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    Clinical Trial Results:
    MEK114267, A Phase III randomized, open-label study comparing GSK1120212 to chemotherapy in subjects with advanced or metastatic BRAF V600E/K mutation-positive melanoma

    Summary
    EudraCT number
    2010-022838-85
    Trial protocol
    DE   SE   BE   CZ   GR   NO   GB   AT   IT  
    Global end of trial date
    16 Dec 2016

    Results information
    Results version number
    v3(current)
    This version publication date
    31 Mar 2018
    First version publication date
    30 Nov 2017
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    114267
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study is to establish the superiority of GSK1120212 over chemotherapy with respect to progression-free survival for subjects with advanced/metastatic BRAF V600E mutation-positive melanoma without a history of prior brain metastases
    Protection of trial subjects
    Not applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Nov 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 26
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Germany: 64
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Russian Federation: 19
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Ukraine: 14
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    322
    EEA total number of subjects
    211
    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)
    251
    From 65 to 84 years
    70
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This was a randomized open-label, multi-center Phase III study to evaluate the efficacy and safety of single agent trametinib compared with chemotherapy (CT) (dacarbazine or paclitaxel). Participants (par.) were enrolled by 86 sites in 19 countries from December 2010 to July 2011. Results as of 16 December 2016 data-cut have been presented.

    Pre-assignment
    Screening details
    Participants (par.) were stratified for lactate dehydrogenase and prior CT for advanced or metastatic disease. 1059 par. were screened and 322 were enrolled to receive trametinib (214 par.) or CT (108 par.) until disease progression, death, or withdrawal. Par. randomized to CT were allowed to cross-over to trametinib if disease progressed.

    Period 1
    Period 1 title
    Randomization and Crossover Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trametinib
    Arm description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF (a human gene encoding for protein called B-Raf, which is involved in a signaling pathway and is important for cell growth) V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received a Trametinib 2 milligram (mg) tablet once daily until disease progression, death, or withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a Trametinib 2 mg tablet once daily until disease progression, death, or withdrawal.

    Arm title
    Chemotherapy
    Arm description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received an intravenous (IV) dose of Dacarbazine 1000 mg per square meter every 3 weeks or Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.
    Arm type
    Active comparator

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received an IV dose of Dacarbazine 1000 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received an IV dose of Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.

    Number of subjects in period 1
    Trametinib Chemotherapy
    Started
    214
    108
    Completed
    173
    77
    Not completed
    41
    31
         Physician decision
    2
    4
         Study closed/ terminated
    23
    14
         Withdrew Consent
    12
    11
         Lost to follow-up
    4
    2
    Period 2
    Period 2 title
    Cross-over Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Cross-over from Chemotherapy to Trametinib
    Arm description
    Participants randomized to chemotherapy and who did not receive subsequent anti-cancer therapy after discontinuing chemotherapy were allowed to cross-over to Trametinib and received 2 mg tablet once daily until disease progression, death or withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a Trametinib 2 mg tablet once daily until disease progression, death, or withdrawal.

    Number of subjects in period 2 [1]
    Cross-over from Chemotherapy to Trametinib
    Started
    70
    Completed
    53
    Not completed
    17
         Physician decision
    1
         Study closed/ terminated
    11
         Withdrew Consent
    4
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 70 of the 108 participants randomized to chemotherapy in randomization period elected to cross-over to Trametinib and were included in cross-over period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trametinib
    Reporting group description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF (a human gene encoding for protein called B-Raf, which is involved in a signaling pathway and is important for cell growth) V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received a Trametinib 2 milligram (mg) tablet once daily until disease progression, death, or withdrawal.

    Reporting group title
    Chemotherapy
    Reporting group description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received an intravenous (IV) dose of Dacarbazine 1000 mg per square meter every 3 weeks or Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.

    Reporting group values
    Trametinib Chemotherapy Total
    Number of subjects
    214 108
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.3 ± 12.97 52.8 ± 13.56 -
    Gender categorical
    Units: Subjects
        Female
    94 55 149
        Male
    120 53 173
    Race/Ethnicity, Customized
    Units: Subjects
        White - Arabic/North African Heritage
    2 0 2
        White - White/Caucasian/European Heritage
    212 107 319
        White - Mixed Race
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Trametinib
    Reporting group description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF (a human gene encoding for protein called B-Raf, which is involved in a signaling pathway and is important for cell growth) V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received a Trametinib 2 milligram (mg) tablet once daily until disease progression, death, or withdrawal.

    Reporting group title
    Chemotherapy
    Reporting group description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received an intravenous (IV) dose of Dacarbazine 1000 mg per square meter every 3 weeks or Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.
    Reporting group title
    Cross-over from Chemotherapy to Trametinib
    Reporting group description
    Participants randomized to chemotherapy and who did not receive subsequent anti-cancer therapy after discontinuing chemotherapy were allowed to cross-over to Trametinib and received 2 mg tablet once daily until disease progression, death or withdrawal.

    Primary: Progression-free survival in BRAF V600E mutation-positive participants without a history of brain metastases as assessed by the Investigator and Independent Review

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    End point title
    Progression-free survival in BRAF V600E mutation-positive participants without a history of brain metastases as assessed by the Investigator and Independent Review
    End point description
    Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.
    End point type
    Primary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    178 [1]
    95
    Units: Months
    median (confidence interval 95%)
        Investigator-Assessed
    4.8 (3.5 to 4.9)
    1.4 (1.4 to 2.7)
        Independent Review
    4.9 (4.5 to 5.1)
    1.6 (1.4 to 2.8)
    Notes
    [1] - Primary Efficacy Population
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Investigator-Assessed PFS. HR <1 indicates a lower risk with Trametinib compared with CT. HR from a stratified log-rank test was adjusted for prior chemotherapy for advanced or metastatic disease and Baseline lactate dehydrogenase.
    Comparison groups
    Trametinib v Chemotherapy
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    0.64
    Notes
    [2] - P-value from a stratified log-rank test was adjusted for prior chemotherapy for advanced or metastatic disease and Baseline lactate dehydrogenase.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Independent Review PFS. HR <1 indicates a lower risk with Trametinib compared with CT. HR from a stratified log-rank test was adjusted for prior chemotherapy for advanced or metastatic disease and Baseline lactate dehydrogenase.
    Comparison groups
    Trametinib v Chemotherapy
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.6
    Notes
    [3] - P-value from a stratified log-rank test was adjusted for prior chemotherapy for advanced or metastatic disease and Baseline lactate dehydrogenase.

    Secondary: Progression-free survival in all participants

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    End point title
    Progression-free survival in all participants
    End point description
    PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    214 [4]
    108
    Units: Months
    median (confidence interval 95%)
        Investigator-Assessed
    4.9 (4.5 to 5.0)
    1.5 (1.4 to 2.8)
        Independent radiologist assessed-Assessed
    4.9 (4.6 to 5.0)
    1.5 (1.4 to 2.8)
    Notes
    [4] - ITT Population
    No statistical analyses for this end point

    Secondary: PFS in BRAF V600E mutation-positive participants without a history of brain metastases and without prior chemotherapy as assessed by the Investigator

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    End point title
    PFS in BRAF V600E mutation-positive participants without a history of brain metastases and without prior chemotherapy as assessed by the Investigator
    End point description
    PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    114 [5]
    62
    Units: Months
    median (confidence interval 95%)
        Months
    4.8 (3.4 to 5.0)
    1.4 (1.4 to 1.7)
    Notes
    [5] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: PFS in BRAF V600E mutation-positive participants without a history of brain metastases and with prior chemotherapy as assessed by the Investigator

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    End point title
    PFS in BRAF V600E mutation-positive participants without a history of brain metastases and with prior chemotherapy as assessed by the Investigator
    End point description
    PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    64 [6]
    33
    Units: Months
    median (confidence interval 95%)
        Months
    4.8 (2.9 to 4.9)
    2.7 (1.4 to 2.9)
    Notes
    [6] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: Overall Survival in all participants

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    End point title
    Overall Survival in all participants
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Day 1 until death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    214 [7]
    108
    Units: Months
    median (confidence interval 95%)
        Months
    15.6 (13.5 to 17.3)
    11.3 (7.2 to 14.8)
    Notes
    [7] - ITT Population
    No statistical analyses for this end point

    Secondary: Overall Survival in BRAF V600E mutation-positive participants without a history of brain metastases

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    End point title
    Overall Survival in BRAF V600E mutation-positive participants without a history of brain metastases
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death due to any cause. 99999 indicates that data were not available.
    End point type
    Secondary
    End point timeframe
    Day 1 until death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    178 [8]
    95
    Units: Months
    median (confidence interval 95%)
        Months
    99999 (-99999 to 99999)
    99999 (6.8 to 99999)
    Notes
    [8] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: Number of BRAF V600E mutation-positive participants without a history of brain metastases with Overall Response (OR) as assessed by the Investigator and Independent Review

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    End point title
    Number of BRAF V600E mutation-positive participants without a history of brain metastases with Overall Response (OR) as assessed by the Investigator and Independent Review
    End point description
    OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    178 [9]
    95
    Units: Participants
        Investigator-Assessed: CR
    4
    0
        Investigator-Assessed: PR
    39
    7
        Independent Review: CR
    0
    0
        Independent Review: PR
    33
    3
    Notes
    [9] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: Number of participants with OR as assessed by the Investigator and Independent Review

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    End point title
    Number of participants with OR as assessed by the Investigator and Independent Review
    End point description
    OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    214 [10]
    108
    Units: Participants
        Investigator-Assessed: CR
    8
    2
        Investigator-Assessed: PR
    53
    8
        Independent Review: CR
    0
    1
        Independent Review: PR
    41
    4
    Notes
    [10] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of BRAF V600E mutation-positive participants classified as confirmed responders (CR and PR) as assessed by the Investigator

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    End point title
    Number of BRAF V600E mutation-positive participants classified as confirmed responders (CR and PR) as assessed by the Investigator
    End point description
    OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    184 [11]
    97
    Units: Participants
        V600E Mutation, CR
    4
    0
        V600E Mutation, PR
    40
    7
    Notes
    [11] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of BRAF V600K mutation-positive participants classified as confirmed responders (CR and PR) as assessed by the Investigator

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    End point title
    Number of BRAF V600K mutation-positive participants classified as confirmed responders (CR and PR) as assessed by the Investigator
    End point description
    OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    29 [12]
    11
    Units: Participants
        V600K Mutation, CR
    0
    0
        V600K Mutation, PR
    3
    2
    Notes
    [12] - ITT Population: only those participants withV600K mutation-positive melanoma were assessed.
    No statistical analyses for this end point

    Secondary: Number of participants with OR following Cross-over to Trametinib

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    End point title
    Number of participants with OR following Cross-over to Trametinib
    End point description
    OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population.
    End point type
    Secondary
    End point timeframe
    Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
    End point values
    Cross-over from Chemotherapy to Trametinib
    Number of subjects analysed
    70 [13]
    Units: Participants
        CR
    2
        PR
    29
    Notes
    [13] - Cross-over Population
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) for all BRAF V600E mutation-positive participants without a prior history of brain metastases classified as confirmed responders (CR or PR) as assessed by the Investigator Review

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    End point title
    Duration of Response (DoR) for all BRAF V600E mutation-positive participants without a prior history of brain metastases classified as confirmed responders (CR or PR) as assessed by the Investigator Review
    End point description
    DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates that data were not available.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    43 [14]
    7
    Units: Months
    median (confidence interval 95%)
        Months
    5.5 (4.9 to 5.9)
    99999 (3.5 to 99999)
    Notes
    [14] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: DoR for all BRAF V600E mutation-positive participants without a prior history of brain metastases classifed as confirmed responders (CR or PR) as assessed by the Independent Review

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    End point title
    DoR for all BRAF V600E mutation-positive participants without a prior history of brain metastases classifed as confirmed responders (CR or PR) as assessed by the Independent Review
    End point description
    DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    33 [15]
    3
    Units: Months
        median (confidence interval 95%)
    5.6 (3.8 to 5.9)
    99999 (3.5 to 99999)
    Notes
    [15] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: DoR for all confirmed responders (CR or PR) as assessed by the Investigator Review

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    End point title
    DoR for all confirmed responders (CR or PR) as assessed by the Investigator Review
    End point description
    DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates that data were not available.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    47 [16]
    9
    Units: Months
    median (confidence interval 95%)
        Months
    5.5 (4.1 to 5.9)
    99999 (5.0 to 99999)
    Notes
    [16] - ITT Population
    No statistical analyses for this end point

    Secondary: DoR for all confirmed responders (CR or PR) as assessed by the Independent Review

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    End point title
    DoR for all confirmed responders (CR or PR) as assessed by the Independent Review
    End point description
    DoR is defined as thetime from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available.
    End point type
    Secondary
    End point timeframe
    Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
    End point values
    Trametinib Chemotherapy
    Number of subjects analysed
    41 [17]
    5
    Units: Months
        median (confidence interval 95%)
    5.6 (4.1 to 5.9)
    99999 (3.5 to 99999)
    Notes
    [17] - ITT Population
    No statistical analyses for this end point

    Secondary: DoR for all responders (CR or PR) following cross-over to Trametinib as assessed by the Investigator

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    End point title
    DoR for all responders (CR or PR) following cross-over to Trametinib as assessed by the Investigator
    End point description
    DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates that data were not available.
    End point type
    Secondary
    End point timeframe
    Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
    End point values
    Cross-over from Chemotherapy to Trametinib
    Number of subjects analysed
    70 [18]
    Units: Months
    median (confidence interval 95%)
        Months
    2.7 (1.3 to 99999)
    Notes
    [18] - Cross-over Population
    No statistical analyses for this end point

    Secondary: PFS following cross-over to Trametinib as assessed by the Investigator

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    End point title
    PFS following cross-over to Trametinib as assessed by the Investigator
    End point description
    PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
    End point values
    Cross-over from Chemotherapy to Trametinib
    Number of subjects analysed
    70 [19]
    Units: Months
    median (confidence interval 95%)
        Months
    3.0 (2.7 to 4.8)
    Notes
    [19] - Cross-over Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants were analyzed from the first dose of study medication to 28 days after discontinuation of study medication (average of 20.3 months in the Randomization Phase and 18.3 months in the Cross-over Phase).
    Adverse event reporting additional description
    Serious adverse events (SAEs) and non-serious AEs were collected in the Safety Population, comprised of all randomized participants included in the study who received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Trametinib
    Reporting group description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF (a human gene encoding for protein called B-Raf, which is involved in a signaling pathway and is important for cell growth) V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received a Trametinib 2 milligram (mg) tablet once daily until disease progression, death, or withdrawal.

    Reporting group title
    Chemotherapy
    Reporting group description
    Participants with histologically confirmed cutaneous advanced or metastatic melanoma (Stage IIIC or Stage IV), with a BRAF V600 E/K mutation-positive tumor sample as determined via the central BRAF mutation assay, received an intravenous (IV) dose of Dacarbazine 1000 mg per square meter every 3 weeks or Paclitaxel 175 mg per square meter every 3 weeks at the discretion of the investigator, provided the participant had not received that type of chemotherapy before randomization, until disease progression, death, or withdrawal.

    Reporting group title
    Cross-over from Chemotherapy to Trametinib
    Reporting group description
    Participants randomized to chemotherapy and who did not receive subsequent anti-cancer therapy after discontinuing chemotherapy were allowed to cross-over to Trametinib and received 2 mg tablet once daily until disease progression, death or withdrawal.

    Serious adverse events
    Trametinib Chemotherapy Cross-over from Chemotherapy to Trametinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 211 (24.64%)
    19 / 99 (19.19%)
    18 / 70 (25.71%)
         number of deaths (all causes)
    172
    22
    53
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corneal graft rejection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Axillary pain
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Edema
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 211 (1.42%)
    4 / 99 (4.04%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood albumin decreased
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemoglobin decreased
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 211 (1.42%)
    2 / 99 (2.02%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    3 / 211 (1.42%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 211 (1.90%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 211 (1.42%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischemic stroke
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery dissection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eyelid ptosis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 211 (1.42%)
    1 / 99 (1.01%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 211 (1.90%)
    0 / 99 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    5 / 211 (2.37%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye infection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localized infection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 99 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Trametinib Chemotherapy Cross-over from Chemotherapy to Trametinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    207 / 211 (98.10%)
    88 / 99 (88.89%)
    66 / 70 (94.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    40 / 211 (18.96%)
    9 / 99 (9.09%)
    9 / 70 (12.86%)
         occurrences all number
    54
    9
    11
    Lymphedema
         subjects affected / exposed
    18 / 211 (8.53%)
    0 / 99 (0.00%)
    6 / 70 (8.57%)
         occurrences all number
    18
    0
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 211 (7.58%)
    3 / 99 (3.03%)
    0 / 70 (0.00%)
         occurrences all number
    22
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 211 (9.95%)
    1 / 99 (1.01%)
    7 / 70 (10.00%)
         occurrences all number
    29
    1
    14
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 211 (6.16%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences all number
    15
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 211 (0.95%)
    5 / 99 (5.05%)
    0 / 70 (0.00%)
         occurrences all number
    17
    7
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 211 (0.47%)
    5 / 99 (5.05%)
    0 / 70 (0.00%)
         occurrences all number
    2
    6
    0
    Weight decreased
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    4
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 211 (2.37%)
    6 / 99 (6.06%)
    0 / 70 (0.00%)
         occurrences all number
    12
    10
    0
    Anemia
         subjects affected / exposed
    13 / 211 (6.16%)
    10 / 99 (10.10%)
    0 / 70 (0.00%)
         occurrences all number
    17
    11
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 211 (0.95%)
    5 / 99 (5.05%)
    0 / 70 (0.00%)
         occurrences all number
    2
    7
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 211 (11.37%)
    6 / 99 (6.06%)
    4 / 70 (5.71%)
         occurrences all number
    29
    6
    6
    Epistaxis
         subjects affected / exposed
    15 / 211 (7.11%)
    1 / 99 (1.01%)
    4 / 70 (5.71%)
         occurrences all number
    22
    1
    5
    Dyspnea
         subjects affected / exposed
    15 / 211 (7.11%)
    6 / 99 (6.06%)
    4 / 70 (5.71%)
         occurrences all number
    16
    6
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 211 (14.22%)
    15 / 99 (15.15%)
    0 / 70 (0.00%)
         occurrences all number
    40
    16
    0
    Paraesthesia
         subjects affected / exposed
    10 / 211 (4.74%)
    9 / 99 (9.09%)
    0 / 70 (0.00%)
         occurrences all number
    11
    10
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 211 (1.42%)
    9 / 99 (9.09%)
    0 / 70 (0.00%)
         occurrences all number
    3
    13
    0
    Dysgeusia
         subjects affected / exposed
    12 / 211 (5.69%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences all number
    14
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    7 / 70 (10.00%)
         occurrences all number
    0
    0
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 211 (5.69%)
    12 / 99 (12.12%)
    4 / 70 (5.71%)
         occurrences all number
    13
    14
    5
    Fatigue
         subjects affected / exposed
    62 / 211 (29.38%)
    29 / 99 (29.29%)
    8 / 70 (11.43%)
         occurrences all number
    79
    37
    9
    Mucosal inflammation
         subjects affected / exposed
    15 / 211 (7.11%)
    0 / 99 (0.00%)
    6 / 70 (8.57%)
         occurrences all number
    23
    0
    8
    Pyrexia
         subjects affected / exposed
    15 / 211 (7.11%)
    8 / 99 (8.08%)
    6 / 70 (8.57%)
         occurrences all number
    20
    9
    6
    Oedema peripheral
         subjects affected / exposed
    55 / 211 (26.07%)
    2 / 99 (2.02%)
    16 / 70 (22.86%)
         occurrences all number
    76
    2
    22
    Inflammation
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    4
    Influenza like illness
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    8
    Peripheral swelling
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 211 (7.11%)
    7 / 99 (7.07%)
    4 / 70 (5.71%)
         occurrences all number
    16
    7
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 211 (9.00%)
    2 / 99 (2.02%)
    0 / 70 (0.00%)
         occurrences all number
    25
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    16 / 211 (7.58%)
    3 / 99 (3.03%)
    4 / 70 (5.71%)
         occurrences all number
    23
    3
    5
    Constipation
         subjects affected / exposed
    34 / 211 (16.11%)
    22 / 99 (22.22%)
    12 / 70 (17.14%)
         occurrences all number
    40
    25
    0
    Diarrhea
         subjects affected / exposed
    94 / 211 (44.55%)
    16 / 99 (16.16%)
    24 / 70 (34.29%)
         occurrences all number
    161
    29
    35
    Dry mouth
         subjects affected / exposed
    19 / 211 (9.00%)
    2 / 99 (2.02%)
    6 / 70 (8.57%)
         occurrences all number
    21
    2
    6
    Nausea
         subjects affected / exposed
    48 / 211 (22.75%)
    39 / 99 (39.39%)
    12 / 70 (17.14%)
         occurrences all number
    64
    55
    14
    Stomatitis
         subjects affected / exposed
    13 / 211 (6.16%)
    1 / 99 (1.01%)
    0 / 70 (0.00%)
         occurrences all number
    20
    1
    0
    Vomiting
         subjects affected / exposed
    33 / 211 (15.64%)
    21 / 99 (21.21%)
    16 / 70 (22.86%)
         occurrences all number
    38
    23
    23
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    38 / 211 (18.01%)
    19 / 99 (19.19%)
    7 / 70 (10.00%)
         occurrences all number
    38
    19
    7
    Dermatitis acneiform
         subjects affected / exposed
    42 / 211 (19.91%)
    2 / 99 (2.02%)
    10 / 70 (14.29%)
         occurrences all number
    46
    2
    15
    Dry skin
         subjects affected / exposed
    30 / 211 (14.22%)
    1 / 99 (1.01%)
    10 / 70 (14.29%)
         occurrences all number
    33
    1
    11
    Eczema
         subjects affected / exposed
    12 / 211 (5.69%)
    0 / 99 (0.00%)
    6 / 70 (8.57%)
         occurrences all number
    13
    0
    6
    Rash
         subjects affected / exposed
    123 / 211 (58.29%)
    10 / 99 (10.10%)
    37 / 70 (52.86%)
         occurrences all number
    183
    12
    51
    Pruritus
         subjects affected / exposed
    25 / 211 (11.85%)
    1 / 99 (1.01%)
    10 / 70 (14.29%)
         occurrences all number
    31
    1
    10
    Hyperhidrosis
         subjects affected / exposed
    0 / 211 (0.00%)
    6 / 99 (6.06%)
    0 / 70 (0.00%)
         occurrences all number
    0
    6
    0
    Skin fissures
         subjects affected / exposed
    21 / 211 (9.95%)
    0 / 99 (0.00%)
    9 / 70 (12.86%)
         occurrences all number
    28
    0
    43
    Rash macular
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    5 / 70 (7.14%)
         occurrences all number
    0
    0
    7
    Rash maculo-papular
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 211 (9.00%)
    10 / 99 (10.10%)
    0 / 70 (0.00%)
         occurrences all number
    25
    13
    0
    Back pain
         subjects affected / exposed
    18 / 211 (8.53%)
    9 / 99 (9.09%)
    0 / 70 (0.00%)
         occurrences all number
    23
    10
    0
    Pain in extremity
         subjects affected / exposed
    13 / 211 (6.16%)
    8 / 99 (8.08%)
    4 / 70 (5.71%)
         occurrences all number
    14
    9
    9
    Myalgia
         subjects affected / exposed
    3 / 211 (1.42%)
    6 / 99 (6.06%)
    0 / 70 (0.00%)
         occurrences all number
    3
    11
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 211 (8.53%)
    10 / 99 (10.10%)
    6 / 70 (8.57%)
         occurrences all number
    23
    10
    6
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    22 / 211 (10.43%)
    2 / 99 (2.02%)
    6 / 70 (8.57%)
         occurrences all number
    26
    2
    7
    Paronychia
         subjects affected / exposed
    26 / 211 (12.32%)
    1 / 99 (1.01%)
    10 / 70 (14.29%)
         occurrences all number
    37
    1
    34
    Nasopharyngitis
         subjects affected / exposed
    15 / 211 (7.11%)
    4 / 99 (4.04%)
    0 / 70 (0.00%)
         occurrences all number
    17
    7
    0
    Rash pustular
         subjects affected / exposed
    11 / 211 (5.21%)
    0 / 99 (0.00%)
    5 / 70 (7.14%)
         occurrences all number
    15
    0
    6
    Nail infection
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    7
    Cellulitis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 99 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2010
    Amendment 01: 1. Corrected the European Clinical Trials Database (Eudra-CT) number. 2. Changed primary endpoint to progression free survival and added crossover to GSK1120212 after progression on the chemotherapy arm based on feedback from the European Medicines Agency (EMEA). 3. After considering the standard of ophthalmological practice across different countries and after consultation with GlaxoSmithKline (GSK) ophthalmologist, GSK recommends the following changes to the ophthalmological guidelines: - Removal of perimetry from ophthalmologic exclusion criteria. Assessment of visual field defects can be done either by automated or confrontational method as per the local standard of care. - Changed requirement for color fundus photos and retinal specialist consultation such that they are recommended if available, but not mandated. Fundus photos were meant to help diagnose any changes to the retina, however adequate documentation of baseline fundus exam would also provide the same information and is the standard ophthalmological practice in a number of countries. - In par. with clinical suspicion of Retinal vein occlusion (RVO) or Central serous retinopathy (CSR), it is recommended that diagnostic studies be completed that are the standard of care in that particular country and may include color fundus photos, fluorescein angiography and/or optical coherence tomography. The studies could be done by an experienced general ophthalmologist or by a retinal specialist. 4. Changed Inclusion Criteria to allow prior treatment with ipilumimab in the adjuvant setting to expand participant population. 5. Changed exclusion to allow par. with prior brain metastases that meet specific criteria to expand participant population. 6. Removed Day 1 Cycle 3 blank column from Time and Events Table and updated several footnotes based on above changes.7. Added crossover study extension Time and Events table 8. Corrected minor administrative and typographical errors.
    02 May 2011
    Amendment 02: Updated contact information. Changed eligibility criteria (EC) to indicate that par. having received one prior chemotherapy regimen in the advanced/metastatic setting must have had documented progression prior to randomization. Clarified EC to allow use of low molecular weight heparin; par. with second malignancies that are indolent or definitively treated to indicate that they must be disease free for at least 3 years; par. with brain metastases to indicate that prior whole brain radiotherapy is not allowed and confirmation of stable and/or no evidence of disease is required prior to randomization; cardiac history to indicate that the time frame of ‘6 months prior to randomization’ applies to all conditions listed in that criterion. Updated crossover eligibility to allow par. who discontinue from chemotherapy arm of the study for a reason other than disease progression, but who do not receive any further anticancer treatment and eventually have documented disease progression to be eligible for crossover to GSK1120212. Clarified dosing instructions and related process. Corrected laboratory values in dose modification instructions for chemotherapy treatment arm. Clarified requirements for submission or Echocardiogram/ Multi-gated acquisition scan (ECHO/MUGA) to the central imaging vendor. Added concomitant palliative radiotherapy to Prohibited Medications Section. Removed allowance for sending tissue for BRAF mutation testing up to 6 months prior to randomization. Changed direct fundoscopy to an optional assessment within the required ophthalmic examination at screening. Changed required duration of adequate contraception usage by women of childbearing potential to 16 weeks after discontinuation of study medication. Changed tumor tissue requirements for BRAF mutation testing to indicate that tissue from the current state of disease is preferred, but tissue from primary site is also acceptable. Corrected minor administrative and typographical errors.
    03 Oct 2011
    Amendment 03: Data from the Phase II study (MEK113583) study with GSK1120212 in V600 mutation positive melanoma par. previously treated with chemotherapy and/or immunotherapy were presented by Dr. Lewis (University of Colorado) at Perspectives in Melanoma meeting on September 16, 2011. These phase 2 data confirm that the 2 mg QD dose of GSK1120212 is well tolerated, has clinical activity in previously treated BRAF-mutant metastatic melanoma par., and suggest that the subset of V600E mutation-positive par. with no history of prior brain metastases has a better median PFS compared to the overall study population. Rationale for Change: Due to these phase II data, the population for the primary analysis of MEK114267 is being changed to only those par. with a BRAF V600E mutational status without a history of prior brain metastases. This change will ensure that the study focuses on the population most likely to benefit from GSK1120212. As it is still important to understand the effect of GSK1120212 in par. with BRAF V600K mutations, the secondary endpoints evaluating this population remain. Due to the limited number of par. with a prior history of brain metastases, secondary endpoints evaluating this population are not planned; however analyses including and excluding par. with a prior history of brain metastases will be explored This change to the primary endpoint is being made prior to Data Base Freeze to conduct the primary endpoint analysis of progression free survival.
    27 Jan 2012
    Amendment 04: Dear Investigator Letter was issued 09 January 2012 which stated that emerging data suggests that par. treated with GSK1120212 may develop hypertension or have worsening control of pre-existing hypertension. As a result, hypertension monitoring and management guidelines are being incorporated into all ongoing studies with GSK1120212.
    16 Feb 2012
    Amendment 05: The planned primary analysis was completed on 27 January 2012 and reviewed by the Independent Data Monitoring Committee (IDMC) that comprised medical oncology experts and a statistician. The IDMC unanimously recommended to allow immediate crossover of any par. enrolled and treated on the chemotherapy arm to GSK1120212 (trametinib). This recommendation is based upon a clinically meaningful, statistically significant improvement in the primary endpoint of progression free survival (PFS) in the trametinib arm versus chemotherapy arm. The safety profile of GSK1120212 is consistent to what has been observed in prior studies.
    10 Sep 2012
    Amendment 06: There is a change from the older Parma supplies (white 0.5 mg tablets) with product codes BQ (0.5 mg), BR (1 mg), BS (2 mg) to the newer Parma supplies with commercial image (non-debossed) tablets with product codes CL/CT (0.5 mg), CM/CS (2 mg) product codes for upcoming resupplies. The investigational product description must be updated to properly describe the new supply.
    16 Jan 2014
    Amendment 07: 1. Updated study objectives to include secondary efficacy objective of long-term overall survival. 2. Updated definition of study completion throughout to allow for collection of long-term survival data. 3. Removed option to transition to rollover study after study completion. 4. Updated withholding criteria for visual changes. 5. Updated QTc stopping criteria. 6. Updated visit schedule. 7. Minor administrative changes and typographical corrections throughout.

    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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