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    Clinical Trial Results:
    A Phase II (BRF113710) single-arm, open-label study of dabrafenib (GSK2118436) in previously treated BRAF mutant metastatic melanoma

    Summary
    EudraCT number
    		 2009-015297-36
    Trial protocol
    		 FR   DE   IT  
    Global end of trial date
    17 Jun 2016

    Results information
    Results version number
    		 v1
    This version publication date
    02 Jul 2017
    First version publication date
    02 Jul 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    113710
    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, 866 435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 866 435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the overall response rate (ORR), defined as the proportion of participants with investigator-assessed complete responses or partial responses, in participants with metastatic melanoma treated with the oral agent GSK2118436 in subjects.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Aug 2010
    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
    Australia: 8
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    92
    EEA total number of subjects
    55
    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)
    65
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible participants received Dabrafenib (GSK2118436) 150 milligram (mg) twice daily and continued on treatment until disease progression, death, unacceptable adverse event (AE), or early termination of the study. The total duration of the study including a long-term follow-up phase was 5 years.

    Pre-assignment
    Screening details
    		 A total of 211 participants with histologically confirmed BRAF mutation positive metastatic melanoma (Stage IV) were screened for eligibility. 152 participants had a BRAF V600E or V600K mutation and 92 participants with positive mutation were included in the study.

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

    Arms
    Arm title
    		 GSK2118436 150 mg
    Arm description
    		 Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436.
    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
    Debrafenib 150 milligram (mg) was administered twice daily under fasting conditions, either 1 hour before or 2 hours after a meal with approximately 200 milliliter (mL) of water.

    Number of subjects in period 1
    		GSK2118436 150 mg
    Started
    92
    Completed
    71
    Not completed
    21
         Study closed/terminated
    16
         Physician decision
    2
         Consent withdrawn by subject
    2
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GSK2118436 150 mg
    Reporting group description
    		 Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436.

    Reporting group values
    		 GSK2118436 150 mg Total
    Number of subjects
    		 92
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.8 ± 14.44 -
    Gender categorical
    Units: Subjects
        Female
    		 43 43
        Male
    		 49 49
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 91 91
        American Indian or Alaska Native
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    GSK2118436 150 mg
    Reporting group description
    		 Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436.

    Primary: Number of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as assessed by the investigator for participants who had a BRAF V600E mutation

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    End point title
    		 Number of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as assessed by the investigator for participants who had a BRAF V600E mutation [1]
    End point description
    A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeter (mm) in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment was required at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later were required to be confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Primary efficacy Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600E mutation. The estimated value for the percentage of participants was 59 with 95% CI as 48.2-70.3.
    End point type
    Primary
    End point timeframe
    Up to 60 months
    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: The estimated value for the percentage of participants and 95% CI was presented in End Point Details Description as it is a single arm study.
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    76 [2]
    Units: Participants
        CR
    5
        PR
    40
    Notes
    [2] - Primary efficacy Population
    No statistical analyses for this end point

    Secondary: Number of participants with a best overall response of CR or PR as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation

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    End point title
    		 Number of participants with a best overall response of CR or PR as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation
    End point description
    A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment had to have been performed at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later should have been confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Secondary efficacy analysis Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600K mutation.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    16 [3]
    Units: Participants
        Investigator-assessed CR
    0
        Investigator-assessed PR
    2
    Notes
    [3] - Secondary Efficacy Population
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) as assessed by the investigator and an independent reviewer for participants who had a BRAF V600E mutation

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    End point title
    		 Progression-free Survival (PFS) as assessed by the investigator and an independent reviewer for participants who had a BRAF V600E mutation
    End point description
    PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent confidence interval (CI). For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    76 [4]
    Units: Weeks
    median (confidence interval 95%)
        Weeks
    6.3 (4.6 to 8.1)
    Notes
    [4] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation

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    End point title
    		 Progression-free Survival (PFS) as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation
    End point description
    PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent CI. For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    16 [5]
    Units: Weeks
    median (confidence interval 95%)
        Weeks
    4 (2.6 to 6.2)
    Notes
    [5] - Secondary Efficacy Population
    No statistical analyses for this end point

    Secondary: Duration of response as assessed by the investigator and an independent reviewer for participants who had a BRAF V600E mutation

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    End point title
    		 Duration of response as assessed by the investigator and an independent reviewer for participants who had a BRAF V600E mutation
    End point description
    Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Primary efficacy Population and only those participants who had a CR or PR were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    76 [6]
    Units: Weeks
    median (confidence interval 95%)
        Weeks
    6.6 (3.9 to 11.1)
    Notes
    [6] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: Duration of response as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation

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    End point title
    		 Duration of response as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation
    End point description
    Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Secondary efficacy Population and only those participants who had a CR or PR were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    16 [7]
    Units: Weeks
    median (confidence interval 95%)
        Weeks
    5.6 (3.7 to 6.8)
    Notes
    [7] - Secondary Efficacy Population
    No statistical analyses for this end point

    Secondary: Overall survival for participants who had a BRAF V600E mutation

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    End point title
    		 Overall survival for participants who had a BRAF V600E mutation
    End point description
    Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using kaplan-Meier model and median and 95 percent CI was presented. The estimated value for the percentage of participants was 20 with 95% CI as 11.6-29.8.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    76 [8]
    Units: Weeks
    median (confidence interval 95%)
        Weeks
    13.1 (9.5 to 21.9)
    Notes
    [8] - Primary Efficacy Population
    No statistical analyses for this end point

    Secondary: Overall survival for participants who had a BRAF V600K mutation

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    End point title
    		 Overall survival for participants who had a BRAF V600K mutation
    End point description
    Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using Kaplan-Meier model and median and 95 percent CI was presented. The estimated value for the percentage of participants was 13 with 95% CI as 2.2-34.6.
    End point type
    Secondary
    End point timeframe
    From the first dose to death due to any cause (up to 60 months)
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    16 [9]
    Units: Weeks
    median (confidence interval 95%)
        Weeks
    12.9 (4.2 to 17.1)
    Notes
    [9] - Secondary Efficacy Population
    No statistical analyses for this end point

    Secondary: Number of participants with AEs and Serious Adverse Events (SAEs)

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    End point title
    		 Number of participants with AEs and Serious Adverse Events (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. AEs including systemic allergic and non-allergic reactions as well as local site injection-related reactions were counted throughout treatment phase and follow up phase. Systemic allergic reactions included facial paralysis, flushing, hypersensitivity and rash pruritic. Injection related reactions were considered as systemic non-allergic reactions. Local site reactions included injection site bruising, erythema, pain and reaction. The analysis was performed on All treated Population which comprised of all participants that receive at least one dose of dabrafenib.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    92 [10]
    Units: Participants
        Any AE
    87
        Any SAE
    33
    Notes
    [10] - All treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with change from Baseline in clinical chemistry and hematology toxicity grades

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    End point title
    		 Number of participants with change from Baseline in clinical chemistry and hematology toxicity grades
    End point description
    Blood samples were collected from participants for evaluation of change from Baseline in toxicity grades in clinical chemistry and hematology parameters. The clinical chemistry parameters included alkaline phosphatase, Alanine amino transferase (ALT), Aspartate amino transferase (AST), total bilirubin, creatinine, glucose, potassium, magnesium, sodium and phosphorus. The hematology parameters included hemoglobin, total neutrophils, platelets and white blood cells (WBC). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. 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 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    92 [11]
    Units: Participants
        Alkaline phosphatase; n= 91
    23
        ALT; n= 91
    18
        AST; n= 91
    18
        Total bilirubin; n= 91
    3
        Creatinine; n= 91
    11
        Glucose; n= 90
    51
        Potassium; n= 91
    2
        Magnesium; n= 89
    2
        Sodium; n= 91
    5
        Phosphorus; n= 91
    36
        Hemoglobin; n= 91
    0
        Total Neutrophils; n= 91
    21
        Platelet; n= 91
    12
        WBC; n= 91
    24
    Notes
    [11] - All treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with change from Baseline in temperature and pulse rate

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    End point title
    		 Number of participants with change from Baseline in temperature and pulse rate
    End point description
    Number of participants with change from Baseline in temperature and pulse rate were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as decrease to <=35, change to normal or no change and increase to >=38. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst case post-baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    91 [12]
    Units: Participants
        Temperature; Decrease to <=35
    3
        Temperature; Change to normal or no change
    84
        Temperature; Increase to >=38
    4
        Pulse rate; Decrease to <=35
    9
        Pulse rate; Change to normal or no change
    66
        Pulse rate; Increase to >=38
    16
    Notes
    [12] - All treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with increase from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)

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    End point title
    		 Number of participants with increase from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)
    End point description
    Number of participants with increase from Baseline in SBP and DBP were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as any increase to >=80 and increase to >=100 for DBP and as any increase to >=120 and increase to >=160 for SBP. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    91 [13]
    Units: Participants
        DBP; Any increase to >=80
    32
        DBP; Increase to >=100
    6
        SBP; Any icrease to >=120
    2
        SBP; Increase to >=160
    7
    Notes
    [13] - All treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with change from Baseline in Left Ventricular Ejection Fraction (LVEF) levels

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    End point title
    		 Number of participants with change from Baseline in Left Ventricular Ejection Fraction (LVEF) levels
    End point description
    LVEF was defined as the percentage of blood pumped out of the left ventricle. Change from Baseline in worst-case post Baseline was presented as no change or any increase and any decrease values. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 GSK2118436 150 mg
    Number of subjects analysed
    92 [14]
    Units: Participants
        No change or any increase
    34
        Any decrease
    54
    Notes
    [14] - All treated Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of investigational product until death of all participants or a follow-up till 60 months.
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in the All Treated Participants Population, comprised of all randomized participants who received at least one dose of study medication, according to the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    GSK2118436 150 mg
    Reporting group description
    		 Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436.

    Serious adverse events
    		 GSK2118436 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 92 (35.87%)
         number of deaths (all causes)
    71
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm of eyelid
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    6 / 92 (6.52%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chills
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 92 (4.35%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Social circumstances
    Miscarriage of partner
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GSK2118436 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 92 (90.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    10 / 92 (10.87%)
         occurrences all number
    14
    Seborrhoeic keratosis
         subjects affected / exposed
    12 / 92 (13.04%)
         occurrences all number
    13
    Skin papilloma
         subjects affected / exposed
    15 / 92 (16.30%)
         occurrences all number
    20
    Vascular disorders
    Hot flush
         subjects affected / exposed
    6 / 92 (6.52%)
         occurrences all number
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 92 (8.70%)
         occurrences all number
    11
    Chills
         subjects affected / exposed
    13 / 92 (14.13%)
         occurrences all number
    14
    Fatigue
         subjects affected / exposed
    22 / 92 (23.91%)
         occurrences all number
    27
    Oedema peripheral
         subjects affected / exposed
    6 / 92 (6.52%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    24 / 92 (26.09%)
         occurrences all number
    58
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 92 (13.04%)
         occurrences all number
    13
    Dyspnoea
         subjects affected / exposed
    11 / 92 (11.96%)
         occurrences all number
    15
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    5
    Depression
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    5
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    6
    Weight decreased
         subjects affected / exposed
    6 / 92 (6.52%)
         occurrences all number
    6
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 92 (20.65%)
         occurrences all number
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 92 (11.96%)
         occurrences all number
    13
    Lymphopenia
         subjects affected / exposed
    7 / 92 (7.61%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 92 (7.61%)
         occurrences all number
    11
    Abdominal pain upper
         subjects affected / exposed
    7 / 92 (7.61%)
         occurrences all number
    7
    Constipation
         subjects affected / exposed
    7 / 92 (7.61%)
         occurrences all number
    9
    Diarrhoea
         subjects affected / exposed
    11 / 92 (11.96%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    19 / 92 (20.65%)
         occurrences all number
    24
    Vomiting
         subjects affected / exposed
    15 / 92 (16.30%)
         occurrences all number
    17
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    8 / 92 (8.70%)
         occurrences all number
    10
    Alopecia
         subjects affected / exposed
    15 / 92 (16.30%)
         occurrences all number
    15
    Dry skin
         subjects affected / exposed
    11 / 92 (11.96%)
         occurrences all number
    11
    Erythema
         subjects affected / exposed
    8 / 92 (8.70%)
         occurrences all number
    8
    Hyperhidrosis
         subjects affected / exposed
    6 / 92 (6.52%)
         occurrences all number
    7
    Hyperkeratosis
         subjects affected / exposed
    27 / 92 (29.35%)
         occurrences all number
    61
    Palmoplantar keratoderma
         subjects affected / exposed
    8 / 92 (8.70%)
         occurrences all number
    8
    Pruritus
         subjects affected / exposed
    9 / 92 (9.78%)
         occurrences all number
    10
    Pruritus generalised
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    10 / 92 (10.87%)
         occurrences all number
    11
    Transient acantholytic dermatosis
         subjects affected / exposed
    6 / 92 (6.52%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    33 / 92 (35.87%)
         occurrences all number
    64
    Back pain
         subjects affected / exposed
    9 / 92 (9.78%)
         occurrences all number
    11
    Musculoskeletal pain
         subjects affected / exposed
    8 / 92 (8.70%)
         occurrences all number
    8
    Myalgia
         subjects affected / exposed
    8 / 92 (8.70%)
         occurrences all number
    14
    Pain in extremity
         subjects affected / exposed
    15 / 92 (16.30%)
         occurrences all number
    19
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    6
    Nasopharyngitis
         subjects affected / exposed
    13 / 92 (14.13%)
         occurrences all number
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 92 (15.22%)
         occurrences all number
    16
    Hyperglycaemia
         subjects affected / exposed
    5 / 92 (5.43%)
         occurrences all number
    6
    Hypophosphataemia
         subjects affected / exposed
    9 / 92 (9.78%)
         occurrences all number
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Aug 2010
    Country specific amendment for France to add valvular toxicity stopping criteria and to add that an Independent data monitoring committee (IDMC) will be established to review data from the study.
    01 Sep 2010
    Applies to all study sites. Modification of overall statistical design to include V600E mutant participants as the primary efficacy population and V600K in secondary efficacy assessments and updated primary and secondary objectives, endpoints, etc. accordingly; removal of V600D population; updates to First time in humans (FTIH) clinical activity and safety data and reference to the current version of the investigational brochure (IB); addition of IDMC to review data from interim analysis and periodically throughout the study; addition of valvular toxicity and Correction in QT interval (QTc) stopping criteria; changes to inclusion criteria to include treatment naïve participants and add computed tomography (CT) as a method for detecting brain metastases if magnetic resonance imaging (MRI) is contraindicated; deletion of exclusion criteria that excludes participants with a presence of rheumatoid arthritis, addition of exclusion criteria to exclude participants with history of alcohol or drug abuse within 6 months of screening and participants with known ocular or primary mucosal melanoma; changes to GSK2118436 storage temperature; modification of the frequency of efficacy assessments to every 8 weeks Week 20 to 52 and every 12 weeks from Week 52 until discontinuation; modifications to pregnancy section to address contraception requirements for female and male participants separately with a subsection on pregnancy; addition of mandatory cfDNA sample at discontinuation; addition of central reading of electrocardiogram (ECG) and Echocardiogram (ECHO)s; correction of minor typographical errors; administrative revisions to add/delete authors and update references.
    14 Nov 2011
    Footnote added to Table 4 Dose Modification that an ophthalmologic consultation is required if uveitis, blurry vision, eye pain, or erythema develops. A guideline for renal insufficiency was added for the management of renal toxicities; minor administrative change corrections; and correction of minor typographical errors.
    19 Dec 2013
    Updated study objectives to include secondary efficacy objective of long-term overall Survival; Updated definition of study completion throughout to allow for collection of long term survival data; Removed option for ongoing participants to transition to rollover study BRF114144 at the time of study completion; Updated dabrafenib dosing instructions; Updated dose modification guidelines for general toxicities and adverse events of special interest; Updated Liver Chemistry Stopping and Follow-up criteria to permit rechallenge/restart following liver toxicity; Updated permitted, prohibited and cautionary concomitant medication information; Updated treatment of dabrafenib overdose information; Updated visit schedule and dermatologic skin assessment frequency; As requested by the European Regulatory Authority, information for new malignancies will be collected throughout study treatment and follow-up; Removed male contraception requirement; As requested by French Regulatory Authority, additional monitoring following discontinuation of dabrafenib was incorporated; Minor administrative changes and typographical corrections throughout.
    11 Mar 2014
    Country specific amendment for Germany to incorporate additional monitoring for cutaneous squamous cell carcinoma, new primary melanoma and non-cutaneous secondary/recurrent malignancy at the request of the German Federal Institute for Drugs and Medical Devices (BfArM).
    14 Sep 2015
    Study will be closed out early. Reason for closure: As the primary endpoint of the study has been achieved and reported, (5 July 2012) it is believed that no significant new data or Overall Survival (OS) follow-up data will be generated in this study; Re-inserted the option for ongoing participants to transition to the roll-over study BRF114144 at the time of study completion or switch to commercially available Dabrafenib; FDA, EMA and other regulatory agencies approved dabrafenib for the treatment of participants with unresectable or metastatic melanoma with BRAF V600E mutation.

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

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