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jul 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Switzerland: 28
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    200
    EEA total number of subjects
    68
    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)
    142
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Female or male patients aged 18 years and over, with unresectable AJCC Stage 3 or 4 malignant melanoma. Patients were to have at least 1 measurable site of disease as defined by RECIST, World Health Organisation (WHO) performance status 0 to 2.

    Pre-assignment
    Screening details
    Two hundred and thirty nine patients were enrolled, of whom 200 were randomised. Of the 39 patients who failed screening and were not randomised, the majority (27) failed inclusion/exclusion criteria.

    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
    AZD6244
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD6244/Selumetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    AZD6244 100mg twice daily

    Arm title
    TMZ_
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TMZ 200mg/m2 per day for 5 days every 28 days

    Number of subjects in period 1
    AZD6244 TMZ_
    Started
    104
    96
    Received treatment
    99
    95
    Completed
    3
    3
    Not completed
    101
    93
         Patients were given maximum 6 cycles 
    -
    3
         Disease Progression
    78
    81
         Physician decision
    1
    3
         Did not receive treatment
    5
    1
         Elegibility criteria not fulled
    -
    1
         Clinical progression
    -
    2
         Not willing to continue study treatment
    5
    -
         Symptomatic deterioration
    1
    -
         Adverse event, non-fatal
    10
    2
         Undergo resection & follow-up with other treatment
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZD6244
    Reporting group description
    -

    Reporting group title
    TMZ_
    Reporting group description
    -

    Reporting group values
    AZD6244 TMZ_ Total
    Number of subjects
    104 96 200
    Age Categorical
    Min
    Units: Subjects
        From 18 - 64 years
    74 68 142
        From 65 – 84 years
    30 28 58
    Age Continuous
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    57.1 ± 14 57 ± 13.4 -
    Gender Categorical
    Units: Subjects
        Female
    49 31 80
        Male
    55 65 120
    World Health Organisation Performance Status
    WHO Performance Status assessed at baseline
    Units: Subjects
        0 (Normal activity)
    67 71 138
        1 (Restricted activity)
    34 23 57
        2 (In bed </= 50% of the time)
    1 2 3
        Performance Status unknown
    2 0 2
    American Joint committee on Cancer Staging
    AJCC assessed at baseline
    Units: Subjects
        Stage 3
    3 3 6
        Stage 4
    99 92 191
        AJCC stage unknown
    2 1 3
    Lactate dehydrogenase level at baseline
    Lactate dehydrogenase level at baseline
    Units: Subjects
        <2 x upper limit of normal
    79 79 158
        >/= 2 x upper limit normal
    17 15 32
        unknown
    8 2 10
    Primary tumour type
    Primary tumour type
    Units: Subjects
        Uveal
    7 13 20
        Mucosal
    6 0 6
        Cutaneous
    75 72 147
        Unknown primary tumour
    16 11 27
    Mutation Status
    Units: Subjects
        BRAF positive
    45 28 73
        NRAS positive
    10 18 28
        Wild-type for both
    29 28 57
        Mutation status unknown
    20 22 42
    Subject analysis sets

    Subject analysis set title
    AZD6244
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients randomised to AZD6244

    Subject analysis set title
    TMZ
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients randomised to TMZ

    Subject analysis sets values
    AZD6244 TMZ
    Number of subjects
    104
    96
    Age Categorical
    Min
    Units: Subjects
        From 18 - 64 years
    74
    68
        From 65 – 84 years
    30
    28
    Age Continuous
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    57.1 ± 14
    57 ± 13.4
    Gender Categorical
    Units: Subjects
        Female
    49
    31
        Male
    55
    65
    World Health Organisation Performance Status
    WHO Performance Status assessed at baseline
    Units: Subjects
        0 (Normal activity)
    67
    71
        1 (Restricted activity)
    34
    23
        2 (In bed </= 50% of the time)
    1
    2
        Performance Status unknown
    2
    0
    American Joint committee on Cancer Staging
    AJCC assessed at baseline
    Units: Subjects
        Stage 3
    3
    3
        Stage 4
    99
    92
        AJCC stage unknown
    2
    1
    Lactate dehydrogenase level at baseline
    Lactate dehydrogenase level at baseline
    Units: Subjects
        <2 x upper limit of normal
    79
    79
        >/= 2 x upper limit normal
    17
    15
        unknown
    8
    2
    Primary tumour type
    Primary tumour type
    Units: Subjects
        Uveal
    7
    13
        Mucosal
    6
    0
        Cutaneous
    75
    72
        Unknown primary tumour
    16
    11
    Mutation Status
    Units: Subjects
        BRAF positive
    45
    28
        NRAS positive
    10
    18
        Wild-type for both
    29
    28
        Mutation status unknown
    20
    22

    End points

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    End points reporting groups
    Reporting group title
    AZD6244
    Reporting group description
    -

    Reporting group title
    TMZ_
    Reporting group description
    -

    Subject analysis set title
    AZD6244
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients randomised to AZD6244

    Subject analysis set title
    TMZ
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients randomised to TMZ

    Primary: PFS

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    End point title
    PFS
    End point description
    End point type
    Primary
    End point timeframe
    Assessment by RECIST criteria conducted at baseline, week 6, week 12 and then every 8 weeks until progression
    End point values
    AZD6244 TMZ_
    Number of subjects analysed
    104
    96
    Units: days
        median (not applicable)
    78 ± 0
    80 ± 0
    Statistical analysis title
    PFS in the Overall Population
    Statistical analysis description
    PFS was analysed using a Cox Proportional Hazards model.
    Comparison groups
    AZD6244 v TMZ_
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.65 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.32
    Notes
    [1] - Overall ITT population
    [2] - 1-sided p-value
    Statistical analysis title
    PFS in BRAF mutant subpopulation
    Statistical analysis description
    PFS was analysed using a Cox Proportional Hazards Model
    Comparison groups
    AZD6244 v TMZ_
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.537 [4]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.49
    Notes
    [3] - BRAF mutant subpopulation
    [4] - 1-sided p-value
    Statistical analysis title
    PFS in BRAF and/or NRAS mutant subpopulation
    Statistical analysis description
    PFS was analysed using a Cox Proportional Hazards Model
    Comparison groups
    AZD6244 v TMZ_
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.547 [6]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.38
    Notes
    [5] - BRAF and/or NRAS mutant subpopulation
    [6] - 1-sided p-value

    Secondary: Time To Death

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    End point title
    Time To Death
    End point description
    Assessed following 130 deatjs
    End point type
    Secondary
    End point timeframe
    Time from randomisation until Death
    End point values
    AZD6244 TMZ_
    Number of subjects analysed
    104
    96
    Units: Days
        median (not applicable)
    284 ± 0
    369 ± 0
    Statistical analysis title
    TTD in the Overall Population
    Statistical analysis description
    Cox Proportional Hazards Model
    Comparison groups
    AZD6244 v TMZ_
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.95 [8]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.351
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    1.07
         upper limit
    1.71
    Notes
    [7] - Overall Population
    [8] - 1-sided p-value
    Statistical analysis title
    TTD in BRAF mutant subpopulation
    Statistical analysis description
    Time To Death analysed using Cox Proportional Hazards Model
    Comparison groups
    AZD6244 v TMZ_
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.949 [10]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.654
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    1.12
         upper limit
    2.45
    Notes
    [9] - BRAF mutant subpopulation
    [10] - 1-sided p-value
    Statistical analysis title
    TTD in BRAF and/or NRAS mutant subpopulation
    Statistical analysis description
    Time To Death analysed using a Cox Proportional Hazards Model
    Comparison groups
    AZD6244 v TMZ_
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.973 [12]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.621
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    1.18
         upper limit
    2.23
    Notes
    [11] - BRAF and/or NRAS mutant subpopulation
    [12] - 1-sided

    Secondary: Objective Tumour response

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    End point title
    Objective Tumour response
    End point description
    End point type
    Secondary
    End point timeframe
    Assessment by RECIST criteria conducted at baseline, week 6, week 12 and then every 8 weeks until progression
    End point values
    AZD6244 TMZ_
    Number of subjects analysed
    104
    96
    Units: No. Patients
        In overall Population
    6
    9
        In BRAF mutant subpopulation
    5
    3
        In BRAF and NRAS mutant subpopulation
    5
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected throughout the study. SAEs were collected until disease progression or 30 days after withdrawal from treatment, whichever was the latest.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Temozolomide
    Reporting group description
    Temozolomide was administered without food, as described in the national prescribing information

    Reporting group title
    AZD6244
    Reporting group description
    AZD6244 was administered orally with 15 mL of Captisol® Aqueous solution (25% w/v) prior to breakfast and an evening meal

    Serious adverse events
    Temozolomide AZD6244
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 95 (16.84%)
    32 / 99 (32.32%)
         number of deaths (all causes)
    57
    73
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to biliary tract
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to gastrointestinal tract
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour haemorrhage
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Patella fracture
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio respiratory arrest
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocturnal dyspnoea
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphasia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 95 (0.00%)
    3 / 99 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric Vein Thrombosis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 95 (1.05%)
    3 / 99 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type two Diabetes mellitus
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 95 (0.00%)
    3 / 99 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Temozolomide AZD6244
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 95 (96.84%)
    99 / 99 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 95 (2.11%)
    8 / 99 (8.08%)
         occurrences all number
    2
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 95 (5.26%)
    7 / 99 (7.07%)
         occurrences all number
    5
    7
    Face oedema
         subjects affected / exposed
    1 / 95 (1.05%)
    7 / 99 (7.07%)
         occurrences all number
    1
    8
    Fatigue
         subjects affected / exposed
    40 / 95 (42.11%)
    29 / 99 (29.29%)
         occurrences all number
    45
    34
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 99 (5.05%)
         occurrences all number
    1
    5
    Oedema peripheral
         subjects affected / exposed
    5 / 95 (5.26%)
    40 / 99 (40.40%)
         occurrences all number
    5
    62
    Pyrexia
         subjects affected / exposed
    10 / 95 (10.53%)
    15 / 99 (15.15%)
         occurrences all number
    10
    22
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 95 (5.26%)
    7 / 99 (7.07%)
         occurrences all number
    5
    7
    Insomnia
         subjects affected / exposed
    6 / 95 (6.32%)
    10 / 99 (10.10%)
         occurrences all number
    6
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 95 (2.11%)
    7 / 99 (7.07%)
         occurrences all number
    2
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 95 (0.00%)
    8 / 99 (8.08%)
         occurrences all number
    0
    8
    Weight decreased
         subjects affected / exposed
    6 / 95 (6.32%)
    4 / 99 (4.04%)
         occurrences all number
    7
    4
    Haemoglobin decreased
         subjects affected / exposed
    4 / 95 (4.21%)
    6 / 99 (6.06%)
         occurrences all number
    4
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 95 (6.32%)
    9 / 99 (9.09%)
         occurrences all number
    6
    10
    Thrombocytopenia
         subjects affected / exposed
    7 / 95 (7.37%)
    2 / 99 (2.02%)
         occurrences all number
    7
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 95 (5.26%)
    9 / 99 (9.09%)
         occurrences all number
    5
    11
    Dyspnoea exertional
         subjects affected / exposed
    6 / 95 (6.32%)
    13 / 99 (13.13%)
         occurrences all number
    6
    15
    Pharyngolaryngeal pain
         subjects affected / exposed
    4 / 95 (4.21%)
    9 / 99 (9.09%)
         occurrences all number
    4
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 95 (7.37%)
    8 / 99 (8.08%)
         occurrences all number
    10
    10
    Headache
         subjects affected / exposed
    23 / 95 (24.21%)
    20 / 99 (20.20%)
         occurrences all number
    27
    24
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 95 (2.11%)
    8 / 99 (8.08%)
         occurrences all number
    2
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 95 (3.16%)
    8 / 99 (8.08%)
         occurrences all number
    3
    9
    Abdominal pain
         subjects affected / exposed
    12 / 95 (12.63%)
    12 / 99 (12.12%)
         occurrences all number
    14
    13
    Abdominal pain upper
         subjects affected / exposed
    4 / 95 (4.21%)
    7 / 99 (7.07%)
         occurrences all number
    7
    9
    Constipation
         subjects affected / exposed
    45 / 95 (47.37%)
    12 / 99 (12.12%)
         occurrences all number
    60
    13
    Diarrhoea
         subjects affected / exposed
    20 / 95 (21.05%)
    55 / 99 (55.56%)
         occurrences all number
    27
    77
    Dry mouth
         subjects affected / exposed
    6 / 95 (6.32%)
    8 / 99 (8.08%)
         occurrences all number
    6
    8
    Flatulence
         subjects affected / exposed
    1 / 95 (1.05%)
    7 / 99 (7.07%)
         occurrences all number
    1
    7
    Dyspepsia
         subjects affected / exposed
    4 / 95 (4.21%)
    11 / 99 (11.11%)
         occurrences all number
    4
    13
    Nausea
         subjects affected / exposed
    61 / 95 (64.21%)
    49 / 99 (49.49%)
         occurrences all number
    79
    64
    Stomatitis
         subjects affected / exposed
    1 / 95 (1.05%)
    9 / 99 (9.09%)
         occurrences all number
    1
    12
    Vomiting
         subjects affected / exposed
    42 / 95 (44.21%)
    26 / 99 (26.26%)
         occurrences all number
    56
    35
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 95 (1.05%)
    7 / 99 (7.07%)
         occurrences all number
    2
    7
    Acne
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 99 (5.05%)
         occurrences all number
    0
    7
    Dermatitis acneiform
         subjects affected / exposed
    3 / 95 (3.16%)
    58 / 99 (58.59%)
         occurrences all number
    3
    70
    Dry skin
         subjects affected / exposed
    0 / 95 (0.00%)
    9 / 99 (9.09%)
         occurrences all number
    0
    10
    Eczema
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 99 (5.05%)
         occurrences all number
    0
    5
    Exfoliative rash
         subjects affected / exposed
    0 / 95 (0.00%)
    7 / 99 (7.07%)
         occurrences all number
    0
    9
    Periorbital oedema
         subjects affected / exposed
    1 / 95 (1.05%)
    14 / 99 (14.14%)
         occurrences all number
    1
    15
    Pruritus
         subjects affected / exposed
    3 / 95 (3.16%)
    10 / 99 (10.10%)
         occurrences all number
    3
    11
    Rash
         subjects affected / exposed
    1 / 95 (1.05%)
    7 / 99 (7.07%)
         occurrences all number
    1
    12
    Rash macular
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 99 (5.05%)
         occurrences all number
    0
    5
    Rash erythematous
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 99 (6.06%)
         occurrences all number
    2
    7
    Skin fissures
         subjects affected / exposed
    0 / 95 (0.00%)
    7 / 99 (7.07%)
         occurrences all number
    0
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 95 (7.37%)
    5 / 99 (5.05%)
         occurrences all number
    7
    7
    Back pain
         subjects affected / exposed
    9 / 95 (9.47%)
    5 / 99 (5.05%)
         occurrences all number
    14
    5
    Musculoskeletal pain
         subjects affected / exposed
    6 / 95 (6.32%)
    2 / 99 (2.02%)
         occurrences all number
    7
    2
    Pain in extremity
         subjects affected / exposed
    7 / 95 (7.37%)
    9 / 99 (9.09%)
         occurrences all number
    7
    9
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    12 / 95 (12.63%)
    9 / 99 (9.09%)
         occurrences all number
    12
    9
    Decreased appetite
         subjects affected / exposed
    4 / 95 (4.21%)
    11 / 99 (11.11%)
         occurrences all number
    4
    12
    Hypokalaemia
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 99 (5.05%)
         occurrences all number
    3
    5
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 99 (5.05%)
         occurrences all number
    1
    7
    Paronychia
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 99 (5.05%)
         occurrences all number
    0
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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