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    Clinical Trial Results:
    The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer): A Multinational, Randomized, Open-Label Phase 3 Study of MEK162 vs. Physician’s Choice Chemotherapy in Patients with Recurrent or Persistent Low-grade Serous Carcinomas of the Ovary, Fallopian Tube or Primary Peritoneum

    Summary
    EudraCT number
    		 2013-000277-72
    Trial protocol
    		 HU   GB   AT   BE   IT   CZ   DE   IE   FI   NO   NL   SE   PL   ES   DK  
    Global end of trial date
    23 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jun 2023
    First version publication date
    18 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C4211003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01849874
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MILO: ARRAY-162-311
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    23 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Demonstrate superior efficacy (increased PFS) of binimetinib vs. physician’s choice of selected chemotherapies (liposomal doxorubicin, paclitaxel and topotecan).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    United States: 99
    Worldwide total number of subjects
    333
    EEA total number of subjects
    147
    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)
    263
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 333
    Number of subjects completed
    		 333

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MEK162
    Arm description
    		 Subjects received an oral dose of 45 milligram (mg) of MEK162 tablets (3 tablets of 15 mg) twice daily for each 28-day treatment cycle until disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, lost to follow-up or death, whichever occurred first. Subjects were followed up to 30 days after last dose of study intervention.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEK162 15 mg film-coated tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg, oral

    Arm title
    		 Physician's Choice
    Arm description
    		 Subjects received chemotherapies as per treating physician’s choice in accordance to the institutional standard of care. Subjects received one of the three intravenous (IV) infusion therapies: Liposomal doxorubicin 40 milligram per meter square (mg/m^2) on Day 1 of each 28-day cycle or Paclitaxel 80 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle or, Topotecan 1.25 mg/m^2 on Days 1 through 5 of each 21-day cycle. Subjects were followed up to 30 days after last dose of study intervention.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Liposomal doxorubicin 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg, IV

    Investigational medicinal product name
    Topotecan 4 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg, IV

    Investigational medicinal product name
    Paclitaxel 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg, IV

    Number of subjects in period 1
    		MEK162 Physician's Choice
    Started
    227
    106
    Treated
    227
    106
    Completed
    0
    0
    Not completed
    227
    106
         Adverse event, serious fatal
    89
    40
         Consent withdrawn by subject
    16
    11
         Physician decision
    7
    1
         Completed as per protocol amendment 6
    3
    -
         Not specified
    16
    4
         Study Termination By Sponsor
    93
    48
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MEK162
    Reporting group description
    		 Subjects received an oral dose of 45 milligram (mg) of MEK162 tablets (3 tablets of 15 mg) twice daily for each 28-day treatment cycle until disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, lost to follow-up or death, whichever occurred first. Subjects were followed up to 30 days after last dose of study intervention.

    Reporting group title
    Physician's Choice
    Reporting group description
    		 Subjects received chemotherapies as per treating physician’s choice in accordance to the institutional standard of care. Subjects received one of the three intravenous (IV) infusion therapies: Liposomal doxorubicin 40 milligram per meter square (mg/m^2) on Day 1 of each 28-day cycle or Paclitaxel 80 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle or, Topotecan 1.25 mg/m^2 on Days 1 through 5 of each 21-day cycle. Subjects were followed up to 30 days after last dose of study intervention.

    Reporting group values
    		 MEK162 Physician's Choice Total
    Number of subjects
    		 227 106 333
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 173 90 263
        From 65-84 years
    		 54 16 70
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 52.26 ( 14.64 ) 50.12 ( 13.35 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 227 106 333
        Male
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 18 9 27
        Not Hispanic or Latino
    		 200 95 295
        Unknown or Not Reported
    		 9 2 11

    End points

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    End points reporting groups
    Reporting group title
    MEK162
    Reporting group description
    		 Subjects received an oral dose of 45 milligram (mg) of MEK162 tablets (3 tablets of 15 mg) twice daily for each 28-day treatment cycle until disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, lost to follow-up or death, whichever occurred first. Subjects were followed up to 30 days after last dose of study intervention.

    Reporting group title
    Physician's Choice
    Reporting group description
    		 Subjects received chemotherapies as per treating physician’s choice in accordance to the institutional standard of care. Subjects received one of the three intravenous (IV) infusion therapies: Liposomal doxorubicin 40 milligram per meter square (mg/m^2) on Day 1 of each 28-day cycle or Paclitaxel 80 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle or, Topotecan 1.25 mg/m^2 on Days 1 through 5 of each 21-day cycle. Subjects were followed up to 30 days after last dose of study intervention.

    Subject analysis set title
    MEK162
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized into MEK162 arm.

    Subject analysis set title
    Physician's Choice
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized into Physician's Choice arm.

    Primary: Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) [1]
    End point description
    PFS was defined as the time from randomization to the earliest documented disease progression date or death due to any cause whichever occurred first. Disease progression was defined as at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including Baseline) and an absolute increase of greater than or equal to (>=) 5 millimeter (mm). Appearance of new lesions >=10 mm in diameter also constituted PD. If a subject did not have an event at the time of the analysis cutoff or at the start of any new therapy, PFS was censored at the date of last adequate tumor assessment. The full analysis set included all randomized subjects. Here "Number of Subjects Analyzed" included all randomized subjects as of primary completion date (PCD). Updated efficacy data were not analyzed at study completion date due to study early termination.
    End point type
    Primary
    End point timeframe
    From randomization until documented progressive disease (PD) or death, whichever occurred first, for censored subjects at the date of last adequate tumor assessment (up to 24 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Analysis was planned only for the arms specified.
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    201
    102
    Units: months
        median (confidence interval 95%)
    9.10 (7.29 to 11.30)
    10.58 (9.20 to 14.52)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. Subjects who were alive at the data cutoff date were censored for overall survival at their last contact date. The full analysis set included all randomized subjects. Here "Number of Subjects Analyzed" included all randomized subjects as of PCD. Updated efficacy data were not analyzed at study completion date due to study early termination.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of death, for censored subjects at their last contact date (up to 24 months)
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    201 [2]
    102 [3]
    Units: months
        median (confidence interval 95%)
    25.33 (18.46 to 999999)
    20.83 (17.45 to 999999)
    Notes
    [2] - Upper limit of 95% CI was not estimable due to low number of subjects with events.
    [3] - Upper limit of 95% CI was not estimable due to low number of subjects with events.
    No statistical analyses for this end point

    Secondary: Objective Response Rate per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (RECIST V1.1)

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    End point title
    		 Objective Response Rate per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (RECIST V1.1)
    End point description
    ORR was defined as the percentage of subjects achieving an overall best response of complete response (CR) or partial response (PR) (responders). CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (<) 10 mm, PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the Baseline sum of diameters. Non-target lesions must be non-progressive disease. Analysis population included all randomized subjects with measurable disease at baseline per BICR. Here "Number of Subjects Analyzed" included all randomized subjects with measurable disease at baseline per BICR as of PCD. Updated efficacy data were not analyzed at study completion date due to study early termination.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression or death (up to 24 months)
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    198
    101
    Units: percentage of subjects
    16
    13
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    Disease control was defined as a best response of CR or PR, or stable disease (SD) documented at Week 24 or later. CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures <10 mm, and PR is defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the Baseline sum of diameters. Non-target lesions must be non-progressive disease. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters on study. Due to the lack of follow-up data at the time of PCD, data reported for this outcome measure was not collected as of PCD. Updated efficacy data was not analyzed at study completion date due to study early termination.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: percentage of subjects
    Notes
    [4] - Due to the lack of follow up data at the time of data cutoff, data was not collected.
    [5] - Due to the lack of follow up data at the time of data cutoff, data was not collected.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was defined as the time from first radiographic evidence of response to the earliest documented progression date or death due to any cause, and was calculated on responders only. Responders with no PD or death date or subsequent anticancer therapy by the data cutoff date, were censored for DOR at their last radiological assessment. Responders who received subsequent anticancer therapy prior to PD or death were censored at their last radiological assessment prior to initiation of subsequent anticancer therapy. Analysis population included all randomized subjects with measurable disease at baseline per BICR. Here, 'Number of Subjects Analyzed' signifies number of subjects evaluable for this outcome measure as of PCD. Updated efficacy data was not analyzed at study completion date due to study early termination.
    End point type
    Secondary
    End point timeframe
    From the first radiographic evidence of response to the first documentation of PD or death, for censored subjects at their last radiological assessment (up to 24 months)
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    23
    8
    Units: months
        median (full range (min-max))
    8.05 (0.03 to 11.99)
    6.67 (0.03 to 9.69)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study intervention without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The safety set included all subjects who received at least 1 dose of study intervention and had at least 1 post-treatment assessment, including death.
    End point type
    Secondary
    End point timeframe
    From the first dose of study intervention until 30 days after the last dose (up to 9 years)
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    227
    106
    Units: subjects
        AEs
    227
    105
        SAEs
    126
    31
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift Greater Than or Equal to Grade 3 From Baseline in Laboratory Parameter Values Based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03

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    End point title
    		 Number of Subjects With Shift Greater Than or Equal to Grade 3 From Baseline in Laboratory Parameter Values Based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03
    End point description
    Number of subjects with shifts from normal Baseline (Grade 0) to abnormal post-baseline on-study (shift to greater than or equal to Grade 3) were reported as per NCI-CTCAE, V4.03 from Grade 1 to 5. Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Shifts in lab parameter from Grade 0 to 3, Grade 0 to 4 and Grade 0 to Low 3 and 4 and Grade 0 to High 3 and 4 (for parameters total hemoglobin, lymphocytes, white blood cells, calcium, magnesium, potassium, and sodium) were reported. The safety set included all subjects who received at least 1 dose of study intervention and had at least 1 post-treatment assessment, including death.
    End point type
    Secondary
    End point timeframe
    From the first dose of study intervention until 30 days after the last dose (up to 9 years)
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    227
    106
    Units: subjects
        International Normalized Ratio: Grade 0 to 3
    0
    0
        International Normalized Ratio: Grade 0 to 4
    0
    0
        Neutrophils: Grade 0 to 3
    3
    7
        Neutrophils: Grade 0 to 4
    0
    1
        Platelet Count: Grade 0 to 3
    0
    0
        Platelet Count: Grade 0 to 4
    1
    0
        Partial Thromboplastin Time: Grade 0 to 3
    4
    2
        Partial Thromboplastin Time: Grade 0 to 4
    0
    0
        Total Hemoglobin: Grade 0 to Low 3
    10
    2
        Total Hemoglobin: Grade 0 to Low 4
    0
    0
        Total Hemoglobin: Grade 0 to High 3
    0
    0
        Total Hemoglobin: Grade 0 to High 4
    0
    0
        Lymphocytes: Grade 0 to Low 3
    8
    3
        Lymphocytes: Grade 0 to Low 4
    1
    0
        Lymphocytes: Grade 0 to High 3
    0
    0
        Lymphocytes: Grade 0 to High 4
    0
    0
        White Blood Cells: Grade 0 to Low 3
    0
    1
        White Blood Cells: Grade 0 to Low 4
    0
    1
        White Blood Cells: Grade 0 to High 3
    0
    0
        White Blood Cells: Grade 0 to High 4
    0
    0
        Albumin: Grade 0 to 3
    1
    1
        Albumin: Grade 0 to 4
    0
    0
        Alkaline Phosphatase: Grade 0 to 3
    4
    1
        Alkaline Phosphatase: Grade 0 to 4
    0
    0
        ALT/SGPT: Grade 0 to 3
    7
    1
        ALT/SGPT: Grade 0 to 4
    0
    0
        AST/SGOT: Grade 0 to 3
    7
    1
        AST/SGOT: Grade 0 to 4
    0
    0
        Creatine Kinase: Grade 0 to 3
    52
    0
        Creatine Kinase: Grade 0 to 4
    12
    0
        Serum Creatinine: Grade 0 to 3
    1
    0
        Serum Creatinine: Grade 0 to 4
    0
    0
        Total Bilirubin: Grade 0 to 3
    1
    0
        Total Bilirubin: Grade 0 to 4
    0
    0
        Calcium: Grade 0 to Low 3
    0
    1
        Calcium: Grade 0 to Low 4
    1
    1
        Calcium: Grade 0 to High 3
    1
    0
        Calcium: Grade 0 to High 4
    0
    0
        Magnesium: Grade 0 to Low 3
    2
    1
        Magnesium: Grade 0 to Low 4
    0
    0
        Magnesium: Grade 0 to High 3
    1
    0
        Magnesium: Grade 0 to High 4
    0
    0
        Potassium: Grade 0 to Low 3
    10
    4
        Potassium: Grade 0 to Low 4
    0
    0
        Potassium: Grade 0 to High 3
    3
    2
        Potassium: Grade 0 to High 4
    0
    0
        Sodium: Grade 0 to Low 3
    5
    2
        Sodium: Grade 0 to Low 4
    1
    0
        Sodium: Grade 0 to High 3
    3
    0
        Sodium: Grade 0 to High 4
    1
    0
    No statistical analyses for this end point

    Secondary: Assessment by the Quality of Life (QOL) Questionnaires European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30

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    End point title
    		 Assessment by the Quality of Life (QOL) Questionnaires European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
    End point description
    The global health status/QOL scale score of the QLQ-C30 was identified as the primary patient-reported outcome variable of interest. Physical functioning, emotional functioning and social functioning scale scores of the QLQ-C30 were considered as secondary. Higher scores for a functional or global QOL scale (Global health status/QOL, Physical functioning, Emotional functioning, and Social functioning) indicate higher QOL. The full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Screening, every 8 weeks from randomization date to Week 72, treatment discontinuation visit, 30-day safety follow-up visit
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Scale (0-100)
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [6] - Patient-reported outcome data were not analyzed due to the early stopping of the trial.
    [7] - Patient-reported outcome data were not analyzed due to the early stopping of the trial.
    No statistical analyses for this end point

    Secondary: Assessment by the QOL Questionnaires EORTC QLQ-OV28

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    End point title
    		 Assessment by the QOL Questionnaires EORTC QLQ-OV28
    End point description
    Analyses on the QLQ-OV28 was considered as secondary patient-reported outcome variable of interest. The parameters included Abdominal/gastrointestinal (GI), Peripheral neuropathy, Hormonal, Body image, Attitude to disease/treatment, Chemotherapy side effects, Other, and Sexuality. Higher scores for Sexuality indicate higher QOL. For all others, higher scores indicate lower QOL. The full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Screening, every 8 weeks from randomization date to Week 72, treatment discontinuation visit, 30-day safety follow-up visit
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Scale (0-100)
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [8] - Patient-reported outcome data were not analyzed due to the early stopping of the trial.
    [9] - Patient-reported outcome data were not analyzed due to the early stopping of the trial.
    No statistical analyses for this end point

    Secondary: Assessment by the QOL Questionnaires FACT/GOG-NTX

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    End point title
    		 Assessment by the QOL Questionnaires FACT/GOG-NTX
    End point description
    Analyses on the FACT/GOG-NTX was considered as secondary patient-reported outcome variable of interest. The parameters included Physical well-being, Social well-being, Emotional well-being, Functional well-being, Neurotoxicity subscale, and Trial outcome index. Higher scores indicate higher QOL. The full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Screening, every 8 weeks from randomization date to Week 72, treatment discontinuation visit, 30-day safety follow-up visit
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Scale (0-100)
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [10] - Patient-reported outcome data were not analyzed due to the early stopping of the trial.
    [11] - Patient-reported outcome data were not analyzed due to the early stopping of the trial.
    No statistical analyses for this end point

    Secondary: Plasma Concentration-time Profiles of MEK162

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    End point title
    		 Plasma Concentration-time Profiles of MEK162
    End point description
    Plasma concentrations of MEK162 were determined using validated assays. The pharmacokinetics (PK) set consisted of all subjects who received at least 1 dose of MEK162 and had at least 1 postdose PK blood collection with associated bioanalytical results.
    End point type
    Secondary
    End point timeframe
    Predose and 2 hours ± 10 minutes postdose on Study Days 1, 57, and 113.
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: nanograms per millilitre (ng/mL)
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [12] - Due to the study early termination, PK data were not analyzed due to the small number of subjects.
    [13] - Due to the study early termination, PK data were not analyzed due to the small number of subjects.
    No statistical analyses for this end point

    Secondary: Model-based PK Parameters of MEK162

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    End point title
    		 Model-based PK Parameters of MEK162
    End point description
    No noncompartmental PK parameters were estimated due to sparse sampling in this study. PK parameters were determined for MEK162 as appropriate using a model-based approach to determine appropriate model-based PK parameters and variability, if deemed appropriate. The PK set consisted of all subjects who received at least 1 dose of MEK162 and had at least 1 postdose PK blood collection with associated bioanalytical results.
    End point type
    Secondary
    End point timeframe
    Predose and 2 hours ± 10 minutes postdose on Study Days 1, 57, and 113.
    End point values
    		 MEK162 Physician's Choice
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [14] - Due to the study early termination, PK data were not analyzed due to the small number of subjects.
    [15] - Due to the study early termination, PK data were not analyzed due to the small number of subjects.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study intervention until 30 days after the last dose (up to 9 years)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Physician's Choice
    Reporting group description
    		 Subjects received chemotherapies as per treating physician’s choice in accordance to the institutional standard of care. Subjects received one of the three intravenous (IV) infusion therapies: Liposomal doxorubicin 40 milligram per meter square (mg/m^2) on Day 1 of each 28-day cycle or Paclitaxel 80 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle or, Topotecan 1.25 mg/m^2 on Days 1 through 5 of each 21-day cycle. Subjects were followed up to 30 days after last dose of study intervention.

    Reporting group title
    MEK162
    Reporting group description
    		 Subjects received an oral dose of 45 milligram (mg) of MEK162 tablets (3 tablets of 15 mg) twice daily for each 28-day treatment cycle until disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, lost to follow-up or death, whichever occurred first. Subjects were followed up to 30 days after last dose of study intervention.

    Serious adverse events
    		 Physician's Choice MEK162
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 106 (29.25%)
    126 / 227 (55.51%)
         number of deaths (all causes)
    28
    92
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         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
    Fatigue
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 106 (0.94%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Asthenia
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 106 (0.94%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pain
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 106 (0.94%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    3 / 106 (2.83%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 106 (1.89%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis allergic
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic reaction
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 106 (0.00%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration pleural cavity
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured coccyx
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dropped head syndrome
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 106 (1.89%)
    9 / 227 (3.96%)
         occurrences causally related to treatment / all
    2 / 2
    15 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 106 (0.00%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choroiditis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal oedema
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    8 / 106 (7.55%)
    12 / 227 (5.29%)
         occurrences causally related to treatment / all
    0 / 15
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 106 (1.89%)
    16 / 227 (7.05%)
         occurrences causally related to treatment / all
    2 / 3
    8 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 106 (3.77%)
    15 / 227 (6.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 19
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 106 (0.94%)
    7 / 227 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 106 (0.00%)
    10 / 227 (4.41%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 106 (1.89%)
    8 / 227 (3.52%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    4 / 106 (3.77%)
    7 / 227 (3.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    0 / 106 (0.00%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 106 (0.00%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 106 (0.94%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 106 (1.89%)
    7 / 227 (3.08%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         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 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis ulcerative
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal ulcer
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal fistula
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         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
    Rash maculo-papular
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 106 (0.00%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 106 (0.94%)
    9 / 227 (3.96%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Urinary tract infection
         subjects affected / exposed
    1 / 106 (0.94%)
    8 / 227 (3.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 106 (0.00%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cystitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 106 (0.00%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         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 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal bacteraemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 106 (0.00%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 227 (0.44%)
         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
    		 Physician's Choice MEK162
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 106 (99.06%)
    226 / 227 (99.56%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    3 / 106 (2.83%)
    15 / 227 (6.61%)
         occurrences all number
    3
    15
    Hypertension
         subjects affected / exposed
    4 / 106 (3.77%)
    46 / 227 (20.26%)
         occurrences all number
    9
    135
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 106 (6.60%)
    11 / 227 (4.85%)
         occurrences all number
    7
    12
    Chills
         subjects affected / exposed
    5 / 106 (4.72%)
    16 / 227 (7.05%)
         occurrences all number
    6
    21
    Face oedema
         subjects affected / exposed
    1 / 106 (0.94%)
    28 / 227 (12.33%)
         occurrences all number
    1
    40
    Asthenia
         subjects affected / exposed
    7 / 106 (6.60%)
    29 / 227 (12.78%)
         occurrences all number
    11
    64
    Pyrexia
         subjects affected / exposed
    17 / 106 (16.04%)
    42 / 227 (18.50%)
         occurrences all number
    26
    59
    Oedema peripheral
         subjects affected / exposed
    16 / 106 (15.09%)
    120 / 227 (52.86%)
         occurrences all number
    19
    238
    Fatigue
         subjects affected / exposed
    54 / 106 (50.94%)
    120 / 227 (52.86%)
         occurrences all number
    100
    232
    Pain
         subjects affected / exposed
    2 / 106 (1.89%)
    14 / 227 (6.17%)
         occurrences all number
    2
    17
    Oedema
         subjects affected / exposed
    2 / 106 (1.89%)
    15 / 227 (6.61%)
         occurrences all number
    7
    23
    Malaise
         subjects affected / exposed
    4 / 106 (3.77%)
    13 / 227 (5.73%)
         occurrences all number
    4
    15
    Influenza like illness
         subjects affected / exposed
    2 / 106 (1.89%)
    12 / 227 (5.29%)
         occurrences all number
    3
    16
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    17 / 106 (16.04%)
    45 / 227 (19.82%)
         occurrences all number
    29
    75
    Cough
         subjects affected / exposed
    23 / 106 (21.70%)
    26 / 227 (11.45%)
         occurrences all number
    39
    35
    Oropharyngeal pain
         subjects affected / exposed
    7 / 106 (6.60%)
    24 / 227 (10.57%)
         occurrences all number
    8
    34
    Epistaxis
         subjects affected / exposed
    4 / 106 (3.77%)
    17 / 227 (7.49%)
         occurrences all number
    4
    22
    Dysphonia
         subjects affected / exposed
    2 / 106 (1.89%)
    13 / 227 (5.73%)
         occurrences all number
    2
    14
    Dyspnoea exertional
         subjects affected / exposed
    0 / 106 (0.00%)
    12 / 227 (5.29%)
         occurrences all number
    0
    14
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 106 (2.83%)
    18 / 227 (7.93%)
         occurrences all number
    3
    22
    Anxiety
         subjects affected / exposed
    6 / 106 (5.66%)
    21 / 227 (9.25%)
         occurrences all number
    11
    28
    Insomnia
         subjects affected / exposed
    12 / 106 (11.32%)
    32 / 227 (14.10%)
         occurrences all number
    20
    37
    Investigations
    Weight decreased
         subjects affected / exposed
    12 / 106 (11.32%)
    15 / 227 (6.61%)
         occurrences all number
    19
    20
    Weight increased
         subjects affected / exposed
    3 / 106 (2.83%)
    18 / 227 (7.93%)
         occurrences all number
    4
    31
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 106 (3.77%)
    28 / 227 (12.33%)
         occurrences all number
    4
    88
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 106 (1.89%)
    33 / 227 (14.54%)
         occurrences all number
    2
    84
    Ejection fraction decreased
         subjects affected / exposed
    11 / 106 (10.38%)
    66 / 227 (29.07%)
         occurrences all number
    15
    103
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 106 (1.89%)
    120 / 227 (52.86%)
         occurrences all number
    3
    644
    Neutrophil count decreased
         subjects affected / exposed
    9 / 106 (8.49%)
    6 / 227 (2.64%)
         occurrences all number
    26
    13
    Blood creatinine increased
         subjects affected / exposed
    2 / 106 (1.89%)
    14 / 227 (6.17%)
         occurrences all number
    2
    25
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 106 (20.75%)
    48 / 227 (21.15%)
         occurrences all number
    33
    75
    Dysgeusia
         subjects affected / exposed
    12 / 106 (11.32%)
    28 / 227 (12.33%)
         occurrences all number
    15
    41
    Dizziness
         subjects affected / exposed
    9 / 106 (8.49%)
    33 / 227 (14.54%)
         occurrences all number
    9
    44
    Neuropathy peripheral
         subjects affected / exposed
    14 / 106 (13.21%)
    20 / 227 (8.81%)
         occurrences all number
    20
    24
    Paraesthesia
         subjects affected / exposed
    4 / 106 (3.77%)
    13 / 227 (5.73%)
         occurrences all number
    5
    18
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 106 (7.55%)
    4 / 227 (1.76%)
         occurrences all number
    10
    5
    Memory impairment
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 227 (1.32%)
         occurrences all number
    6
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    14 / 106 (13.21%)
    5 / 227 (2.20%)
         occurrences all number
    27
    11
    Anaemia
         subjects affected / exposed
    21 / 106 (19.81%)
    38 / 227 (16.74%)
         occurrences all number
    72
    135
    Eye disorders
    Vision blurred
         subjects affected / exposed
    8 / 106 (7.55%)
    41 / 227 (18.06%)
         occurrences all number
    9
    51
    Retinal detachment
         subjects affected / exposed
    0 / 106 (0.00%)
    37 / 227 (16.30%)
         occurrences all number
    0
    59
    Dry eye
         subjects affected / exposed
    7 / 106 (6.60%)
    25 / 227 (11.01%)
         occurrences all number
    7
    29
    Eyelid oedema
         subjects affected / exposed
    0 / 106 (0.00%)
    16 / 227 (7.05%)
         occurrences all number
    0
    23
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 106 (0.00%)
    15 / 227 (6.61%)
         occurrences all number
    0
    19
    Periorbital oedema
         subjects affected / exposed
    1 / 106 (0.94%)
    17 / 227 (7.49%)
         occurrences all number
    1
    21
    Retinal disorder
         subjects affected / exposed
    0 / 106 (0.00%)
    12 / 227 (5.29%)
         occurrences all number
    0
    29
    Conjunctivitis
         subjects affected / exposed
    3 / 106 (2.83%)
    12 / 227 (5.29%)
         occurrences all number
    3
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    39 / 106 (36.79%)
    160 / 227 (70.48%)
         occurrences all number
    59
    369
    Vomiting
         subjects affected / exposed
    32 / 106 (30.19%)
    129 / 227 (56.83%)
         occurrences all number
    58
    286
    Abdominal pain
         subjects affected / exposed
    27 / 106 (25.47%)
    77 / 227 (33.92%)
         occurrences all number
    50
    139
    Constipation
         subjects affected / exposed
    31 / 106 (29.25%)
    66 / 227 (29.07%)
         occurrences all number
    49
    91
    Nausea
         subjects affected / exposed
    55 / 106 (51.89%)
    135 / 227 (59.47%)
         occurrences all number
    98
    263
    Abdominal pain upper
         subjects affected / exposed
    6 / 106 (5.66%)
    23 / 227 (10.13%)
         occurrences all number
    8
    33
    Abdominal distension
         subjects affected / exposed
    6 / 106 (5.66%)
    25 / 227 (11.01%)
         occurrences all number
    9
    32
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 106 (6.60%)
    23 / 227 (10.13%)
         occurrences all number
    9
    25
    Dry mouth
         subjects affected / exposed
    9 / 106 (8.49%)
    37 / 227 (16.30%)
         occurrences all number
    13
    39
    Dyspepsia
         subjects affected / exposed
    11 / 106 (10.38%)
    32 / 227 (14.10%)
         occurrences all number
    13
    40
    Stomatitis
         subjects affected / exposed
    35 / 106 (33.02%)
    54 / 227 (23.79%)
         occurrences all number
    77
    88
    Ascites
         subjects affected / exposed
    6 / 106 (5.66%)
    15 / 227 (6.61%)
         occurrences all number
    9
    24
    Rectal haemorrhage
         subjects affected / exposed
    6 / 106 (5.66%)
    10 / 227 (4.41%)
         occurrences all number
    6
    14
    Flatulence
         subjects affected / exposed
    2 / 106 (1.89%)
    17 / 227 (7.49%)
         occurrences all number
    3
    18
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    6 / 106 (5.66%)
    110 / 227 (48.46%)
         occurrences all number
    8
    267
    Alopecia
         subjects affected / exposed
    28 / 106 (26.42%)
    57 / 227 (25.11%)
         occurrences all number
    38
    63
    Rash maculo-papular
         subjects affected / exposed
    17 / 106 (16.04%)
    57 / 227 (25.11%)
         occurrences all number
    34
    140
    Dry skin
         subjects affected / exposed
    14 / 106 (13.21%)
    77 / 227 (33.92%)
         occurrences all number
    17
    110
    Skin fissures
         subjects affected / exposed
    1 / 106 (0.94%)
    34 / 227 (14.98%)
         occurrences all number
    1
    65
    Rash
         subjects affected / exposed
    10 / 106 (9.43%)
    36 / 227 (15.86%)
         occurrences all number
    15
    51
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    36 / 106 (33.96%)
    11 / 227 (4.85%)
         occurrences all number
    104
    27
    Pruritus
         subjects affected / exposed
    11 / 106 (10.38%)
    51 / 227 (22.47%)
         occurrences all number
    16
    78
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 106 (0.94%)
    15 / 227 (6.61%)
         occurrences all number
    1
    21
    Dysuria
         subjects affected / exposed
    4 / 106 (3.77%)
    16 / 227 (7.05%)
         occurrences all number
    4
    16
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 106 (0.94%)
    20 / 227 (8.81%)
         occurrences all number
    3
    29
    Muscular weakness
         subjects affected / exposed
    3 / 106 (2.83%)
    21 / 227 (9.25%)
         occurrences all number
    3
    30
    Pain in extremity
         subjects affected / exposed
    7 / 106 (6.60%)
    25 / 227 (11.01%)
         occurrences all number
    9
    36
    Arthralgia
         subjects affected / exposed
    8 / 106 (7.55%)
    38 / 227 (16.74%)
         occurrences all number
    11
    50
    Myalgia
         subjects affected / exposed
    14 / 106 (13.21%)
    44 / 227 (19.38%)
         occurrences all number
    15
    75
    Back pain
         subjects affected / exposed
    11 / 106 (10.38%)
    31 / 227 (13.66%)
         occurrences all number
    12
    51
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 106 (12.26%)
    43 / 227 (18.94%)
         occurrences all number
    24
    84
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 106 (7.55%)
    20 / 227 (8.81%)
         occurrences all number
    11
    26
    Rash pustular
         subjects affected / exposed
    2 / 106 (1.89%)
    15 / 227 (6.61%)
         occurrences all number
    4
    24
    Paronychia
         subjects affected / exposed
    2 / 106 (1.89%)
    12 / 227 (5.29%)
         occurrences all number
    2
    22
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    6 / 106 (5.66%)
    23 / 227 (10.13%)
         occurrences all number
    10
    38
    Hypomagnesaemia
         subjects affected / exposed
    6 / 106 (5.66%)
    28 / 227 (12.33%)
         occurrences all number
    13
    56
    Decreased appetite
         subjects affected / exposed
    21 / 106 (19.81%)
    55 / 227 (24.23%)
         occurrences all number
    24
    79
    Dehydration
         subjects affected / exposed
    1 / 106 (0.94%)
    13 / 227 (5.73%)
         occurrences all number
    1
    15
    Hypocalcaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    12 / 227 (5.29%)
         occurrences all number
    1
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2017
    Protocol Amendment 6 was issued on 15 March 2017. Any subjects still receiving binimetinib/MEK162 at the time Protocol Amendment 6 was implemented were allowed to continue at the discretion of the investigator until any treatment discontinuation criteria were met. After treatment withdrawal, all subjects were discontinued from the study after their 30-day Safety Follow-up Visit. No further survival follow up were performed and BICR scans were no longer being collected or read. Crossover from physician’s choice chemotherapy treatment to binimetinib treatment was no longer permitted. Subjects receiving physician’s choice chemotherapy were transitioned to standard of care therapy according to institutional standards.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Apr 2016
    Per recommendation of the Data Monitoring Committee, enrollment into the study was discontinued in April 2016 after the planned interim efficacy analysis showed the hazard ratio for PFS crossed the predefined futility boundary. As such, screening and randomization was discontinued.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Additional efficacy data after PCD and PRO data were not analyzed due to study early termination. PK data were not analyzed due to the small number of subjects. Analysis was not performed due to the low number of subjects in the crossover set.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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