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    Clinical Trial Results:
    An Open-label, Single-arm, Phase II, Multicentre Study to Evaluate the Efficacy of Vemurafenib in Metastatic Melanoma Patients with Brain Metastases

    Summary
    EudraCT number
    2011-000954-46
    Trial protocol
    DE   ES   GB   IT  
    Global end of trial date
    21 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    06 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO25743
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01378975
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F.Hoffmann-La Roche AG., F.Hoffmann-La Roche AG., 41 616878333, global.trial_information@roche.com
    Scientific contact
    F.Hoffmann-La Roche AG., F.Hoffmann-La Roche AG., 41 616878333, global.trial_information@roche.com
    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
    21 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To evaluate the efficacy of vemurafenib using Best Overall Response Rate (BORR), as assessed by an Independent Review Committee (IRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST, v1.1) in the brain of metastatic melanoma subjects with previously untreated brain metastases.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    146
    EEA total number of subjects
    102
    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)
    108
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 289 subjects with metastatic melanoma were screened for entry into the study, out of which 146 subjects were enrolled 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
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Previously Untreated Subjects
    Arm description
    Subjects who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligram (mg) oral doses twice daily from day 1 until disease progression, unacceptable toxicity or consent withdrawal.

    Arm title
    Cohort 2: Previously Treated Subjects
    Arm description
    Subjects who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 mg oral doses twice daily from Day 1 until disease progression, unacceptable toxicity or consent withdrawal.

    Number of subjects in period 1
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Started
    90
    56
    Completed
    4
    6
    Not completed
    86
    50
         Investigator Request
    1
    -
         Death
    77
    46
         Withdrew Consent
    4
    3
         Lost to follow-up
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Previously Untreated Subjects
    Reporting group description
    Subjects who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.

    Reporting group title
    Cohort 2: Previously Treated Subjects
    Reporting group description
    Subjects who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.

    Reporting group values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects Total
    Number of subjects
    90 56 146
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ± 12.73 52.7 ± 13.85 -
    Gender categorical
    Units: Subjects
        Female
    34 22 56
        Male
    56 34 90

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Previously Untreated Subjects
    Reporting group description
    Subjects who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.

    Reporting group title
    Cohort 2: Previously Treated Subjects
    Reporting group description
    Subjects who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.

    Primary: Best Overall Response Rate (BORR) Within Brain of Previously Untreated Subjects (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST])

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    End point title
    Best Overall Response Rate (BORR) Within Brain of Previously Untreated Subjects (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST]) [1] [2]
    End point description
    BORR assessed by IRC is defined as percentage of subjects who were responders (with best overall response (BOR) documented as confirmed complete response [CR] or partial response [PR]). The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in brain to be >=5 mm by contrast-enhanced magnetic resonance imaging scan (RECIST v1.1 this is >=10 mm), allowing up to 5 target lesions in brain (RECIST v1.1 only 2 target lesions), and examining lesions within brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. The intent-to-treat (ITT) population included all subjects who were enrolled in study.
    End point type
    Primary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    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: Only descriptive data was planned to be reported.
    [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: The data for this endpoint was planned to be reported for one reporting arm (Cohort 2: Previously Untreated Subjects).
    End point values
    Cohort 1: Previously Untreated Subjects
    Number of subjects analysed
    90
    Units: percentage of subjects
        number (confidence interval 95%)
    17.8 (10.5 to 27.3)
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate (BORR) in the Brain of Subjects With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1

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    End point title
    Best Overall Response Rate (BORR) in the Brain of Subjects With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1
    End point description
    Percentage of subjects who were responders with best overall response (BOR) documented as confirmed CR, PR, SD, PD. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The ITT population included all subjects who were enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: percentage of subjects
    number (not applicable)
        Complete Response
    2.2
    0
        Partial Response
    15.6
    17.9
        Stable Disease
    43.3
    41.1
        Progressive Disease
    32.2
    33.9
        Unevaluable
    6.7
    7.1
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate (BORR) in the Brain of Subject With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1

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    End point title
    Best Overall Response Rate (BORR) in the Brain of Subject With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1 [3]
    End point description
    BORR within brain assessed by IRC is defined as percentage of subjects who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The ITT population included all subjects who were enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    Notes
    [3] - 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: The data for this endpoint was planned to be reported for one reporting arm (Cohort 2: Previously Treated Subjects).
    End point values
    Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    56
    Units: percentage of subjects
        number (confidence interval 95%)
    17.9 (8.9 to 30.4)
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate Outside the Brain (Assessed by IRC)

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    End point title
    Best Overall Response Rate Outside the Brain (Assessed by IRC)
    End point description
    BORR outside of brain assessed by IRC is defined as percentage of subjects who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The ITT population included all subject who were enrolled in the study. Here, number of subjects analysed is the total number of subjects who had measurable disease outside brain at Baseline.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    79
    49
    Units: percentage of subjects
        number (confidence interval 95%)
    32.9 (22.7 to 44.4)
    22.5 (10.8 to 38.5)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) (Assessed by Investigator and IRC)

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    End point title
    Duration of Response (DOR) (Assessed by Investigator and IRC)
    End point description
    Duration of response was defined as the time interval between the date of the earliest qualifying response and the earliest date of PD or death from any cause. For subject who were alive without progression following the qualifying response, DOR were censored on the date of last available tumor assessment on or before the data cutoff date. The ITT population included all subjects who were enrolled in the study. Here, 'n' indicates number of subjects who were responders within brain or outside brain assessed by investigator or IRC.
    End point type
    Secondary
    End point timeframe
    Date of the earliest qualifying response until the earliest date of PD or death from any cause (approximately up to 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: months
    median (full range (min-max))
        Investigator: DOR (Within Brain) (n=26, 13)
    4.67 (2.66 to 24.21)
    6.64 (1.87 to 21.98)
        Investigator: DOR (Outside Brain) (n=25, 11)
    5.55 (1.84 to 25.63)
    10.74 (1.84 to 23.1)
        IRC: DOR (Within Brain) (n=16, 10)
    4.6 (2.66 to 29.9)
    6.64 (0.95 to 18.4)
        IRC: DOR (Outside Brain) (n=26, 9)
    7.72 (1.84 to 21.55)
    11.07 (1.84 to 23.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator)

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    End point title
    Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator)
    End point description
    Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within or outside the brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first. The ITT population included all subjects who were enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: months
        median (full range (min-max))
    3.65 (0.3 to 33.35)
    3.71 (0.26 to 27.37)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator )

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    End point title
    Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator )
    End point description
    Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first. The ITT population included all subjects who were enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: months
        median (full range (min-max))
    3.68 (0.36 to 33.35)
    4.04 (0.26 to 27.37)
    No statistical analyses for this end point

    Secondary: Time to Development of New Brain Metastases in Responders

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    End point title
    Time to Development of New Brain Metastases in Responders
    End point description
    Time to development of new lesions within the brain was defined as the interval between the date of first treatment and the earliest date of documentation of new brain lesions. Subjects who were known to be free of new lesions were censored on the date of last tumor assessment. The ITT population included all subjects who were enrolled in the study. Here, number of subjects analysed is the subjects who were responders.
    End point type
    Secondary
    End point timeframe
    Date of first treatment and the earliest date of documentation of new brain lesions (approximately up to 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    26
    13
    Units: months
        median (full range (min-max))
    14.92 (3.48 to 33.35)
    14.52 (2.79 to 27.37)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival was defined as time between enrollment on Day 1 and date of death, irrespective of the cause of death. Subjects for whom no death was captured on the clinical database were censored at the latest date they were known to be alive prior to or on the cutoff date. The ITT population included all subject who were enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: months
        median (full range (min-max))
    8.87 (0.59 to 34.53)
    9.63 (0.66 to 34.3)
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator)

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    End point title
    Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator)
    End point description
    Percentage of subjects who were responders with BOR documented as confirmed CR or PR, SD, PD. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum diameters while on study. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. ITT population. Here, 'n' indicates the number subjects who were evaluable for within brain assessment and who had measurable disease outside brain at baseline for outside brain assessment.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: percentage of subjects
    number (not applicable)
        Complete Response (Within Brain) (n=90, 56)
    2.2
    0
        Partial Response (Within Brain) (n=90, 56)
    26.7
    23.2
        Stable Disease (Within Brain) (n=90, 56)
    40
    53.6
        Progressive Disease (Within Brain) (n=90, 56)
    27.8
    19.6
        Unevaluable (Within Brain) (n=90, 56)
    3.3
    3.6
        Complete Response (Outside Brain) (n=79, 40)
    0
    5
        Partial Response (Outside Brain) (n=79, 40)
    31.6
    22.5
        Stable Disease (Outside Brain) (n=79, 40)
    49.4
    52.5
        Progressive Disease (Outside Brain) (n=79, 40)
    11.4
    15
        Unevaluable (Outside Brain) (n=79, 40)
    7.6
    5
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator)

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    End point title
    Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator)
    End point description
    Percentage of subject who were responders (with BOR documented as confirmed CR or PR) were reported. The ITT population included all subjects who were enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until the disease progression or death from any cause (approximately 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: percentage of subjects
        number (confidence interval 95%)
    18.9 (11.4 to 28.5)
    17.9 (8.9 to 30.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events (AE)

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    End point title
    Percentage of Subjects With Adverse Events (AE)
    End point description
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. The safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent form up to 28 days after the last dose of study drug (approximately up to 4 years)
    End point values
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Number of subjects analysed
    90
    56
    Units: percentage of subjects
        number (not applicable)
    97.8
    94.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent form up to 28 days after the last dose of study drug (Up to approximately 4 years)
    Adverse event reporting additional description
    The safety population included all subject who received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort 1: Previously Untreated Subjects
    Reporting group description
    Subjects who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.

    Reporting group title
    Cohort 2: Previously Treated Subjects
    Reporting group description
    Subjects who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering subject's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.

    Serious adverse events
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 90 (41.11%)
    27 / 56 (48.21%)
         number of deaths (all causes)
    77
    46
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    11 / 90 (12.22%)
    6 / 56 (10.71%)
         occurrences causally related to treatment / all
    19 / 19
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    11 / 90 (12.22%)
    4 / 56 (7.14%)
         occurrences causally related to treatment / all
    14 / 14
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         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
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar neoplasm benign
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (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
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ocular ischaemic syndrome
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (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
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         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 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Abscess rupture
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 56 (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 / 90 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 56 (1.79%)
         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
    Cohort 1: Previously Untreated Subjects Cohort 2: Previously Treated Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 90 (94.44%)
    53 / 56 (94.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 90 (6.67%)
    4 / 56 (7.14%)
         occurrences all number
    7
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
         subjects affected / exposed
    7 / 90 (7.78%)
    1 / 56 (1.79%)
         occurrences all number
    7
    1
    Basal cell carcinoma
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 56 (5.36%)
         occurrences all number
    1
    3
    Skin papilloma
         subjects affected / exposed
    15 / 90 (16.67%)
    12 / 56 (21.43%)
         occurrences all number
    17
    13
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 90 (24.44%)
    19 / 56 (33.93%)
         occurrences all number
    26
    25
    Asthenia
         subjects affected / exposed
    13 / 90 (14.44%)
    6 / 56 (10.71%)
         occurrences all number
    14
    8
    Oedema peripheral
         subjects affected / exposed
    7 / 90 (7.78%)
    8 / 56 (14.29%)
         occurrences all number
    8
    14
    Pyrexia
         subjects affected / exposed
    11 / 90 (12.22%)
    7 / 56 (12.50%)
         occurrences all number
    11
    8
    Pain
         subjects affected / exposed
    6 / 90 (6.67%)
    5 / 56 (8.93%)
         occurrences all number
    6
    5
    Chest pain
         subjects affected / exposed
    1 / 90 (1.11%)
    4 / 56 (7.14%)
         occurrences all number
    2
    4
    Xerosis
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 56 (1.79%)
         occurrences all number
    5
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 90 (5.56%)
    7 / 56 (12.50%)
         occurrences all number
    5
    10
    Confusional state
         subjects affected / exposed
    0 / 90 (0.00%)
    4 / 56 (7.14%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    6 / 90 (6.67%)
    2 / 56 (3.57%)
         occurrences all number
    6
    3
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    22 / 90 (24.44%)
    8 / 56 (14.29%)
         occurrences all number
    26
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 90 (6.67%)
    3 / 56 (5.36%)
         occurrences all number
    10
    4
    Blood bilirubin increased
         subjects affected / exposed
    6 / 90 (6.67%)
    4 / 56 (7.14%)
         occurrences all number
    10
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 90 (6.67%)
    5 / 56 (8.93%)
         occurrences all number
    8
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 90 (5.56%)
    2 / 56 (3.57%)
         occurrences all number
    11
    2
    Weight decreased
         subjects affected / exposed
    6 / 90 (6.67%)
    6 / 56 (10.71%)
         occurrences all number
    6
    6
    Blood creatinine increased
         subjects affected / exposed
    5 / 90 (5.56%)
    3 / 56 (5.36%)
         occurrences all number
    7
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 90 (8.89%)
    6 / 56 (10.71%)
         occurrences all number
    8
    6
    Dyspnoea
         subjects affected / exposed
    5 / 90 (5.56%)
    3 / 56 (5.36%)
         occurrences all number
    7
    3
    Oropharyngeal pain
         subjects affected / exposed
    3 / 90 (3.33%)
    3 / 56 (5.36%)
         occurrences all number
    3
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 90 (7.78%)
    6 / 56 (10.71%)
         occurrences all number
    8
    7
    Neutropenia
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 56 (5.36%)
         occurrences all number
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 90 (17.78%)
    8 / 56 (14.29%)
         occurrences all number
    20
    9
    Paraesthesia
         subjects affected / exposed
    9 / 90 (10.00%)
    2 / 56 (3.57%)
         occurrences all number
    9
    2
    Dysgeusia
         subjects affected / exposed
    6 / 90 (6.67%)
    4 / 56 (7.14%)
         occurrences all number
    6
    4
    Seizure
         subjects affected / exposed
    2 / 90 (2.22%)
    6 / 56 (10.71%)
         occurrences all number
    2
    6
    Dizziness
         subjects affected / exposed
    3 / 90 (3.33%)
    3 / 56 (5.36%)
         occurrences all number
    3
    3
    Balance disorder
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    0
    5
    Tremor
         subjects affected / exposed
    0 / 90 (0.00%)
    5 / 56 (8.93%)
         occurrences all number
    0
    5
    Eye disorders
    Photophobia
         subjects affected / exposed
    2 / 90 (2.22%)
    3 / 56 (5.36%)
         occurrences all number
    2
    3
    Visual impairment
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 56 (5.36%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 90 (16.67%)
    14 / 56 (25.00%)
         occurrences all number
    19
    17
    Diarrhoea
         subjects affected / exposed
    14 / 90 (15.56%)
    10 / 56 (17.86%)
         occurrences all number
    16
    13
    Vomiting
         subjects affected / exposed
    8 / 90 (8.89%)
    8 / 56 (14.29%)
         occurrences all number
    9
    13
    Constipation
         subjects affected / exposed
    5 / 90 (5.56%)
    2 / 56 (3.57%)
         occurrences all number
    6
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 56 (5.36%)
         occurrences all number
    1
    3
    Dyspepsia
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    0
    3
    Faecal incontinence
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Hyperkeratosis
         subjects affected / exposed
    28 / 90 (31.11%)
    13 / 56 (23.21%)
         occurrences all number
    39
    16
    Rash
         subjects affected / exposed
    29 / 90 (32.22%)
    17 / 56 (30.36%)
         occurrences all number
    36
    19
    Photosensitivity reaction
         subjects affected / exposed
    18 / 90 (20.00%)
    17 / 56 (30.36%)
         occurrences all number
    22
    19
    Erythema
         subjects affected / exposed
    13 / 90 (14.44%)
    9 / 56 (16.07%)
         occurrences all number
    20
    13
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 90 (7.78%)
    8 / 56 (14.29%)
         occurrences all number
    19
    12
    Alopecia
         subjects affected / exposed
    16 / 90 (17.78%)
    13 / 56 (23.21%)
         occurrences all number
    16
    13
    Pruritus
         subjects affected / exposed
    16 / 90 (17.78%)
    6 / 56 (10.71%)
         occurrences all number
    20
    6
    Dry skin
         subjects affected / exposed
    11 / 90 (12.22%)
    10 / 56 (17.86%)
         occurrences all number
    12
    10
    Actinic keratosis
         subjects affected / exposed
    6 / 90 (6.67%)
    5 / 56 (8.93%)
         occurrences all number
    8
    5
    Keratosis pilaris
         subjects affected / exposed
    9 / 90 (10.00%)
    2 / 56 (3.57%)
         occurrences all number
    9
    2
    Dermal cyst
         subjects affected / exposed
    4 / 90 (4.44%)
    3 / 56 (5.36%)
         occurrences all number
    5
    3
    Rash follicular
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 56 (5.36%)
         occurrences all number
    1
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    31 / 90 (34.44%)
    23 / 56 (41.07%)
         occurrences all number
    44
    30
    Pain in extremity
         subjects affected / exposed
    8 / 90 (8.89%)
    5 / 56 (8.93%)
         occurrences all number
    9
    6
    Myalgia
         subjects affected / exposed
    8 / 90 (8.89%)
    5 / 56 (8.93%)
         occurrences all number
    9
    5
    Musculoskeletal pain
         subjects affected / exposed
    6 / 90 (6.67%)
    3 / 56 (5.36%)
         occurrences all number
    6
    6
    Back pain
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 56 (1.79%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 90 (8.89%)
    3 / 56 (5.36%)
         occurrences all number
    8
    3
    Hypokalaemia
         subjects affected / exposed
    2 / 90 (2.22%)
    5 / 56 (8.93%)
         occurrences all number
    2
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 90 (5.56%)
    4 / 56 (7.14%)
         occurrences all number
    5
    5
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 56 (7.14%)
         occurrences all number
    2
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 56 (7.14%)
         occurrences all number
    2
    4
    Conjunctivitis
         subjects affected / exposed
    2 / 90 (2.22%)
    3 / 56 (5.36%)
         occurrences all number
    2
    3
    Folliculitis
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2012
    • The start-of-screening date was taken as date on which first archival tumor tissue sample was sent (collected by courier) to the central testing laboratory for BRAF mutation testing EXCEPT when a study procedure is performed prior to sending tumor sample to laboratory (e.g., if a new tumor biopsy sample must be taken from subject). • Monitoring of any possible additional cancerous growths and determination of their type(s) was added to the study procedures during the screening period, treatment period, treatment discontinuation, and follow-up visit. The ICF also was updated with this information. • A clarification was added denoting that only a protocol violation that endangers subject safety will mandate discontinuation of study treatment. • An additional subgroup analysis within previously treated cohort for subjects with leptomeningeal involvement versus subjects with no leptomeningeal involvement in the previously treated cohort was planned. • Exclusion criterion 5 was changed to align with ongoing vemurafenib studies and based on recommendation from the Steering Committee. • The follow-up of chest CT for evaluation of non-cuSCC was conservatively increased from 3 to 6 months. • A statement was added to clarify that cuSCC should be reported as an SAE instead of an AE of special interest to ensure its reporting to the Health Authorities in an appropriate and timely manner. • A statement was added that available biopsies from all suspicious lesions should be sent to the study-designated central pathology laboratory to ensure available specimen blocks from any suspicious lesions (including keratoacanthoma/cuSCC or new primary melanoma) are sent to a designated central pathology laboratory for the confirmation of diagnosis. • A clarification on safety reporting due to progression of the underlying malignancy was added, stating that, “An SAE with outcome death solely due to progression of the underlying malignancy does not need to be reported as an SAE".

    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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