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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
    v1
    This version publication date
    21 Oct 2016
    First version publication date
    21 Oct 2016
    Other versions
    v2

    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
    27 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2015
    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
    Efficacy, Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    France: 57
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Norway: 1
    Worldwide total number of subjects
    166
    EEA total number of subjects
    104
    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)
    71
    From 65 to 84 years
    88
    85 years and over
    7

    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
    Product 1
    Investigational medicinal product code
    Dabrafenib (GSK2118436)
    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 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
    Product 1
    Investigational medicinal product code
    Trametinib (GSK1120212)
    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 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
    Product 1
    Investigational medicinal product code
    Trametinib (GSK1120212)
    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

    Investigational medicinal product name
    Product 1
    Investigational medicinal product code
    Dabrafenib (GSK2118436)
    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.

    Number of subjects in period 1
    Monotherapy All Treated Combination Second-Line Plus Combination First-Line
    Started
    84
    57
    25
    Completed
    0
    0
    0
    Not completed
    84
    57
    25
         Transferred to Other Arm/Group
    8
    -
    -
         Adverse event, serious fatal
    57
    23
    1
         Ongoing
    10
    32
    24
         Consent withdrawn by subject
    6
    -
    -
         Lost to follow-up
    3
    2
    -

    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 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 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 25
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    64.8 ± 10.51 65.1 ± 10.14 70.8 ± 9.5 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    44 28 15 87
        Male
    40 29 10 79
    Race/Ethnicity, Customized
    Units: Subjects
        Asian - East Asian Heritage
    14 3 1 18
        Asian - Central/South Asian Heritage
    2 0 0 2
        Asian - Japanese Heritage
    2 1 0 3
        African American/African Heritage
    2 2 0 4
        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 23 132
        Other-African American/African Heritage
    0 1 0 1
        Other-missing
    0 1 0 1

    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 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 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 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.

    Subject analysis set title
    Combination Second-Line Plus
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who had received 1-3 prior lines of systemic anti-cancer therapies 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.

    Subject analysis set title
    Combination First-Line
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who had not received any prior systemic anti-cancer 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.

    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 (RECIST) criteria version 1.1. RECIST criteria 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. 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
    Arm 1: From First dose until 21-Nov-2014; Arm 2 and 3: From first dose until 07-Oct-2015.
    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: No statistical analysis is available.
    End point values
    Combination Second-Line Plus Monotherapy Second-Line Plus Combination First-Line
    Number of subjects analysed
    57 [3]
    78
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    63.2 (49.3 to 75.6)
    33.3 (23.1 to 44.9)
    53.3 (26.6 to 78.7)
    Notes
    [3] - 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 [4]
    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 estimated using the Brookmeyer Crowley method. Upper limit of confidence interval was not reached as data were not yet mature. The data for Cohort C is not posted as study is ongoing. Second-Line All Treated Population for Coh-A and Coh-B, and First-Line All Treated Population for Coh-C.
    End point type
    Secondary
    End point timeframe
    Arm 1: From First dose until 21-Nov-2014; Arm 2 and 3: From first dose until 07-Oct-2015
    Notes
    [4] - 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: No statistical analysis is available.
    End point values
    Combination Second-Line Plus Monotherapy Second-Line Plus Combination First-Line
    Number of subjects analysed
    36
    26
    0 [5]
    Units: Months
        median (confidence interval 95%)
    9 (6.9 to 18.3)
    9.6 (5.4 to 15.2)
    ( to )
    Notes
    [5] - The data for Cohort C is not posted as study is ongoing.
    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
    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 or Computed tomography every 6 wks after initiation of study treatment until Week 36 and then every 12 wks. Confidence Intervals estimated using the Brookmeyer Crowley method. The data for Cohort C is not posted as study is ongoing. First-Line Second-Line All Treated Population for Coh-A and Coh-B, and First-Line All Treated Population for Coh-C.
    End point type
    Secondary
    End point timeframe
    Arm 1: From First dose until 21-Nov-2014; Arm 2 and 3: From first dose until 07-Oct-2015
    End point values
    Monotherapy Second-Line Plus Combination Second-Line Plus Combination First-Line
    Number of subjects analysed
    78
    57
    0 [6]
    Units: Months
        median (confidence interval 95%)
    5.5 (3.4 to 7.3)
    9.7 (6.9 to 19.6)
    ( to )
    Notes
    [6] - The data for Cohort C is not posted as study is ongoing.
    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 [7]
    End point description
    OS defined as the time from first dose until death due to any cause. Confidence Intervals estimated using the Brookmeyer Crowley method. The data for Cohort C is not posted as study is ongoing. A value of "99999" indicates where no data is available or not able to determine the value. First-LineSecond-Line All Treated Population for Coh-A and Coh-B, and First-Line All Treated Population for Coh-C.
    End point type
    Secondary
    End point timeframe
    Arm 1 and 2: From First dose until 07-Oct-2015
    Notes
    [7] - 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: No statistical analysis is available.
    End point values
    Combination Second-Line Plus Monotherapy Second-Line Plus Combination First-Line
    Number of subjects analysed
    57
    78
    0 [8]
    Units: Months
        median (confidence interval 95%)
    17.6 (14.3 to 99999)
    12.7 (7.3 to 16.3)
    ( to )
    Notes
    [8] - The data for Cohort C is not posted as study is ongoing.
    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
    18.1
    Reporting groups
    Reporting group title
    Monotherapy
    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 Therapy
    Reporting group description
    Combination of participants who had received 1-3 prior lines of systemic anti-cancer therapies and participants who had not received any prior systemic anti-cancer therapies 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.

    Serious adverse events
    Monotherapy Combination Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 84 (42.86%)
    38 / 82 (46.34%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    4 / 84 (4.76%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    8 / 84 (9.52%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 84 (5.95%)
    10 / 82 (12.20%)
         occurrences causally related to treatment / all
    3 / 6
    9 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic thrombosis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal dystrophy
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery thrombosis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Legionella infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Monotherapy Combination Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 84 (97.62%)
    77 / 82 (93.90%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 84 (7.14%)
    7 / 82 (8.54%)
         occurrences all number
    6
    8
    Hypertension
         subjects affected / exposed
    5 / 84 (5.95%)
    3 / 82 (3.66%)
         occurrences all number
    6
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 82 (0.00%)
         occurrences all number
    5
    0
    Keratoacanthoma
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 82 (0.00%)
         occurrences all number
    6
    0
    Melanocytic naevus
         subjects affected / exposed
    9 / 84 (10.71%)
    2 / 82 (2.44%)
         occurrences all number
    12
    3
    Seborrhoeic keratosis
         subjects affected / exposed
    8 / 84 (9.52%)
    2 / 82 (2.44%)
         occurrences all number
    10
    2
    Papilloma
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 82 (0.00%)
         occurrences all number
    6
    0
    Skin papilloma
         subjects affected / exposed
    23 / 84 (27.38%)
    1 / 82 (1.22%)
         occurrences all number
    40
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    6 / 84 (7.14%)
    5 / 82 (6.10%)
         occurrences all number
    7
    6
    Asthenia
         subjects affected / exposed
    25 / 84 (29.76%)
    18 / 82 (21.95%)
         occurrences all number
    31
    20
    Chills
         subjects affected / exposed
    12 / 84 (14.29%)
    15 / 82 (18.29%)
         occurrences all number
    15
    20
    Fatigue
         subjects affected / exposed
    25 / 84 (29.76%)
    14 / 82 (17.07%)
         occurrences all number
    27
    16
    Malaise
         subjects affected / exposed
    5 / 84 (5.95%)
    5 / 82 (6.10%)
         occurrences all number
    5
    6
    Mucosal inflammation
         subjects affected / exposed
    5 / 84 (5.95%)
    3 / 82 (3.66%)
         occurrences all number
    6
    4
    Oedema
         subjects affected / exposed
    2 / 84 (2.38%)
    5 / 82 (6.10%)
         occurrences all number
    2
    6
    Oedema peripheral
         subjects affected / exposed
    3 / 84 (3.57%)
    19 / 82 (23.17%)
         occurrences all number
    7
    24
    Pyrexia
         subjects affected / exposed
    29 / 84 (34.52%)
    33 / 82 (40.24%)
         occurrences all number
    43
    81
    Pain
         subjects affected / exposed
    2 / 84 (2.38%)
    5 / 82 (6.10%)
         occurrences all number
    2
    5
    Xerosis
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 82 (4.88%)
         occurrences all number
    7
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 84 (7.14%)
    6 / 82 (7.32%)
         occurrences all number
    6
    6
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 84 (5.95%)
    8 / 82 (9.76%)
         occurrences all number
    5
    9
    Weight increased
         subjects affected / exposed
    0 / 84 (0.00%)
    7 / 82 (8.54%)
         occurrences all number
    0
    7
    Weight decreased
         subjects affected / exposed
    15 / 84 (17.86%)
    9 / 82 (10.98%)
         occurrences all number
    15
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 84 (11.90%)
    8 / 82 (9.76%)
         occurrences all number
    11
    9
    Lymphopenia
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 82 (2.44%)
         occurrences all number
    7
    2
    Neutropenia
         subjects affected / exposed
    2 / 84 (2.38%)
    11 / 82 (13.41%)
         occurrences all number
    2
    24
    Thrombocytopenia
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 82 (4.88%)
         occurrences all number
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    8 / 84 (9.52%)
    1 / 82 (1.22%)
         occurrences all number
    8
    1
    Cough
         subjects affected / exposed
    24 / 84 (28.57%)
    14 / 82 (17.07%)
         occurrences all number
    30
    15
    Haemoptysis
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 82 (4.88%)
         occurrences all number
    7
    4
    Dyspnoea
         subjects affected / exposed
    17 / 84 (20.24%)
    11 / 82 (13.41%)
         occurrences all number
    19
    12
    Productive cough
         subjects affected / exposed
    6 / 84 (7.14%)
    6 / 82 (7.32%)
         occurrences all number
    6
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 84 (8.33%)
    8 / 82 (9.76%)
         occurrences all number
    7
    9
    Dysgeusia
         subjects affected / exposed
    4 / 84 (4.76%)
    6 / 82 (7.32%)
         occurrences all number
    4
    8
    Headache
         subjects affected / exposed
    16 / 84 (19.05%)
    10 / 82 (12.20%)
         occurrences all number
    18
    15
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 82 (6.10%)
         occurrences all number
    3
    6
    Vision blurred
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 82 (1.22%)
         occurrences all number
    5
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 84 (0.00%)
    5 / 82 (6.10%)
         occurrences all number
    0
    9
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 84 (2.38%)
    7 / 82 (8.54%)
         occurrences all number
    2
    10
    Constipation
         subjects affected / exposed
    9 / 84 (10.71%)
    13 / 82 (15.85%)
         occurrences all number
    9
    15
    Abdominal pain
         subjects affected / exposed
    8 / 84 (9.52%)
    3 / 82 (3.66%)
         occurrences all number
    10
    3
    Diarrhoea
         subjects affected / exposed
    16 / 84 (19.05%)
    22 / 82 (26.83%)
         occurrences all number
    22
    37
    Dyspepsia
         subjects affected / exposed
    2 / 84 (2.38%)
    6 / 82 (7.32%)
         occurrences all number
    2
    6
    Dry mouth
         subjects affected / exposed
    1 / 84 (1.19%)
    5 / 82 (6.10%)
         occurrences all number
    1
    5
    Nausea
         subjects affected / exposed
    24 / 84 (28.57%)
    32 / 82 (39.02%)
         occurrences all number
    31
    49
    Vomiting
         subjects affected / exposed
    18 / 84 (21.43%)
    23 / 82 (28.05%)
         occurrences all number
    26
    54
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    10 / 84 (11.90%)
    4 / 82 (4.88%)
         occurrences all number
    17
    4
    Alopecia
         subjects affected / exposed
    18 / 84 (21.43%)
    5 / 82 (6.10%)
         occurrences all number
    18
    5
    Dry skin
         subjects affected / exposed
    21 / 84 (25.00%)
    19 / 82 (23.17%)
         occurrences all number
    23
    22
    Erythema
         subjects affected / exposed
    1 / 84 (1.19%)
    5 / 82 (6.10%)
         occurrences all number
    1
    6
    Hair texture abnormal
         subjects affected / exposed
    7 / 84 (8.33%)
    3 / 82 (3.66%)
         occurrences all number
    7
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    19 / 84 (22.62%)
    3 / 82 (3.66%)
         occurrences all number
    22
    4
    Hyperkeratosis
         subjects affected / exposed
    25 / 84 (29.76%)
    6 / 82 (7.32%)
         occurrences all number
    55
    6
    Madarosis
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 82 (0.00%)
         occurrences all number
    5
    0
    Pruritus
         subjects affected / exposed
    12 / 84 (14.29%)
    10 / 82 (12.20%)
         occurrences all number
    12
    16
    Rash
         subjects affected / exposed
    16 / 84 (19.05%)
    15 / 82 (18.29%)
         occurrences all number
    16
    21
    Papule
         subjects affected / exposed
    8 / 84 (9.52%)
    2 / 82 (2.44%)
         occurrences all number
    8
    2
    Rash maculo-papular
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 82 (0.00%)
         occurrences all number
    5
    0
    Rash papular
         subjects affected / exposed
    6 / 84 (7.14%)
    3 / 82 (3.66%)
         occurrences all number
    6
    3
    Skin lesion
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 82 (2.44%)
         occurrences all number
    8
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 84 (19.05%)
    12 / 82 (14.63%)
         occurrences all number
    25
    14
    Muscular weakness
         subjects affected / exposed
    6 / 84 (7.14%)
    1 / 82 (1.22%)
         occurrences all number
    7
    1
    Muscle spasms
         subjects affected / exposed
    2 / 84 (2.38%)
    6 / 82 (7.32%)
         occurrences all number
    2
    7
    Back pain
         subjects affected / exposed
    10 / 84 (11.90%)
    7 / 82 (8.54%)
         occurrences all number
    11
    9
    Pain in extremity
         subjects affected / exposed
    15 / 84 (17.86%)
    3 / 82 (3.66%)
         occurrences all number
    17
    3
    Myalgia
         subjects affected / exposed
    12 / 84 (14.29%)
    9 / 82 (10.98%)
         occurrences all number
    15
    12
    Musculoskeletal pain
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 82 (2.44%)
         occurrences all number
    7
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 84 (27.38%)
    19 / 82 (23.17%)
         occurrences all number
    30
    21
    Hypokalaemia
         subjects affected / exposed
    5 / 84 (5.95%)
    5 / 82 (6.10%)
         occurrences all number
    8
    5
    Hyperglycaemia
         subjects affected / exposed
    5 / 84 (5.95%)
    3 / 82 (3.66%)
         occurrences all number
    6
    4
    Hypophosphataemia
         subjects affected / exposed
    6 / 84 (7.14%)
    5 / 82 (6.10%)
         occurrences all number
    11
    5
    Hyponatraemia
         subjects affected / exposed
    3 / 84 (3.57%)
    7 / 82 (8.54%)
         occurrences all number
    4
    9
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    5 / 84 (5.95%)
    5 / 82 (6.10%)
         occurrences all number
    6
    6
    Nasopharyngitis
         subjects affected / exposed
    9 / 84 (10.71%)
    5 / 82 (6.10%)
         occurrences all number
    10
    7
    Bronchitis
         subjects affected / exposed
    6 / 84 (7.14%)
    5 / 82 (6.10%)
         occurrences all number
    7
    8
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 84 (8.33%)
    1 / 82 (1.22%)
         occurrences all number
    7
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 84 (5.95%)
    6 / 82 (7.32%)
         occurrences all number
    6
    6

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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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