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    Clinical Trial Results:
    A Phase II study of the BRAF inhibitor dabrafenib as a single agent and in combination with the MEK inhibitor trametinib in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer

    Summary
    EudraCT number
    2011-001161-41
    Trial protocol
    GB   DE   ES   NL   IT  
    Global end of trial date

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Aug 2017
    First version publication date
    21 Oct 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    113928
    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
    Interim
    Date of interim/final analysis
    09 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess the overall response rate (ORR) in subjects with stage IV BRAF V600E mutant non-small cell lung cancer administered dabrafenib as a single agent (Cohort A) and in combination with trametinib (Cohorts B and C)
    Protection of trial subjects
    Participants in this study received supportive care according to standard medical practice.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    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
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    France: 59
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Netherlands: 26
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    177
    EEA total number of subjects
    112
    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)
    79
    From 65 to 84 years
    90
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible participants (par.) were enrolled in Cohort (Coh) A (monotherapy [Dabrafenib{DAB}]). Par. in Coh-A who had disease progression and adequately tolerating DAB were given option to crossover to Coh-B who received combination therapy (DAB+Trametinib). In Coh-C, par. without prior anti-cancer treatment received combination therapy.

    Pre-assignment
    Screening details
    Par. with metastatic non-small cell lung cancer (NSCLC) were screened and allocated to Coh-A (DAB twice daily [BID] i.e. monotherapy), Coh-B (Combination Second-Line Plus) and Coh-C (Combination First-Line) according to their eligibility. The results presented are based on the Interim Analysis.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Monotherapy All Treated
    Arm description
    Participants with or without prior systemic anti-cancer therapy received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabrafenib (GSK2118436)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    It will be provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Dabrafenib will be administered as a single agent in all cohorts

    Arm title
    Combination Second-Line Plus
    Arm description
    Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received dabrafenib 150 mg BID and trametinib 2 mg once daily (OD). It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabrafenib (GSK2118436)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    It will be provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Dabrafenib will be administered as a single agent in all cohorts

    Investigational medicinal product name
    Trametinib (GSK1120212)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    It will be provided as 0.5 mg and 2 mg tablets. Trametinib will be administered in combination with dabrafenib in Cohorts B and C

    Arm title
    Combination First-Line
    Arm description
    Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given dabrafenib 150 mg BID and trametinib 2 mg OD. It was continued until disease progression or death or unacceptable AEs or at investigator discretion to discontinue.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabrafenib (GSK2118436)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    It will be provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Dabrafenib will be administered as a single agent in all cohorts

    Investigational medicinal product name
    Trametinib (GSK1120212)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    It will be provided as 0.5 mg and 2 mg tablets. Trametinib will be administered in combination with dabrafenib in Cohorts B and C

    Number of subjects in period 1
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Started
    84
    57
    36
    Completed
    0
    0
    0
    Not completed
    84
    57
    36
         Physician decision
    1
    1
    -
         Adverse event, serious fatal
    60
    33
    10
         Ongoing
    15
    22
    24
         Consent withdrawn by subject
    6
    -
    1
         Lost to follow-up
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Monotherapy All Treated
    Reporting group description
    Participants with or without prior systemic anti-cancer therapy received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.

    Reporting group title
    Combination Second-Line Plus
    Reporting group description
    Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received dabrafenib 150 mg BID and trametinib 2 mg once daily (OD). It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue.

    Reporting group title
    Combination First-Line
    Reporting group description
    Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given dabrafenib 150 mg BID and trametinib 2 mg OD. It was continued until disease progression or death or unacceptable AEs or at investigator discretion to discontinue.

    Reporting group values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line Total
    Number of subjects
    84 57 36
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.8 ± 10.51 65.1 ± 10.14 67.8 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    44 28 22 94
        Male
    40 29 14 83
    Race/Ethnicity, Customized
    Units: Subjects
        Asian - East Asian Heritage
    14 3 3 20
        Asian - Central/South Asian Heritage
    2 0 0 2
        Asian - Japanese Heritage
    2 1 0 3
        African American/African Heritage
    2 2 1 5
        Native Hawaiian Or Other Pacific Islander
    0 0 1 1
        White - Arabic/North African Heritage
    2 2 0 4
        White - White/Caucasian/European Heritage
    62 47 30 139
        Other-African American/African Heritage
    0 1 0 1
        Other-missing
    0 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Monotherapy All Treated
    Reporting group description
    Participants with or without prior systemic anti-cancer therapy received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.

    Reporting group title
    Combination Second-Line Plus
    Reporting group description
    Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received dabrafenib 150 mg BID and trametinib 2 mg once daily (OD). It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue.

    Reporting group title
    Combination First-Line
    Reporting group description
    Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given dabrafenib 150 mg BID and trametinib 2 mg OD. It was continued until disease progression or death or unacceptable AEs or at investigator discretion to discontinue.

    Subject analysis set title
    monotherapy second-line plus
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.

    Primary: Percentage of participants with overall response rate (ORR) at the date of analysis

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    End point title
    Percentage of participants with overall response rate (ORR) at the date of analysis [1] [2]
    End point description
    ORR is defined as the percentage of par. with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per Response Evaluation Criteria In Solid Tumors evaluates the response on the basis of target and non-target lesions, and best over all response. The response rate was analyzed every 6 weeks (wks) after initiation of study treatment until Week 36 and then every 12 wks until discharge or crossover. Percentage of par. analyzed as number of par. having overall response on the date of analysis from Baseline multiply by 100. The Second Line Plus All Treated Population used for cohort A and B consisted of all par. in the All Treated Population who had received at least one line of prior anti-cancer therapy for advanced/metastatic disease. The First-Line All Treated Population used for cohort C consisted of all par. in the All Treated Population who had not received any prior anti-cancer therapy for advanced/metastatic disease.
    End point type
    Primary
    End point timeframe
    At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is available
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    Combination Second-Line Plus Combination First-Line monotherapy second-line plus
    Number of subjects analysed
    57 [3]
    36 [4]
    78 [5]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants
    66.7 (52.9 to 78.6)
    61.1 (43.5 to 76.9)
    33.3 (23.1 to 44.9)
    Notes
    [3] - Second-Line All Treated Population for Coh-A and Coh-B, First-Line All Treated Population for Coh-C
    [4] - Second-Line All Treated Population for Coh-A and Coh-B, First-Line All Treated Population for Coh-C
    [5] - Second-Line All Treated Population for Coh-A and Coh-B, First-Line All Treated Population for Coh-C
    No statistical analyses for this end point

    Secondary: Duration of response (DoR) at the date of analysis

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    End point title
    Duration of response (DoR) at the date of analysis [6]
    End point description
    DoR is defined for the subset of participants with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause. The response was analyzed every 6 weeks after initiation of study treatment until Week 36 and then every 12 wks. Disease progression will be based on radiological assessments [magnetic resonance imaging (MRI) or computed tomography (CT)]. Confidence Intervals (CIs) estimated using the Brookmeyer Crowley method. Upper limit of confidence interval was not reached as data were not yet mature. A value of 99999 indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in that population (27 percent).
    End point type
    Secondary
    End point timeframe
    At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    Combination Second-Line Plus Combination First-Line monotherapy second-line plus
    Number of subjects analysed
    57 [7]
    36 [8]
    78 [9]
    Units: Months
    median (confidence interval 95%)
        Months
    9.8 (6.9 to 16)
    99999 (8.3 to 99999)
    9.6 (5.4 to 15.2)
    Notes
    [7] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    [8] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    [9] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) at the date of analysis

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    End point title
    Progression free survival (PFS) at the date of analysis [10]
    End point description
    PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. The target and non-target lesions were identified at time of screening and the same lesions were re-assessed by a contrast-enhanced brain magnetic resonance imaging (MRI) or Computed tomography (CT) every 6 wks after initiation of study treatment until Week 36 and then every 12 wks. CI estimated using the Brookmeyer Crowley method. A value of 99999 indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in the population (36 percent).
    End point type
    Secondary
    End point timeframe
    At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    Combination Second-Line Plus Combination First-Line monotherapy second-line plus
    Number of subjects analysed
    57 [11]
    36 [12]
    78 [13]
    Units: Months
    median (confidence interval 95%)
        Months
    10.2 (6.9 to 16.7)
    99999 (7 to 99999)
    5.5 (3.4 to 7.3)
    Notes
    [11] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    [12] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    [13] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    No statistical analyses for this end point

    Secondary: Overall survival (OS) at the date of analysis

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    End point title
    Overall survival (OS) at the date of analysis [14]
    End point description
    OS defined as the time from first dose until death due to any cause. CI estimated using the Brookmeyer Crowley method. A value of 99999 indicates where no data is available or not able to determine the value. The upper bound of the 95 percent CI for the median was not reached due to insufficient event rates for Arm 2 (58 percent) and Arm 3 (28 percent).
    End point type
    Secondary
    End point timeframe
    At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    Combination Second-Line Plus Combination First-Line monotherapy second-line plus
    Number of subjects analysed
    57 [15]
    36 [16]
    78 [17]
    Units: Months
    median (confidence interval 95%)
        Months
    18.2 (14.3 to 99999)
    24.6 (11.7 to 99999)
    12.7 (7.3 to 16.3)
    Notes
    [15] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    [16] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    [17] - Second-Line All Treated Population for Coh-A, Coh-B, and First-Line All Treated Population for Coh-C
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal vital signs values

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    End point title
    Number of participants with abnormal vital signs values
    End point description
    Number of participants with abnormal values of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and temperature were evaluated. Participants with worst case post-Baseline vital sign values were presented at the given timepoints. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). All treated population was used for monotherapy cohort which comprised of all participants in the monotherapy cohort who receive at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 12 and then every 3 weeks until discharge
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    84 [18]
    57 [19]
    36 [20]
    Units: Participants
        Heart rate; decrease to <60; n= 83, 56, 35
    9
    10
    8
        Heart rate; increase to >100; n= 83, 56, 35
    22
    17
    8
        SBP; grade 0 to 0; n= 83,56, 35
    13
    1
    2
        SBP; grade 0 to 1; n= 83, 56, 35
    11
    9
    7
        SBP; grade 0 to 2; n= 83, 56, 35
    3
    4
    4
        SBP; grade 0 to 3; n= 83, 56, 35
    2
    0
    2
        SBP; grade 1 to 0; n= 83, 56, 35
    5
    0
    1
        SBP; grade 1 to 1; n= 83, 56, 35
    13
    10
    1
        SBP; grade 1 to 2; n= 83, 56, 35
    13
    13
    5
        SBP; grade 1 to 3; n= 83, 56, 35
    4
    6
    5
        SBP; grade 2 to 0; n= 83, 56, 35
    2
    0
    0
        SBP; grade 2 to 1; n= 83, 56, 35
    1
    1
    0
        SBP; grade 2 to 2; n= 83, 56, 35
    6
    4
    2
        SBP; grade 2 to 3; n= 83, 56, 35
    6
    5
    3
        SBP; grade 3 to 0; n= 83, 56, 35
    1
    0
    0
        SBP; grade 3 to 1; n= 83, 56, 35
    0
    0
    0
        SBP; grade 3 to 2; n= 83, 56, 35
    0
    1
    0
        SBP; grade 3 to 3; n= 83, 56, 35
    3
    2
    3
        DBP; grade 0 to 0; n= 83, 56, 35
    28
    4
    19
        DBP; grade 0 to 1; n= 83, 56, 35
    15
    12
    9
        DBP; grade 0 to 2; n= 83, 56, 35
    4
    6
    3
        DBP; grade 0 to 3; n= 83, 56, 35
    3
    5
    1
        DBP; grade 1 to 0; n= 83, 56, 35
    3
    0
    0
        DBP; grade 1 to 1; n= 83, 56, 35
    11
    6
    1
        DBP; grade 1 to 2; n= 83, 56, 35
    5
    12
    1
        DBP; grade 1 to 3; n= 83, 56, 35
    3
    5
    1
        DBP; grade 2 to 0; n= 83, 56, 35
    3
    0
    0
        DBP; grade 2 to 1; n= 83, 56, 35
    1
    0
    0
        DBP; grade 2 to 2; n= 83, 56, 35
    4
    2
    0
        DBP; grade 2 to 3; n= 83, 56, 35
    1
    3
    0
        DBP; grade 3 to 0; n= 83, 56, 35
    0
    0
    0
        DBP; grade 3 to 1; n= 83, 56, 35
    0
    0
    0
        DBP; grade 3 to 2; n= 83, 56, 35
    1
    1
    0
        DBP; grade 3 to 3; n= 83, 56, 35
    1
    0
    0
        Temperature; decrease to <=35; n= 82, 56, 35
    2
    4
    3
        Temperature; increase to >=38; n= 82, 56, 35
    20
    15
    14
    Notes
    [18] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [19] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [20] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal electrocardiogram (ECG) values

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    End point title
    Number of participants with abnormal electrocardiogram (ECG) values
    End point description
    Single measurements of 12-lead ECGs were obtained at given time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) interval. ECG values at worst case post-Baseline were categorized as 'clinically significant change from Baseline' and 'not a clinically significant change'.
    End point type
    Secondary
    End point timeframe
    Week 3, Week 6, Week 15 and then every 9 weeks until discharge
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    80 [21]
    56 [22]
    35 [23]
    Units: Participants
        Clinically significant
    3
    1
    1
        Not clinically significant
    77
    55
    34
    Notes
    [21] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [22] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [23] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal echocardiogram findings

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    End point title
    Number of participants with abnormal echocardiogram findings
    End point description
    Echocardiography scans were obtained at given time points using an echocardiogram and the findings for left ventricular ejection fraction (LVEF) were obtained. LVEF values at worst case post-Baseline were recorded as any increase and any decrease values.
    End point type
    Secondary
    End point timeframe
    Week 6, Week 15 and then every 9 weeks until discharge
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    77 [24]
    50 [25]
    32 [26]
    Units: Participants
        Any increase
    14
    5
    5
        Any decrease
    51
    39
    20
        No change
    12
    6
    7
    Notes
    [24] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [25] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [26] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal clinical chemistry values

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    End point title
    Number of participants with abnormal clinical chemistry values
    End point description
    Blood samples were collected from participants for evaluation of clinical chemistry parameters by worst case post-Baseline increase. The clinical chemistry parameters included creatinine, phosphate and high and low calcium, glucose, magnesium, potassium and sodium. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Up to Week 12 and then every 3 weeks until discharge
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    84 [27]
    57 [28]
    36 [29]
    Units: Participants
        Calcium high;n=80,55, 35
    9
    7
    0
        Calcium, low;n=80,55,35
    10
    8
    7
        Creatinine;n=80,55,35
    8
    11
    6
        Glucose high;n=80, 55,35
    54
    40
    24
        Glucose low;n=80, 55,35
    9
    9
    4
        Magnesium high; n=80, 55,35
    1
    1
    4
        Magnesium low; n= 80, 55,35
    9
    9
    1
        Phosphate; n= 81,55,35
    19
    16
    15
        Potassium high; n= 80,55,35
    2
    4
    1
        Potassium low; n= 80,55,35
    13
    7
    5
        Sodium high; n= 80, 55,35
    4
    1
    0
        Sodium low; n= 80, 55,35
    18
    36
    17
    Notes
    [27] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [28] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [29] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal hematology values

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    End point title
    Number of participants with abnormal hematology values
    End point description
    Blood samples were collected from participants for evaluation of hematology parameters by worst case post-Baseline increase. The hematology parameters included leukocytes, neutrophils, platelets and high and low hemoglobin and lymphocytes. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Up to Week 12 and then every 3 weeks until discharge
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    84 [30]
    57 [31]
    36 [32]
    Units: Participants
        Hemoglobin high; n= 81,56,35
    1
    0
    0
        Hemoglobin low; n= 81, 56,35
    28
    31
    18
        Leukocytes; n= 82, 56,35
    17
    27
    16
        Lymphocytes high; n= 82, 56,35
    3
    2
    0
        Lymphocytes low; n= 82, 56,35
    21
    18
    16
        Neutrophils; n= 82, 56,35
    10
    25
    13
        Platelets; n= 81,56,35
    5
    11
    4
    Notes
    [30] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [31] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [32] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    No statistical analyses for this end point

    Secondary: Number of participants with AEs and serious AEs (SAEs)

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    End point title
    Number of participants with AEs and serious AEs (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function.
    End point type
    Secondary
    End point timeframe
    Up to Week 12 and then every 3 weeks up to follow up
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    84 [33]
    57 [34]
    36 [35]
    Units: Participants
        Any AE
    83
    56
    36
        Any SAE
    37
    35
    21
    Notes
    [33] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [34] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    [35] - All treated Population for Coh- A,Second line All Treated for Coh-B, First Line All treated for CohC
    No statistical analyses for this end point

    Secondary: Apparent clearance (CL/F) of Dabrafenib and trametinib

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    End point title
    Apparent clearance (CL/F) of Dabrafenib and trametinib
    End point description
    Blood samples from participants were collected for pharmacokinetic analysis including CL/F following oral dosing of dabrafenib and trametinib.
    End point type
    Secondary
    End point timeframe
    Week 3, Week 6, Week 12 and Week 18
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    0 [36]
    0 [37]
    0 [38]
    Units: Liter/day
    arithmetic mean (standard error)
        Liter/day
    ±
    ±
    ±
    Notes
    [36] - No data was analyzed
    [37] - No data was analyzed
    [38] - No data was analyzed
    No statistical analyses for this end point

    Secondary: Volume of distribution (V/F) of Dabrafenib and trametinib

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    End point title
    Volume of distribution (V/F) of Dabrafenib and trametinib
    End point description
    Blood samples from participants were collected for pharmacokinetic analysis including V/F following oral dosing of dabrafenib and trametinib.
    End point type
    Secondary
    End point timeframe
    Week 3, Week 6, Week 12 and Week 18
    End point values
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    0 [39]
    0 [40]
    0 [41]
    Units: Liter
    arithmetic mean (standard error)
        Liter
    ±
    ±
    ±
    Notes
    [39] - No data was analyzed
    [40] - No data was analyzed
    [41] - No data was analyzed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events will be collected from time the first study dose is administered until 30 days following discontinuation of study treatment.
    Adverse event reporting additional description
    Adverse events will be graded according to the common terminology criteria for adverse events (CTCAE), version 4. For participants in the Crossover Population, any treatment-emergent AEs related to the initiation of combination treatment will be summarized for Crossover Population only.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Monotherapy All Treated
    Reporting group description
    Participants with or without prior systemic anti-cancer therapy received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy.

    Reporting group title
    Combination Second-Line Plus
    Reporting group description
    Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received dabrafenib 150 mg BID and trametinib 2 mg once daily (OD). It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue.

    Reporting group title
    Combination First-Line
    Reporting group description
    Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given dabrafenib 150 mg BID and trametinib 2 mg OD. It was continued until disease progression or death or unacceptable AEs or at investigator discretion to discontinue.

    Serious adverse events
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 84 (44.05%)
    35 / 57 (61.40%)
    21 / 36 (58.33%)
         number of deaths (all causes)
    1
    7
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Hypotension
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Basal cell carcinoma
         subjects affected / exposed
    4 / 84 (4.76%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Keratoacanthoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Lip squamous cell carcinoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Neoplasm progression
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    8 / 84 (9.52%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Chest pain
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    0 / 36 (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
    Chills
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    General physical health deterioration
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    0 / 36 (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
    Malaise
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    0 / 36 (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
    Pyrexia
         subjects affected / exposed
    5 / 84 (5.95%)
    9 / 57 (15.79%)
    4 / 36 (11.11%)
         occurrences causally related to treatment / all
    3 / 6
    8 / 13
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Confusional state
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Incisional hernia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    4 / 36 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Ejection fraction decreased
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 57 (7.02%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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 arrest
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Pericardial effusion
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Ventricular fibrillation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Cough
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    0 / 36 (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
    Pneumonia aspiration
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Pneumonitis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Lymphopenia
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Splenic thrombosis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Encephalopathy
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Facial paresis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Neuropathy peripheral
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Eye disorders
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal dystrophy
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Vertigo positional
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Colitis ischaemic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Constipation
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Gastric haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Melaena
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 84 (1.19%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic duct stenosis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Renal artery thrombosis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Urinary retention
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    0 / 36 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Hepatocellular injury
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Hypophosphataemia
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Catheter site infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Cystitis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (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
    Influenza
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Legionella infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Lung infection
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 57 (0.00%)
    0 / 36 (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
    Sepsis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 36 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 84 (97.62%)
    54 / 57 (94.74%)
    36 / 36 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 84 (4.76%)
    5 / 57 (8.77%)
    2 / 36 (5.56%)
         occurrences all number
    4
    6
    2
    Hypotension
         subjects affected / exposed
    6 / 84 (7.14%)
    6 / 57 (10.53%)
    5 / 36 (13.89%)
         occurrences all number
    6
    7
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    2
    Keratoacanthoma
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    6
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    9 / 84 (10.71%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences all number
    12
    3
    0
    Papilloma
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    6
    0
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    9 / 84 (10.71%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences all number
    11
    1
    1
    Skin papilloma
         subjects affected / exposed
    23 / 84 (27.38%)
    2 / 57 (3.51%)
    0 / 36 (0.00%)
         occurrences all number
    40
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    25 / 84 (29.76%)
    19 / 57 (33.33%)
    3 / 36 (8.33%)
         occurrences all number
    31
    23
    4
    Chest pain
         subjects affected / exposed
    7 / 84 (8.33%)
    9 / 57 (15.79%)
    1 / 36 (2.78%)
         occurrences all number
    8
    10
    1
    Chills
         subjects affected / exposed
    12 / 84 (14.29%)
    13 / 57 (22.81%)
    9 / 36 (25.00%)
         occurrences all number
    16
    18
    14
    Fatigue
         subjects affected / exposed
    23 / 84 (27.38%)
    9 / 57 (15.79%)
    11 / 36 (30.56%)
         occurrences all number
    24
    14
    11
    Hyperthermia
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 57 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    0
    3
    1
    Influenza like illness
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 57 (7.02%)
    3 / 36 (8.33%)
         occurrences all number
    2
    6
    6
    Malaise
         subjects affected / exposed
    5 / 84 (5.95%)
    3 / 57 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    5
    4
    4
    Mucosal inflammation
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 57 (7.02%)
    2 / 36 (5.56%)
         occurrences all number
    6
    5
    2
    Oedema peripheral
         subjects affected / exposed
    3 / 84 (3.57%)
    20 / 57 (35.09%)
    12 / 36 (33.33%)
         occurrences all number
    7
    27
    14
    Pain
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 57 (1.75%)
    3 / 36 (8.33%)
         occurrences all number
    1
    1
    3
    Pyrexia
         subjects affected / exposed
    30 / 84 (35.71%)
    24 / 57 (42.11%)
    22 / 36 (61.11%)
         occurrences all number
    47
    83
    62
    Xerosis
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 57 (7.02%)
    0 / 36 (0.00%)
         occurrences all number
    7
    4
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    2
    6
    1
    Depression
         subjects affected / exposed
    3 / 84 (3.57%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    3
    3
    0
    Insomnia
         subjects affected / exposed
    6 / 84 (7.14%)
    4 / 57 (7.02%)
    3 / 36 (8.33%)
         occurrences all number
    6
    4
    3
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 84 (3.57%)
    4 / 57 (7.02%)
    2 / 36 (5.56%)
         occurrences all number
    3
    5
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 57 (8.77%)
    2 / 36 (5.56%)
         occurrences all number
    3
    6
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 84 (5.95%)
    9 / 57 (15.79%)
    1 / 36 (2.78%)
         occurrences all number
    5
    10
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    5 / 57 (8.77%)
    1 / 36 (2.78%)
         occurrences all number
    0
    6
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 57 (8.77%)
    1 / 36 (2.78%)
         occurrences all number
    4
    6
    2
    Lipase increased
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    4
    0
    Weight decreased
         subjects affected / exposed
    15 / 84 (17.86%)
    8 / 57 (14.04%)
    4 / 36 (11.11%)
         occurrences all number
    16
    9
    4
    Weight increased
         subjects affected / exposed
    0 / 84 (0.00%)
    8 / 57 (14.04%)
    1 / 36 (2.78%)
         occurrences all number
    0
    9
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 57 (1.75%)
    2 / 36 (5.56%)
         occurrences all number
    4
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 84 (30.95%)
    14 / 57 (24.56%)
    6 / 36 (16.67%)
         occurrences all number
    35
    14
    6
    Dysphonia
         subjects affected / exposed
    8 / 84 (9.52%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences all number
    8
    2
    2
    Dyspnoea
         subjects affected / exposed
    16 / 84 (19.05%)
    12 / 57 (21.05%)
    5 / 36 (13.89%)
         occurrences all number
    18
    16
    6
    Epistaxis
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    1
    4
    2
    Haemoptysis
         subjects affected / exposed
    7 / 84 (8.33%)
    3 / 57 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    8
    3
    1
    Nasal congestion
         subjects affected / exposed
    3 / 84 (3.57%)
    0 / 57 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    3
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 57 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    3
    1
    Productive cough
         subjects affected / exposed
    6 / 84 (7.14%)
    7 / 57 (12.28%)
    0 / 36 (0.00%)
         occurrences all number
    6
    11
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 84 (11.90%)
    8 / 57 (14.04%)
    4 / 36 (11.11%)
         occurrences all number
    11
    11
    6
    Leukopenia
         subjects affected / exposed
    4 / 84 (4.76%)
    5 / 57 (8.77%)
    1 / 36 (2.78%)
         occurrences all number
    4
    7
    1
    Lymphopenia
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 57 (3.51%)
    1 / 36 (2.78%)
         occurrences all number
    7
    2
    3
    Neutropenia
         subjects affected / exposed
    2 / 84 (2.38%)
    11 / 57 (19.30%)
    1 / 36 (2.78%)
         occurrences all number
    2
    23
    3
    Thrombocytopenia
         subjects affected / exposed
    5 / 84 (5.95%)
    5 / 57 (8.77%)
    0 / 36 (0.00%)
         occurrences all number
    5
    6
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 84 (8.33%)
    7 / 57 (12.28%)
    5 / 36 (13.89%)
         occurrences all number
    7
    8
    5
    Dysgeusia
         subjects affected / exposed
    4 / 84 (4.76%)
    6 / 57 (10.53%)
    1 / 36 (2.78%)
         occurrences all number
    4
    8
    1
    Headache
         subjects affected / exposed
    16 / 84 (19.05%)
    8 / 57 (14.04%)
    7 / 36 (19.44%)
         occurrences all number
    18
    14
    10
    Sciatica
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 84 (4.76%)
    6 / 57 (10.53%)
    1 / 36 (2.78%)
         occurrences all number
    5
    7
    1
    Eye pain
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    2
    Periorbital oedema
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Photopsia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    Vision blurred
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences all number
    5
    3
    0
    Visual acuity reduced
         subjects affected / exposed
    3 / 84 (3.57%)
    6 / 57 (10.53%)
    1 / 36 (2.78%)
         occurrences all number
    3
    7
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 84 (0.00%)
    5 / 57 (8.77%)
    1 / 36 (2.78%)
         occurrences all number
    0
    9
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 84 (9.52%)
    4 / 57 (7.02%)
    3 / 36 (8.33%)
         occurrences all number
    10
    4
    3
    Abdominal pain upper
         subjects affected / exposed
    3 / 84 (3.57%)
    8 / 57 (14.04%)
    0 / 36 (0.00%)
         occurrences all number
    3
    12
    0
    Constipation
         subjects affected / exposed
    9 / 84 (10.71%)
    10 / 57 (17.54%)
    5 / 36 (13.89%)
         occurrences all number
    9
    13
    5
    Diarrhoea
         subjects affected / exposed
    17 / 84 (20.24%)
    17 / 57 (29.82%)
    13 / 36 (36.11%)
         occurrences all number
    27
    32
    19
    Dry mouth
         subjects affected / exposed
    1 / 84 (1.19%)
    3 / 57 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    1
    4
    3
    Dyspepsia
         subjects affected / exposed
    2 / 84 (2.38%)
    5 / 57 (8.77%)
    2 / 36 (5.56%)
         occurrences all number
    2
    5
    2
    Dysphagia
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    3
    0
    Nausea
         subjects affected / exposed
    24 / 84 (28.57%)
    22 / 57 (38.60%)
    19 / 36 (52.78%)
         occurrences all number
    32
    38
    29
    Vomiting
         subjects affected / exposed
    18 / 84 (21.43%)
    22 / 57 (38.60%)
    9 / 36 (25.00%)
         occurrences all number
    27
    59
    18
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    10 / 84 (11.90%)
    1 / 57 (1.75%)
    3 / 36 (8.33%)
         occurrences all number
    17
    1
    3
    Alopecia
         subjects affected / exposed
    18 / 84 (21.43%)
    6 / 57 (10.53%)
    2 / 36 (5.56%)
         occurrences all number
    18
    6
    2
    Dermal cyst
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    Dry skin
         subjects affected / exposed
    20 / 84 (23.81%)
    19 / 57 (33.33%)
    11 / 36 (30.56%)
         occurrences all number
    22
    22
    11
    Eczema
         subjects affected / exposed
    3 / 84 (3.57%)
    3 / 57 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    3
    5
    1
    Erythema
         subjects affected / exposed
    1 / 84 (1.19%)
    5 / 57 (8.77%)
    4 / 36 (11.11%)
         occurrences all number
    1
    6
    5
    Hair texture abnormal
         subjects affected / exposed
    7 / 84 (8.33%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    7
    3
    0
    Hyperhidrosis
         subjects affected / exposed
    3 / 84 (3.57%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    3
    4
    1
    Hyperkeratosis
         subjects affected / exposed
    25 / 84 (29.76%)
    6 / 57 (10.53%)
    0 / 36 (0.00%)
         occurrences all number
    54
    6
    0
    Madarosis
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences all number
    5
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    19 / 84 (22.62%)
    2 / 57 (3.51%)
    1 / 36 (2.78%)
         occurrences all number
    22
    3
    1
    Papule
         subjects affected / exposed
    8 / 84 (9.52%)
    1 / 57 (1.75%)
    1 / 36 (2.78%)
         occurrences all number
    8
    1
    1
    Pruritus
         subjects affected / exposed
    12 / 84 (14.29%)
    9 / 57 (15.79%)
    4 / 36 (11.11%)
         occurrences all number
    12
    11
    5
    Pruritus generalised
         subjects affected / exposed
    1 / 84 (1.19%)
    3 / 57 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    1
    5
    1
    Rash
         subjects affected / exposed
    15 / 84 (17.86%)
    13 / 57 (22.81%)
    7 / 36 (19.44%)
         occurrences all number
    15
    19
    7
    Rash generalised
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    2
    4
    1
    Rash macular
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    3
    Rash maculo-papular
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 57 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    0
    Rash papular
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences all number
    6
    2
    3
    Skin lesion
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 57 (3.51%)
    2 / 36 (5.56%)
         occurrences all number
    8
    2
    3
    Urticaria
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 57 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    5
    3
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 84 (20.24%)
    12 / 57 (21.05%)
    3 / 36 (8.33%)
         occurrences all number
    26
    15
    3
    Back pain
         subjects affected / exposed
    10 / 84 (11.90%)
    4 / 57 (7.02%)
    5 / 36 (13.89%)
         occurrences all number
    11
    6
    5
    Muscle spasms
         subjects affected / exposed
    2 / 84 (2.38%)
    6 / 57 (10.53%)
    3 / 36 (8.33%)
         occurrences all number
    2
    8
    3
    Muscular weakness
         subjects affected / exposed
    6 / 84 (7.14%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences all number
    7
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 84 (4.76%)
    3 / 57 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    5
    3
    3
    Musculoskeletal pain
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 57 (7.02%)
    3 / 36 (8.33%)
         occurrences all number
    7
    5
    3
    Myalgia
         subjects affected / exposed
    12 / 84 (14.29%)
    7 / 57 (12.28%)
    4 / 36 (11.11%)
         occurrences all number
    15
    10
    5
    Pain in extremity
         subjects affected / exposed
    15 / 84 (17.86%)
    2 / 57 (3.51%)
    3 / 36 (8.33%)
         occurrences all number
    17
    2
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    24 / 84 (28.57%)
    15 / 57 (26.32%)
    9 / 36 (25.00%)
         occurrences all number
    31
    20
    10
    Dehydration
         subjects affected / exposed
    4 / 84 (4.76%)
    3 / 57 (5.26%)
    2 / 36 (5.56%)
         occurrences all number
    4
    3
    2
    Hyperglycaemia
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    8
    5
    1
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 84 (3.57%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    5
    4
    1
    Hypokalaemia
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 57 (7.02%)
    3 / 36 (8.33%)
         occurrences all number
    7
    4
    3
    Hypomagnesaemia
         subjects affected / exposed
    3 / 84 (3.57%)
    1 / 57 (1.75%)
    2 / 36 (5.56%)
         occurrences all number
    4
    1
    5
    Hyponatraemia
         subjects affected / exposed
    3 / 84 (3.57%)
    9 / 57 (15.79%)
    4 / 36 (11.11%)
         occurrences all number
    4
    11
    6
    Hypophosphataemia
         subjects affected / exposed
    6 / 84 (7.14%)
    4 / 57 (7.02%)
    1 / 36 (2.78%)
         occurrences all number
    12
    4
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 84 (7.14%)
    6 / 57 (10.53%)
    0 / 36 (0.00%)
         occurrences all number
    9
    10
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 57 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    4
    0
    Folliculitis
         subjects affected / exposed
    3 / 84 (3.57%)
    4 / 57 (7.02%)
    0 / 36 (0.00%)
         occurrences all number
    3
    4
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 57 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    3
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    9 / 84 (10.71%)
    7 / 57 (12.28%)
    2 / 36 (5.56%)
         occurrences all number
    10
    9
    2
    Pneumonia
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 57 (3.51%)
    3 / 36 (8.33%)
         occurrences all number
    0
    2
    3
    Rhinitis
         subjects affected / exposed
    5 / 84 (5.95%)
    5 / 57 (8.77%)
    0 / 36 (0.00%)
         occurrences all number
    6
    8
    0
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 84 (8.33%)
    1 / 57 (1.75%)
    0 / 36 (0.00%)
         occurrences all number
    7
    1
    0
    Urinary tract infection
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 57 (7.02%)
    4 / 36 (11.11%)
         occurrences all number
    6
    5
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2011
    Updated the inclusion / exclusion criteria, updated the QTc withdrawal criteria and the Dose Modification section, added an Independent Data Monitoring Committee. In addition, language specific to French sites was added. Throughout the protocol, minor administrative and typographical changes were made.
    13 Oct 2011
    Increased the frequency of cardiac monitoring from every 12 weeks to every 9 weeks. Other clarifications to the PGx sections in the main text and in Appendix 1, description of physical exam and list of laboratory tests were made. Guidelines for management of renal insufficiency were added. A Baseline sample for cytokine profiling was added (in the event a subject develops fever, the baseline cytokine values are available).
    30 Apr 2012
    Is a country specific amendment that changed the QTc stopping criteria to 500 msec for UK subjects and clarified the definition of abstinence.
    15 Jun 2012
    Changed Inclusion to clarify that the failed chemotherapy regimen must have been a platinum-based chemotherapy; changed Exclusion Criteria #9 regarding the length of time a subject must be disease free from 5 years to 3 years; allowed for continued treatment with GSK2118436 beyond disease progression; updated the Dose Modification Guidelines for Fever and the Renal Insufficiency Guidelines for consistency with the current asset-specific language; added the UK to Appendix 3 (country-specific QTc stopping criteria of 500 msec); clarified restrictions on certain foods known to affect drug metabolism; clarified when an MRI or CT is required at baseline and on-study; removed the requirement for males who choose abstinence as their contraceptive method to begin abstinence 14 days BEFORE administration of GSK2118436; clarified the definition of abstinence; fixed T&E footnotes, lessened the frequency of efficacy assessments beginning at Week 36 and onwards, and removed the ANC measurement on Day 8; clarified SAE language for consistency with current asset language.
    20 Aug 2012
    Updated the Background section (Section 1.1) to include the currently available safety and efficacy data for GSK2118436; changed Inclusion Criterion (#7) to clarify for the reader that additional details on mutation testing and central confirmation of mutation testing are provided in Section 7.1.1; changes to Section 7.1.1 included clarification onBRAF mutation testing and intent that all subject have tissue available for central confirmation (when testing at inclusion is performed at a local laboratory) (also affected T&E footnote); removed the requirement for men to use contraception (Inclusion Criterion #9 and Section 7.4.2); changed the limit for use of anti-cancer treatment prior to dosing with GSK2118436 from 28 days to 14 days (Exclusion Criteria #2 and #3); added defined safety and efficacy criteria that need to be met in order to allow treatment with GSK2118436 beyond disease progression (Section 4.2.1); updated Section 5.7, Guidelines for Dose Modification and Events of Special Interest, in line with current asset language; clarified QTc Stopping Criteria to delineate QTcF v QTcB and QTc uncorrected stopping values; and clarified protocol-specific SAE language for consistency with current asset language (removed LVEF stopping criteria as a protocol specific SAE).
    24 Jan 2013
    Is a country specific amendment for France and the UK that specifies QTc stopping criteria in Appendix 3. Footnotes to the Time and Events Table were also renumbered.
    16 Apr 2013
    Added the study expansion cohort (n=20) increasing total sample size to 60 subjects, updated the eligibility criteria to remove the requirement of disease progression on a platinum-based chemotherapy prior to study enrollment to allow inclusion of first line metastatic patients in the expansion cohort and allow subjects with HCV clearance, updated QTc stopping criteria, removed herbal remedies as a prohibitive medication (St Johns Wort still prohibited), updated the prohibitive and cautionary medication list, increased the frequency of dermatologic assessments to every 9 weeks, changed blood sample for cfDNA at disease progression from optional to required, replaced “GSK2118436” with “dabrafenib” throughout the document and additional administrative level clarifications and edits. Section 1.2.1 deleted, please refer to the Dabrafenib Investigator’s Brochure for all background/clinical trial information on dabrafenib.
    25 Sep 2013
    Added the dabrafenib/trametinib combination therapy cohort (n=40) increasing the total sample size to 100 subjects, ophthalmic examination added at screening, Week 6 and as clinically necessary thereafter for combination treatment only, combination cohort specific inclusion/exclusion criteria added, combination cohort specific dose modification and toxicity management guidelines added, option to crossover from monotherapy to combination treatment at time of radiologic disease progression added, ECHO and ECG schedule clarified as baseline, Week 6 and every 9 weeks thereafter
    14 Oct 2014
    Updated secondary medical monitor. Added Cohort C to enroll 25 first line subjects. Additional language added to study rationale in Section 1.2.1. Revised required laboratory value for PT/INR and PTT in Section 4.1.2. Removed HIV from ExclusionCriterion #7 and revised Exclusion Criterion #15 in Section 4.1.3. Additional language added to Section 4.2.1 and Section 4.2.3 to clarify requirements for continuing study treatment post-PD and for crossover requirements. Updated dose modification and toxicity management language throughout Section 5.9. Updated general dose modification guidelines in Section 5.9.2. Updated dose modification guidelines and stopping criteria for LVEF in Section 5.10.1. Updated liver chemistry stopping and follow-up criteria in Section 5.10.3. Guidelines for holding study drug following radiation treatment added to Section 6.1. Specified that body fluid sample (e.g., pleural effusion) is not acceptable for BRAF mutation testing sample in Section 7.1.1. Added confirmation of measurable disease by independent review at baseline prior to enrolment in Section 7.1.2. Updated language regarding ophthalmic examination requirements in Section 7.3.2.3. Added language in Section 7.3.2.9.2 allowing investigator to decide if basal cell carcinoma should be reported as SAE or not. Specified in Section 7.4.1 that females should wait at least 4 months after last dose of the combination therapy before nursing. Specified in Section 7.7 that body fluid sample (e.g., pleural effusion) is not preferred for PD biomarker sample. Added Section 9.1.3 to describe hypothesis and study design for Cohort C. Updated Section 9.2 regarding Cohort C. Updated Investigator Brochures citations to current versions. Appendix 4 added regarding additional monitoring requirements for subjects in France only.

    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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