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    Clinical Trial Results:
    A double blind randomised phase 2 trial of docetaxel with or without AZD6244 in wt BRAF advanced melanoma

    Summary
    EudraCT number
    		 2009-018153-23
    Trial protocol
    		 GB  
    Global end of trial date
    20 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Mar 2021
    First version publication date
    14 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO_015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, 1st floor, Boundary Brook House, Churchill Drive, Headington,, Oxford, United Kingdom, OX3 7GB
    Public contact
    Linda Collins, OCTO, octo-dock-mek@oncology.ox.ac.uk
    Scientific contact
    Linda Collins, OCTO, octo-dock-mek@oncology.ox.ac.uk
    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
    01 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of AZD6244 in combination with docetaxel, compared with docetaxel alone, in first line treatment of patients with wild type BRAF advanced malignant melanoma.
    Protection of trial subjects
    The protocol was conducted in compliance with the UK Clinical Trials Regulations, the Principles of Good Clinical Practice (GCP) and the applicable policies of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of investigational medicinal products under the European Union Clinical Trials Directive.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Oct 2010
    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
    United Kingdom: 83
    Worldwide total number of subjects
    83
    EEA total number of subjects
    83
    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)
    50
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eighty–three patients were recruited to DOC-MEK from 26October2010 to 22May2012 from 16 centres. 41 were recruited in the AZD6244 arm (docetaxel plus selumetinib ) and 42 in the Placebo arm (docetaxel plus placebo) The 16 centres were across the UK under the auspices of the NCRI Melanoma Clinical Study Group.

    Pre-assignment
    Screening details
    		 Assessed for eligibility (n=260) Excluded (n=177): Reasons for exclusion: Not meeting inclusion criteria (n=134), Declined to participate (n=30), Other reasons (n = 13) Randomised (n=83) Did not start treatment (n=4)

    Pre-assignment period milestones
    Number of subjects started
    		 83
    Number of subjects completed
    		 83

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    A placebo (matched to selumetinib) was used in the control group to ensure this blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doc + AZD6244
    Arm description
    		 Patients receive docetaxel with AZD6244 (selumetinib). Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles. Selumetinib 75 mg was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    AZD6244/selumetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Selumetinib 75 mg was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles.

    Arm title
    		 Doc + placebo
    Arm description
    		 Patients receive docetaxel with AZD6244 (selumetinib). Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles. placebo (matched to selumetinib) was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles.

    Number of subjects in period 1
    		Doc + AZD6244 Doc + placebo
    Started
    41
    42
    Completed
    38
    41
    Not completed
    3
    1
         Did not start allocated intervention
    3
    -
         Did not start treatment
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doc + AZD6244
    Reporting group description
    		 Patients receive docetaxel with AZD6244 (selumetinib). Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles. Selumetinib 75 mg was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.

    Reporting group title
    Doc + placebo
    Reporting group description
    		 Patients receive docetaxel with AZD6244 (selumetinib). Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles. placebo (matched to selumetinib) was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.

    Reporting group values
    		 Doc + AZD6244 Doc + placebo Total
    Number of subjects
    		 41 42 83
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.5 ± 12.0 59.2 ± 13.3 -
    Gender categorical
    Units: Subjects
        Female
    		 10 15 25
        Male
    		 31 27 58
    Stage
    Units: Subjects
        M1c
    		 33 32 65
        M0 or M1a or M1b
    		 8 10 18
    ECOG Performance Score
    Units: Subjects
        PS = 0
    		 28 34 62
        PS=1
    		 13 8 21
    Smoking status
    Units: Subjects
        Yes
    		 4 3 7
        No, but smoked in the past
    		 22 27 49
        Never smoked
    		 15 12 27
    LDH
    Units: Subjects
        Above Upper limit normal
    		 20 27 47
        BBelow Upper limit normal
    		 21 15 36
    ECG (at screening)
    Units: Subjects
        Abnormal
    		 4 4 8
        Normal
    		 37 37 74
        Not evaluated
    		 0 1 1
    Urinalysis
    Units: Subjects
        Abnormal
    		 9 8 17
        Normal
    		 30 30 60
        Not evaluated
    		 2 4 6
    Conmeds
    Number of pts reporting taking con meds at baseline
    Units: Subjects
        Yes for conmeds at baseline
    		 35 33 68
        No
    		 6 9 15
    Vital signs-Temperature
    Out of 40 (active) and 40 (placebo) patients with data
    Units: degrees Celsius
        median (full range (min-max))
    		 36.2 (35.2 to 37.3) 36.5 (35 to 37.4) -
    Vital signs- Pulse rate
    Available data: 41 active, 41 placebo
    Units: bpm
        median (full range (min-max))
    		 70 (56 to 100) 72 (42 to 120) -
    Vital signs- Systolic BP
    Available data: 41 active, 41 placebo
    Units: mmHg
        median (full range (min-max))
    		 137 (97 to 192) 136 (113 to 175) -
    Vital signs- diastolic BP
    Available data, 41 active, 41 placebo
    Units: mmHg
        median (full range (min-max))
    		 85 (56 to 115) 82 (68 to 95) -
    Height
    Out of 40 active and 40 placebo with data
    Units: metres
        arithmetic mean (standard deviation)
    		 1.74 ± 0.1 1.7 ± 0.1 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 88.4 ± 19 83 ± 19.5 -
    BSA
    Units: msquared
        arithmetic mean (standard deviation)
    		 2.022 ± 0.232 1.939 ± 0.260 -
    Biochemistry-ALT
    Out of 41 active and 41 placebo with data
    Units: U/L
        median (full range (min-max))
    		 26 (7 to 93) 22 (6 to 54) -
    Biochemistry-AST
    Available data for 37 active and 38 placebo patients.
    Units: U/L
        median (full range (min-max))
    		 24 (12 to 104) 22 (14 to 58) -
    Bilirubin
    Data availability 41 active and 41 placebo patients.
    Units: umol/L
        median (full range (min-max))
    		 10 (4 to 21) 8 (2 to 18) -
    Biochemistry Creatine clearance
    Available data for 40 active and 41 placebo patients
    Units: ml/min
        median (full range (min-max))
    		 111 (54 to 233) 94 (39 to 194) -
    Haematology-Haemoglobin
    Data available for 41 active and 41 placebo patients
    Units: g/dL
        median (full range (min-max))
    		 14 (10 to 16) 14 (10 to 17) -
    Haematology- White cell count
    Data available for 41 active and 41 placebo patients
    Units: x10^9/L
        median (full range (min-max))
    		 8 (4 to 15) 7 (5 to 13) -
    Haematology- Neutrophils
    Data available for 41 active and 41 placebo patients
    Units: x10^9/L
        median (full range (min-max))
    		 5 (2 to 11) 5 (2 to 11) -
    Haematology- Platelets
    Data available for 41 active and 41 placebo patients
    Units: x10^9/L
        median (full range (min-max))
    		 259 (147 to 681) 255 (177 to 754) -
    Target lesion Sum LD
    Units: mm
        median (full range (min-max))
    		 98 (16 to 243) 56 (11 to 450) -

    End points

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    End points reporting groups
    Reporting group title
    Doc + AZD6244
    Reporting group description
    		 Patients receive docetaxel with AZD6244 (selumetinib). Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles. Selumetinib 75 mg was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.

    Reporting group title
    Doc + placebo
    Reporting group description
    		 Patients receive docetaxel with AZD6244 (selumetinib). Docetaxel 75 mg/m2 was administered intravenously on day 1 of a 21-day cycle up to a maximum of six cycles. placebo (matched to selumetinib) was given orally twice daily on a continuous schedule until disease progression or unacceptable toxicity.

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all patients who were randomly assigned.

    Subject analysis set title
    Sensitivity population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients that had CT scans as per protocol. Doc + Placebo = 33 and Doc+AZD6244 = 28

    Subject analysis set title
    Sensitivity population- per protocol
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This includes 77 patients. Four patients who did not start treatment and two patients who were later found to be ineligible are excluded.

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    The primary endpoint is Progression Free Survival (PFS). This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
    End point type
    Primary
    End point timeframe
    From first patient randomised to date last known alive before 01 Oct 2012.
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41 [1]
    42 [2]
    83 [3]
    Units: Patients
    32
    36
    68
    Notes
    [1] - Count given is the number of events
    [2] - Count given is the number of events
    [3] - Count given is the number of events
    Statistical analysis title
    		 Cox Proportional Hazards analysis
    Statistical analysis description
    Adjusted for M status and performance status
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.753
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.498
         upper limit
    		 1.138
    Notes
    [4] - p value < 0.1 one-sided considered to be significant.

    Secondary: Progression free survival at 6 months

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    End point title
    		 Progression free survival at 6 months
    End point description
    PFS at 6 months is defined as the percentage progression free survival at 6 months from the PFS Kaplan Meier graph. This would allow all patients randomised to be included.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Doc + AZD6244 Doc + placebo
    Number of subjects analysed
    41
    42
    Units: %
        number (confidence interval 90%)
    40 (27 to 53)
    26 (15 to 38)
    Statistical analysis title
    		 PFS rate
    Statistical analysis description
    Progression free survival rate at 6 months was estimated from the KM plot.
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.187
    Method
    		 Logrank
    Parameter type
    		 Difference in PFS rate (%)
    Point estimate
    14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 31.4
    Notes
    [5] - Result is the estimated difference in PFS rate (%)

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    This is defined as the time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
    End point type
    Secondary
    End point timeframe
    Trial duration i.e. from start of recruitment to 01 Oct 2012 . Patients without an event at the time of the datalock on 01 Oct 2012 were censored at their last known alive time (date last seen).
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41
    42
    83
    Units: Patients
    20
    17
    37
    Statistical analysis title
    		 Cox Proportional Hazards analysis
    Statistical analysis description
    Unadjusted
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.169
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.373
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.797
         upper limit
    		 2.369

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Best overall response recorded from the start date of treatment until disease progression. The numerator of the objective response rate is the number of patients achieving a CR or PR. The denominator is all patients randomised.
    End point type
    Secondary
    End point timeframe
    From the start date of treatment until disease progression.
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41
    42
    83
    Units: Patients
    13
    6
    19
    Statistical analysis title
    		 Chi squared test
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Lab analysis

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    End point title
    		 Lab analysis
    End point description
    This secondary endpoint includes multiple lab based measures: vital signs (temperature, pulse rate and blood pressure), weight, biochemistry, haematology and urinalysis measures, physical examination outcomes (general appearance, skin etc.) and ECG measures. Analysis was descriptive- data were graphed on a per- patient basis. The measurement type is not 'number' as selected above but it is the relevant unit for each measure, for example for temperature, the data points graphed are in degrees Celsius.
    End point type
    Secondary
    End point timeframe
    Trial duration.
    End point values
    		 Intention-to-treat population
    Number of subjects analysed
    83
    Units: multiple measures
        number (not applicable)
    83
    Attachments
    		 Lab data- all graphs
    No statistical analyses for this end point

    Secondary: Overall survival-updated

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    End point title
    		 Overall survival-updated
    End point description
    time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
    End point type
    Secondary
    End point timeframe
    OS analysis was carried out at the final analysis time point on data taken on 01Oct2012. Another data extraction was taken on 05Mar2013 in order to carry out posthoc analyses, OS was analysed again on this data which has more death events.
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41
    42
    83
    Units: Patients
    26
    28
    54
    Statistical analysis title
    		 Cox Regression model
    Statistical analysis description
    Adjusted for with Mstatus and Performance Score
    Comparison groups
    Doc + placebo v Doc + AZD6244
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.318
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.84

    Secondary: Overall survival-updated sensitivity

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    End point title
    		 Overall survival-updated sensitivity
    End point description
    End point type
    Secondary
    End point timeframe
    This is OS analysis done on a later timepoint to the final analysis and has a few more events (see OS-updated), this is on the per protocol population.
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    37
    40
    77
    Units: Patients
    23
    26
    49
    Statistical analysis title
    		 Cox Regression model
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.348
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.87

    Other pre-specified: Progression Free survival- sensitivity analysis

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    End point title
    		 Progression Free survival- sensitivity analysis
    End point description
    Survival is from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
    End point type
    Other pre-specified
    End point timeframe
    Trial duration i.e. from start of recruitment to 01 Oct 2012 . Patients without an event at the time of the datalock on 01 Oct 2012 were censored at their last known alive time (date last seen).
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population
    Number of subjects analysed
    28 [6]
    33 [7]
    61 [8]
    Units: Patients
    24
    27
    51
    Notes
    [6] - only pts with ct scans as per protocol
    [7] - only pts with ct scans as per protocol
    [8] - Doc + Placebo = 33 and Doc+AZD6244 = 28
    Statistical analysis title
    		 Cox Proportional Hazards analysis
    Statistical analysis description
    Adjusted for mstatus, performance status
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.468
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.022
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.649
         upper limit
    		 1.612

    Other pre-specified: Progression Free Survival- Sensitivity analysis (per-protocol)

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    End point title
    		 Progression Free Survival- Sensitivity analysis (per-protocol)
    End point description
    Survival is from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
    End point type
    Other pre-specified
    End point timeframe
    Trial duration i.e. from start of recruitment to 01 Oct 2012 . Patients without an event at the time of the datalock on 01 Oct 2012 were censored at their last known alive time (date last seen).
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    37
    40
    77
    Units: Patients
    28
    34
    62
    Statistical analysis title
    		 Cox Proportional Hazards analysis
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.106
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.721
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.468
         upper limit
    		 1.09

    Other pre-specified: Progression Free Survival- Sensitivity analysis adjusted

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    End point title
    		 Progression Free Survival- Sensitivity analysis adjusted
    End point description
    Survival is from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
    End point type
    Other pre-specified
    End point timeframe
    Trial duration i.e. from start of recruitment to 01 Oct 2012 . Patients without an event at the time of the datalock on 01 Oct 2012 were censored at their last known alive time (date last seen).
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41
    42
    83
    Units: Patients
    32
    36
    68
    Statistical analysis title
    		 Cox Proportional Hazards analysis
    Statistical analysis description
    Adjusted for mstatus, performance status, LDH, target lesion sum and time interval between randomisation and baseline CT scan
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.113
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.723
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.465
         upper limit
    		 1.123

    Other pre-specified: Progression Free survival- centre effect

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    End point title
    		 Progression Free survival- centre effect
    End point description
    Survival is from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
    End point type
    Other pre-specified
    End point timeframe
    Trial duration i.e. from start of recruitment to 01 Oct 2012 . Patients without an event at the time of the datalock on 01 Oct 2012 were censored at their last known alive time (date last seen).
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41
    42
    83
    Units: Patients
    32
    36
    68
    Statistical analysis title
    		 Cox Proportional Hazards analysis
    Statistical analysis description
    Centre effects were limited to the three biggest recruiters and all other centres are combined.
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.305
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.348
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.602
         upper limit
    		 3.016

    Post-hoc: Progression Free Survival - Sensitivity analysis interval

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    End point title
    		 Progression Free Survival - Sensitivity analysis interval
    End point description
    Survival is from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.
    End point type
    Post-hoc
    End point timeframe
    Trial duration i.e. from start of recruitment to 01 Oct 2012 . Patients without an event at the time of the datalock on 01 Oct 2012 were censored at their last known alive time (date last seen).
    End point values
    		 Doc + AZD6244 Doc + placebo Intention-to-treat population
    Number of subjects analysed
    41
    42
    83
    Units: Patients
    32
    36
    68
    Statistical analysis title
    		 Survival analysis with interval censoring
    Statistical analysis description
    Patients are assessed periodically for the response so progression is known only to have occurred at some time between visits, the exact time is not known. We carried out interval censored analysis as a sensitivity analysis to demonstrate if allowing for interval censoring gives a different interpretation of the primary outcome.
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.302 [9]
    Method
    		 Survival analysis with interval censorin
    Confidence interval
    Notes
    [9] - Generalized log rank test compares between treatment groups. P-value given are from applying the Zhao & Sun. 2004 method is SAS version 9.2.

    Post-hoc: Progression free survival- NRAS

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    End point title
    		 Progression free survival- NRAS
    End point description
    On 05Mar2013 (post final analysis) we had 64/83 (77%) patients with NRAS data available. The main analysis included the per-protocol sample. A sensitivity analysis will be carried out for patients who had changed BRAF status on re-testing carried out with the NRAS test. The ITT sample is not relevant to this analysis and NRAS is not available on all randomised patients. We have N = 77/83 (93%) in the PP-sample of which 60/77 (78%) have NRAS data and 75/83 in the sensitivity analysis sample of which 58/75 (77%) have NRAS data.
    End point type
    Post-hoc
    End point timeframe
    Trial duration. NRAS mutational analysis for all patients has been derived from archival melanoma tumour tissue samples. Progression times used was from the trial.
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    29 [10]
    31 [11]
    60 [12]
    Units: Patients
    25
    28
    53
    Notes
    [10] - PP population with NRAS data
    [11] - PP population with NRAS data
    [12] - pp sample with NRAS data
    Statistical analysis title
    		 Cox Regression model
    Statistical analysis description
    The impact of NRAS mutation status (Mutated/Wild type]) on effectiveness of treatment in PFS was assessed by adding an interaction term with treatment in the COX model. What we mean by interaction is that the effect of the treatment may be different, depending on NRAS mutation status. Model also adjusted for stratification variables
    Comparison groups
    Doc + AZD6244 v Doc + placebo v Sensitivity population- per protocol
    Number of subjects included in analysis
    120
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.824 [13]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [13] - p-value is for interaction term HRs (95% CI) for active vs placebo arms are below for wild type and mutated NRAS respectively 0.63 (0.25, 1.53) 0.71 (0.349, 1.44)

    Post-hoc: Progression free survival- NRAS sensitivity

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    End point title
    		 Progression free survival- NRAS sensitivity
    End point description
    On 05Mar2013 (post final analysis) we had 64/83 (77%) patients with NRAS data available. The main analysis included the per-protocol sample. A sensitivity analysis (results here)will be carried out for patients who had changed BRAF status on re-testing carried out with the NRAS test. The ITT sample is not relevant to this analysis and NRAS is not available on all randomised patients. We have N = 77/83 (93%) in the PP-sample of which 60/77 (78%) have NRAS data and 75/83 in the sensitivity analysis sample of which 58/75 (77%) have NRAS data.
    End point type
    Post-hoc
    End point timeframe
    Trial duration. NRAS mutational analysis for all patients has been derived from archival melanoma tumour tissue samples. Progression times used was from the trial.
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    28 [14]
    30 [15]
    58 [16]
    Units: Patients
    24
    27
    51
    Notes
    [14] - PP population with NRAS data minus one pt with BRAF mutation
    [15] - PP population with NRAS data minus one pt with BRAF mutation
    [16] - PP sample with NRAS data, further excludes 2 samples found to have BRAF mutation on retesting
    Statistical analysis title
    		 Cox Regression model
    Statistical analysis description
    Model with interaction term and stratification variables
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.797 [17]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [17] - p-value is for interaction term. HRs (95% CI) between active vs placebo treatment groups are below 0.61 (0.24, 1.58) - wild type 0.71 (0.350, 1.45) -mutated NRAS

    Post-hoc: Overall survival-NRAS

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    End point title
    		 Overall survival-NRAS
    End point description
    On 05Mar2013 (post final analysis) we had 64/83 (77%) patients with NRAS data available. The main analysis included the per-protocol sample. A sensitivity analysis will be carried out for patients who had changed BRAF status on re-testing carried out with the NRAS test. The ITT sample is not relevant to this analysis and NRAS is not available on all randomised patients. We have N = 77/83 (93%) in the PP-sample of which 60/77 (78%) have NRAS data and 75/83 in the sensitivity analysis sample of which 58/75 (77%) have NRAS data.
    End point type
    Post-hoc
    End point timeframe
    Trial duration. NRAS mutational analysis for all patients has been derived from archival melanoma tumour tissue samples. Progression times used was from the trial.
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    29
    31
    60 [18]
    Units: Patients
    18
    20
    38
    Notes
    [18] - with NRAS data only
    Statistical analysis title
    		 Cox Regression model
    Statistical analysis description
    The impact of NRAS mutation status (Mutated/Wild type]) on OS was assessed by adding an interaction term with treatment in the Cox model. Model has interaction term and stratification variables
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.072 [20]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [19] - HRs (95%CI) between active vs placebo groups below 0.51 (0.16, 1.60)- WT 1.97 (0.73, 5.33)-mutated NRAS
    [20] - p-value is for interaction term

    Post-hoc: Overall survival-NRAS sensitivity

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    End point title
    		 Overall survival-NRAS sensitivity
    End point description
    On 05Mar2013 (post final analysis) we had 64/83 (77%) patients with NRAS data available. The main analysis included the per-protocol sample. A sensitivity analysis will be carried out for patients who had changed BRAF status on re-testing carried out with the NRAS test. The ITT sample is not relevant to this analysis and NRAS is not available on all randomised patients. We have N = 77/83 (93%) in the PP-sample of which 60/77 (78%) have NRAS data and 75/83 in the sensitivity analysis sample of which 58/75 (77%) have NRAS data.
    End point type
    Post-hoc
    End point timeframe
    Trial duration. NRAS mutational analysis for all patients has been derived from archival melanoma tumour tissue samples. Progression times used was from the trial.
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    28
    30
    58 [21]
    Units: Patients
    18
    19
    37
    Notes
    [21] - This excludes the patients in the per-protocol sample found to have BRAF mutation on retesting
    Statistical analysis title
    		 Cox Regression model
    Statistical analysis description
    Model with interaction term and stratification variables
    Comparison groups
    Doc + AZD6244 v Doc + placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.12
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [22] - Hazard ratio (95%CI) for AZD6244 vs Placebo groups 0.60 (0.18, 1.97)- WT 1.99 (0.73, 5.38)- mutated NRAS

    Post-hoc: Objective response rate for mutated NRAS patients

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    End point title
    		 Objective response rate for mutated NRAS patients
    End point description
    Best overall response as reported for evaluable/measurable scans including target, non-target and new lesion for NRAS mutated patients in PP population
    End point type
    Post-hoc
    End point timeframe
    Trial duration
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    20 [23]
    17 [24]
    Units: Patients
        Complete response
    1
    0
    1
        Partial response
    6
    2
    8
        Stable disease
    7
    9
    16
        Progressive disease
    2
    6
    8
        Not applicable
    4
    0
    4
    Notes
    [23] - Mutated only
    [24] - Mutated only
    No statistical analyses for this end point

    Post-hoc: Objective response rate for WT NRAS patients

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    End point title
    		 Objective response rate for WT NRAS patients
    End point description
    Best overall response as reported for evaluable/measurable scans including target, non-target and new lesion for NRAS wild type patients in PP population
    End point type
    Post-hoc
    End point timeframe
    Trial duration
    End point values
    		 Doc + AZD6244 Doc + placebo Sensitivity population- per protocol
    Number of subjects analysed
    9 [25]
    14
    Units: Patients
        Complete response
    0
    0
    0
        Partial response
    2
    2
    4
        Stable disease
    4
    4
    8
        Progressive disease
    3
    8
    11
        Not applicable*
    0
    0
    0
    Notes
    [25] - WT total=23
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event monitoring starts from the time the patient receives any of the research procedures until they complete the trial.
    Adverse event reporting additional description
    In addition to the AEs entered below, there are 99 (nonserious) events where the System Organ Class was classed as "Other" so cannot be entered. 3 AEs on placebo arm were fatal but were part of the 99 that had no SOC.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Docetaxel+AZD6244
    Reporting group description
    		 -

    Reporting group title
    Docetaxel+ Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Docetaxel+AZD6244 Docetaxel+ Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 38 (76.32%)
    20 / 41 (48.78%)
         number of deaths (all causes)
    23
    27
         number of deaths resulting from adverse events
    2
    0
    Investigations
    Neutrophil Count Decreased
    Additional description: Neutrophil Count Decreased
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Arrest
    Additional description: Cardiac Arrest
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Presyncope
    Additional description: Presyncope
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
    Additional description: Febrile Neutropenia
         subjects affected / exposed
    20 / 38 (52.63%)
    13 / 41 (31.71%)
         occurrences causally related to treatment / all
    25 / 25
    15 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
    Additional description: Fever
         subjects affected / exposed
    5 / 38 (13.16%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic Reaction
    Additional description: Allergic Reaction
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal Vascular Disorder
    Additional description: Retinal Vascular Disorder
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric Haemorrhage
    Additional description: Gastric Haemorrhage
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
    Additional description: Abdominal Pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: Dyspnea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle Weakness Lower Limb
    Additional description: Muscle Weakness Lower Limb
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Other - Source Unknown
    Additional description: Other - Source Unknown
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Infectious
    Additional description: Enterocolitis Infectious
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
    Additional description: Skin Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
    Additional description: Lung Infection
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Infection
    Additional description: Upper Respiratory Infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Docetaxel+AZD6244 Docetaxel+ Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 38 (92.11%)
    40 / 41 (97.56%)
    Vascular disorders
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 41 (14.63%)
         occurrences all number
    4
    7
    Thromboembolic Event
    Additional description: Thromboembolic Event
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Localized Edema
    Additional description: Localized Edema
         subjects affected / exposed
    16 / 38 (42.11%)
    9 / 41 (21.95%)
         occurrences all number
    24
    13
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    28 / 38 (73.68%)
    32 / 41 (78.05%)
         occurrences all number
    58
    60
    Fever
    Additional description: Fever
         subjects affected / exposed
    7 / 38 (18.42%)
    3 / 41 (7.32%)
         occurrences all number
    9
    3
    Immune system disorders
    Allergic Reaction
    Additional description: Allergic Reaction
         subjects affected / exposed
    4 / 38 (10.53%)
    5 / 41 (12.20%)
         occurrences all number
    5
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: Dyspnea
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 41 (14.63%)
         occurrences all number
    4
    6
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    9 / 38 (23.68%)
    4 / 41 (9.76%)
         occurrences all number
    13
    7
    Cough
    Additional description: Cough
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 41 (7.32%)
         occurrences all number
    3
    5
    Psychiatric disorders
    Depression
    Additional description: Depression
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 41 (0.00%)
         occurrences all number
    8
    0
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 41 (9.76%)
         occurrences all number
    2
    6
    Investigations
    Neutrophil Count Decreased
    Additional description: Neutrophil Count Decreased
         subjects affected / exposed
    4 / 38 (10.53%)
    13 / 41 (31.71%)
         occurrences all number
    6
    15
    Platelet Count Decreased
    Additional description: Platelet Count Decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    Nervous system disorders
    Peripheral Sensory Neuropathy
    Additional description: Peripheral Sensory Neuropathy
         subjects affected / exposed
    9 / 38 (23.68%)
    14 / 41 (34.15%)
         occurrences all number
    11
    17
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 41 (9.76%)
         occurrences all number
    11
    4
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    14 / 38 (36.84%)
    13 / 41 (31.71%)
         occurrences all number
    19
    18
    Headache
    Additional description: Headache
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 41 (9.76%)
         occurrences all number
    3
    5
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 41 (9.76%)
         occurrences all number
    6
    5
    Febrile Neutropenia
    Additional description: Febrile Neutropenia
         subjects affected / exposed
    8 / 38 (21.05%)
    5 / 41 (12.20%)
         occurrences all number
    11
    6
    Eye disorders
    Blurred Vision
    Additional description: Blurred Vision
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 41 (2.44%)
         occurrences all number
    5
    1
    Dry Eye
    Additional description: Dry Eye
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    Floaters
    Additional description: Floaters
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Watering Eyes
    Additional description: Watering Eyes
         subjects affected / exposed
    5 / 38 (13.16%)
    5 / 41 (12.20%)
         occurrences all number
    7
    5
    Gastrointestinal disorders
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    19 / 38 (50.00%)
    15 / 41 (36.59%)
         occurrences all number
    30
    18
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    11 / 38 (28.95%)
    11 / 41 (26.83%)
         occurrences all number
    13
    15
    Flatulence
    Additional description: Flatulence
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 41 (2.44%)
         occurrences all number
    3
    2
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    5 / 38 (13.16%)
    10 / 41 (24.39%)
         occurrences all number
    8
    13
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    33 / 38 (86.84%)
    20 / 41 (48.78%)
         occurrences all number
    82
    29
    Dry Mouth
    Additional description: Dry Mouth
         subjects affected / exposed
    6 / 38 (15.79%)
    3 / 41 (7.32%)
         occurrences all number
    9
    3
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    11 / 38 (28.95%)
    8 / 41 (19.51%)
         occurrences all number
    15
    9
    Abdominal Pain
    Additional description: Abdominal Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    Mucositis Oral
    Additional description: Mucositis Oral
         subjects affected / exposed
    21 / 38 (55.26%)
    17 / 41 (41.46%)
         occurrences all number
    36
    27
    Skin and subcutaneous tissue disorders
    Other Rash
    Additional description: Other Rash
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Nail Ridging
    Additional description: Nail Ridging
         subjects affected / exposed
    7 / 38 (18.42%)
    9 / 41 (21.95%)
         occurrences all number
    8
    12
    Rash Acneiform
    Additional description: Rash Acneiform
         subjects affected / exposed
    31 / 38 (81.58%)
    20 / 41 (48.78%)
         occurrences all number
    56
    26
    Dry Skin
    Additional description: Dry Skin
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 41 (2.44%)
         occurrences all number
    5
    1
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    20 / 38 (52.63%)
    21 / 41 (51.22%)
         occurrences all number
    21
    22
    Palmar-Plantar Erythrodysesthesia Syndrome
    Additional description: Palmar-Plantar Erythrodysesthesia Syndrome
         subjects affected / exposed
    5 / 38 (13.16%)
    1 / 41 (2.44%)
         occurrences all number
    6
    1
    Periorbital Edema
    Additional description: Periorbital Edema
         subjects affected / exposed
    6 / 38 (15.79%)
    0 / 41 (0.00%)
         occurrences all number
    7
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    4 / 38 (10.53%)
    10 / 41 (24.39%)
         occurrences all number
    7
    13
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    5 / 38 (13.16%)
    8 / 41 (19.51%)
         occurrences all number
    7
    11
    Pain - Other
    Additional description: Pain - Other
         subjects affected / exposed
    17 / 38 (44.74%)
    12 / 41 (29.27%)
         occurrences all number
    43
    19
    Infections and infestations
    Nail Infection
    Additional description: Nail Infection
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Upper Respiratory Infection
    Additional description: Upper Respiratory Infection
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 41 (2.44%)
         occurrences all number
    4
    1
    Mucosal Infection
    Additional description: Mucosal Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 41 (12.20%)
         occurrences all number
    2
    6
    Bronchial Infection
    Additional description: Bronchial Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    5 / 41 (12.20%)
         occurrences all number
    0
    5
    Wound Infection
    Additional description: Wound Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Urinary Tract Infection
    Additional description: Urinary Tract Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Other Infection
    Additional description: Other Infection
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 41 (2.44%)
         occurrences all number
    6
    1
    Skin Infection
    Additional description: Skin Infection
         subjects affected / exposed
    5 / 38 (13.16%)
    3 / 41 (7.32%)
         occurrences all number
    7
    4
    Metabolism and nutrition disorders
    Hypoalbuminemia
    Additional description: Hypoalbuminemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Anorexia
    Additional description: Anorexia
         subjects affected / exposed
    9 / 38 (23.68%)
    8 / 41 (19.51%)
         occurrences all number
    12
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2011
    Inclusion of the use of generic docetaxel as well as the brand Taxotere
    05 Jul 2012
    Addition of an independent Data and Safety Management Committee.
    25 Mar 2013
    Inclusion of the use of open label AZD6244 (selumetinib)

    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.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24567366
    http://www.ncbi.nlm.nih.gov/pubmed/31839677
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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