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    Clinical Trial Results:
    A Phase III Randomized, Double-blind, Placebo-controlled Trial Comparing Capecitabine Plus Sorafenib Versus Capecitabine Plus Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer

    Summary
    EudraCT number
    2010-018501-10
    Trial protocol
    BE   DE   GB   AT   CZ   IE   ES   HU   IT   GR   SE  
    Global end of trial date
    20 Oct 2017

    Results information
    Results version number
    v3(current)
    This version publication date
    17 Feb 2019
    First version publication date
    28 May 2015
    Other versions
    v1 , v2
    Version creation reason
    • New data added to full data set
    Control of data.

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY43-9006/12444
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01234337
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    Interim
    Date of interim/final analysis
    12 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy endpoint was to compare the Progression Free Survival (PFS) as assessed by the independent review panel according to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 between the treatment groups (sorafenib in combination of capecitabine versus placebo in combination of capecitabine).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Capecitabine dose was escalated to 1,250 mg/m^2 twice daily if fatigue, dermatologic toxicities, and/or gastrointestinal toxicities in a prior cycle in which the subject received sorafenib at a total daily dose of 800 mg/4 tablets (400 mg/2 tablets, twice daily) were Grade 1 or less as per the common terminology criteria for adverse events version 4.0 (CTCAE v4.0).
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Feb 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    39 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Ireland: 17
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    China: 34
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Japan: 62
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    United States: 43
    Country: Number of subjects enrolled
    Spain: 111
    Country: Number of subjects enrolled
    South Africa: 13
    Worldwide total number of subjects
    537
    EEA total number of subjects
    321
    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)
    447
    From 65 to 84 years
    90
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    At 154 sites in 22 countries, subjects with histologically or cytologically confirmed human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast, and locally advanced or metastatic disease, were screened.

    Pre-assignment
    Screening details
    Of 707 subjects screened, 537 subjects were randomized and 527 subjects received at least 1 dose of study treatment. The reasons for 170 screen failures were adverse event in 21 subjects, disease progression, recurrence or relapse in 2, consent withdrawn in 16, death in 4, and protocol violation in 127 subjects.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Assessor, Subject
    Blinding implementation details
    In compliance with applicable regulations, in the event of a suspected unexpected serious adverse reaction (SUSARs) that was considered to be related to the blinded treatment, the subject’s treatment code was usually unblinded before reporting to the health authorities, ethic committees, and investigators. Unblinding occurred for emergency purposes only.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine
    Arm description
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.
    Arm type
    Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Capecitabine dose was escalated to 1,250 mg/m^2 twice daily if fatigue, dermatologic toxicities, and/or gastrointestinal toxicities in a prior cycle in which the subject received sorafenib at a dose of 800 mg (400 mg twice daily) were Grade 1 or less as per the CTCAE v4.0.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). Sorafenib dose was escalated to 800 mg (400 mg twice daily) in Cycle 2 or beyond if fatigue, dermatologic toxicities, and/or gastrointestinal toxicities in a prior cycle in which the subject received sorafenib at a total daily dose of 600 mg were Grade 1 or less as per CTCAE v4.0.

    Arm title
    Placebo + Capecitabine
    Arm description
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.
    Arm type
    Placebo

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Capecitabine dose was escalated to 1,250 mg/m^2 twice daily if fatigue, dermatologic toxicities, and/or gastrointestinal toxicities in a prior cycle in which the subject received placebo at a dose of 4 tablets (2 tablets twice daily) were Grade 1 or less as per the CTCAE v4.0.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). Placebo dose was escalated to 4 tablets (2 tablets twice daily) in Cycle 2 or beyond if fatigue, dermatologic toxicities, and/or gastrointestinal toxicities in a prior cycle in which the subject received placebo at a total daily dose of 3 tablets were Grade 1 or less as per CTCAE v4.0.

    Number of subjects in period 1
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Started
    266
    271
    Subjects received treatment
    260
    267
    Completed
    0
    0
    Not completed
    266
    271
         Death
    -
    1
         Protocol deviation
    2
    3
         Randomized but not treated
    6
    4
         Disease progression/recurrence/relapse
    181
    223
         Non-compliant with study medication
    3
    2
         Adverse event, non-fatal
    58
    21
         Switch to commercial drug
    -
    1
         Consent withdrawn by subject
    11
    9
         Investi. decision not protocol driven
    5
    6
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine
    Reporting group description
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.

    Reporting group title
    Placebo + Capecitabine
    Reporting group description
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.

    Reporting group values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine Total
    Number of subjects
    266 271 537
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.3 ± 10.2 54.4 ± 10.9 -
    Gender categorical
    Units: Subjects
        Female
    265 268 533
        Male
    1 3 4
    Race
    Units: Subjects
        White
    205 212 417
        Black
    7 4 11
        Asian
    50 50 100
        Hispanic
    4 5 9
    Region
    Other countries in the below category included Argentina, Australia, China, Israel and Japan.
    Units: Subjects
        Europe
    166 168 334
        North America
    23 26 49
        Other
    77 77 154
    Baseline performance status (Eastern Cooperative Oncology Group [ECOG])
    Units: Subjects
        ECOG status=0
    152 161 313
        ECOG status=1
    114 110 224
    Number of prior chemotherapies for metastatic disease
    Assessed by Interactive voice response system (IVRS). Subjects with more than 1 actual number of prior chemotherapies were combined with subjects with 1 prior chemotherapy.
    Units: Subjects
        Prior chemotherapies=0
    114 118 232
        Prior chemotherapies=1
    152 153 305
    Hormone receptor status
    The hormone receptor status was assessed by IVRS, and considered as follows: in case, the tumor expressed estrogen and/or progesterone receptor, the subject was considered to have positive hormone receptor status. Otherwise, if both receptors were not expressed, then subject was considered to have a negative hormone receptor status.
    Units: Subjects
        Negative
    83 84 167
        Positive
    183 187 370
    Visceral disease at baseline
    Units: Subjects
        Missing
    1 1 2
        No
    66 57 123
        Yes
    199 213 412

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine
    Reporting group description
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.

    Reporting group title
    Placebo + Capecitabine
    Reporting group description
    Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (also considered the Intent-to-treat (ITT) analysis set) population (N=537) was defined as all randomized subjects. Subjects were analyzed as randomized, that is, even if a subject was randomized and received no drug or if randomized and initially received incorrect drug prior to switching to correct study drug, these subjects were still analyzed for efficacy under FAS, as randomized.

    Subject analysis set title
    Pharmacokinetic analysis set (PKS)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PKS (N=182) included all subjects with a valid pharmacokinetic profile of capecitabine.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    SAF (N=527) was comprised of all randomized subjects who received at least one dose of study medication (sorafenib, placebo or capecitabine). Subjects were analyzed as treated.

    Primary: Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1

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    End point title
    Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1
    End point description
    PFS was defined as the time from date of randomization to disease progression, radiological or death due to any cause, whichever occurs first. Subjects without progression or death at the time of analysis were censored at their last date of evaluable tumor evaluation. Median and other 95% CIs computed using Kaplan-Meier estimates.
    End point type
    Primary
    End point timeframe
    From randomization of the first subject until approximately 3 years or until disease radiological progression
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    266 [1]
    271 [2]
    Units: days
        median (confidence interval 95%)
    166 (131 to 206)
    165 (126 to 204)
    Notes
    [1] - FAS.
    [2] - FAS.
    Statistical analysis title
    PFS by central review panel
    Statistical analysis description
    PFS was compared using a stratified log-rank test with a one-sided alpha of 0.005, stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease. The hazard ratio (sorafenib + capecitabine / placebo + capecitabine) and its 95 percent (%) confidence intervals (CIs) were calculated using the Cox model, stratified by the above factors.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.405618 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.973
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.779
         upper limit
    1.217
    Notes
    [3] - A Hazard ratio of less than (<) 1 indicates superiority of Sorafenib + Capecitabine over Placebo + Capecitabine.
    [4] - One-sided p-value from log rank test (stratified per randomization as in interactive voice response system [IVRS]).

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last known alive date. Median and other 95% CIs computed using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until approximately 3 years later
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    266 [5]
    271 [6]
    Units: days
        median (confidence interval 95%)
    575 (467 to 645)
    616 (546 to 687)
    Notes
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    Statistical analysis for Overall Survival
    Statistical analysis description
    At the time of PFS final analysis, it was OS interim analysis (IA) with 285 total death events. According to protocol specified O'Brien-Fleming type alpha spending function and 285 death events at IA, the pre-specified alpha for this analysis was 0.0075 (one-sided).The hazard ratio (sorafenib + capecitabine / placebo + capecitabine) and its 95% CIs were calculated using the Cox model, stratified by randomization factors.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.930088 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.195
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.943
         upper limit
    1.513
    Notes
    [7] - A Hazard ratio < 1 indicates superiority of Sorafenib+Capecitabine over Placebo+Capecitabine.
    [8] - One-sided p-value from log rank test (stratified per randomization as in IVRS). OS was compared using a stratified log-rank test, stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease.

    Secondary: Time to Progression (TTP) by Central Review

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    End point title
    Time to Progression (TTP) by Central Review
    End point description
    TTP was defined as the time from date of randomization to disease radiological progression by central review. Subjects without progression at the time of analysis were censored at their last evaluable tumor assessment date. Median and its 95% CIs were computed using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until approximately 3 years later or until disease radiological progression
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    266 [9]
    271 [10]
    Units: days
        median (confidence interval 95%)
    168 (139 to 215)
    165 (127 to 208)
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    TTP by central review panel
    Statistical analysis description
    TTP was compared using a stratified log-rank test with a one-sided alpha of 0.025, stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease. The hazard ratio (sorafenib + capecitabine / placebo + capecitabine) and its 95% CIs were calculated using the Cox model, stratified by the above factors.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.2105 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.723
         upper limit
    1.146
    Notes
    [11] - A Hazard ratio <1 indicates superiority of Sorafenib+Capecitabine over Placebo+Capecitabine.
    [12] - One-sided p-value from log rank test (stratified per randomization as in IVRS).

    Secondary: Objective Response Rate (ORR) by Central Review

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    End point title
    Objective Response Rate (ORR) by Central Review
    End point description
    ORR was defined as the best tumor response (Complete Response [CR] or Partial Response [PR]) observed during treatment or within 30 days after termination of study treatment, assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. CR and PR needed to be confirmed by another scan at least 4 weeks later.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until approximately 3 years later or until disease radiological progression
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    266 [13]
    271 [14]
    Units: percentage (%) of subjects
        number (confidence interval 95%)
    13.5 (9.7 to 18.2)
    15.5 (11.4 to 20.4)
    Notes
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    Statistical Analysis for Objective Tumor Response
    Statistical analysis description
    ORR and 95% CI based on Cochran Mantel-Haenszel Test stratified by region, hormone receptor status, number of previous chemotherapies for metastatic disease. Difference = (Placebo + Capecitabine) - (Sorafenib + Capecitabine).
    Comparison groups
    Placebo + Capecitabine v Sorafenib (Nexavar, BAY43-9006) + Capecitabine
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.257412 [15]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percent Difference
    Point estimate
    1.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.9
         upper limit
    7.77
    Notes
    [15] - One-sided p-value from Cochran-Mantel-Haenszel test (stratified per randomization as in IVRS)

    Secondary: Disease Control Rate (DCR) by Central Review

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    End point title
    Disease Control Rate (DCR) by Central Review
    End point description
    Disease control rate (DCR) was defined as the proportion of subjects whose best response was complete response (CR), partial response (PR), stable disease (SD) or Non CR/Non progressive disease (PD). CR and PR needed to be confirmed by another scan at least 4 weeks later. SD and Non CR/Non PD had to be documented at least 6 weeks after randomization.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until approximately 3 years later or until disease radiological progression
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    266 [16]
    271 [17]
    Units: percentage (%) of subjects
        number (confidence interval 95%)
    60.5 (54.4 to 66.4)
    58.3 (52.2 to 64.2)
    Notes
    [16] - FAS
    [17] - FAS
    Statistical analysis title
    Statistical Analysis for Disease Control Rate
    Statistical analysis description
    DCR and 95% CI based on “general association Cochran-Mantel-Haenszel statistic” with one-sided alpha of 0.025 stratified by number of prior chemotherapies for metastatic disease, hormone receptor status, and region. Difference = Placebo + Capecitabine - Sorafenib + Capecitabine.
    Comparison groups
    Placebo + Capecitabine v Sorafenib (Nexavar, BAY43-9006) + Capecitabine
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.284674 [18]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percent Difference
    Point estimate
    -2.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.4
         upper limit
    5.72
    Notes
    [18] - One-sided p-value from Cochran-Mantel-Haenszel test (stratified per randomization as in IVRS).

    Secondary: Duration of Response (DOR) by Central Reader

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    End point title
    Duration of Response (DOR) by Central Reader
    End point description
    DOR was defined as the time from date of first response (CR or PR) to the date when Progressive Disease (PD) is first documented, or to the date of death, whichever occurred first according to RECIST version 1.1. Subjects still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. Duration of response defined for confirmed responders only (that is, CR or PR). '99999' indicates that value could not be estimated due to censored data. Median and 95% CIs were computed using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until approximately 3 years later or until disease radiological progression
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    36 [19]
    42 [20]
    Units: days
        median (confidence interval 95%)
    313 (209 to 99999)
    290 (169 to 99999)
    Notes
    [19] - Only responders in FAS
    [20] - Only responders in FAS
    No statistical analyses for this end point

    Other pre-specified: Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 item) (FBSI-8)

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    End point title
    Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 item) (FBSI-8)
    End point description
    The FBSI-8 was an 8-item questionnaire. Subjects responded to each item using a 5-point Likert-type scale ranging from 0 (not at all) to 4 (very much). A total scale score was calculated (range from 0 to 32), with higher scores indicating low symptomatology and reflecting a better Health-Related Quality of Life (HRQoL). The results on the analysis of covariance (ANCOVA) of time-adjusted area under curve (AUC) for the FBSI-8 score were reported. Only subjects with a baseline assessment and at least one post-baseline assessment during the study were used for the AUC-based analyses. Please find the statistical analyses in the attachment below.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, 31, 34, 37, and end of treatment (EOT, 21 days after last dose of study drug)
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    233 [21]
    243 [22]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    20.915 (20.459 to 21.37)
    21.356 (20.911 to 21.801)
    Attachments
    Statistical Analyses_Other_FBSI-8
    Notes
    [21] - FAS
    [22] - FAS
    No statistical analyses for this end point

    Other pre-specified: Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score

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    End point title
    Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score
    End point description
    The EQ-5D was a generic Quality of life (QoL) preference based instrument and has been validated in the cancer populations. EQ-5D questionnaire contained a 5-item descriptive system of health states (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a visual analogue scale (VAS). From the answers to these 5 health states a single HRQoL score ranging from -0.59 to 1 were generated according to the standard scoring algorithm developed by the EuroQoL Group for the instrument. This single score was referred to as the EQ-5D index score. For the EQ-5D, higher scores represented better health status. A change of at least 0.10 to 0.12 points on the EQ-5D index is considered clinically meaningful. The results on ANCOVA of time-adjusted AUC were reported. Only subjects with a baseline assessment and at least one post-baseline assessment during the study were used for the AUC-based analyses. Please find the statistical analyses in the attachment below.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, and EOT (21 days after last dose of study drug)
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    236 [23]
    247 [24]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    0.665 (0.641 to 0.688)
    0.69 (0.667 to 0.713)
    Attachments
    12444_Statistical Analyses_Other_EQ-5D Index
    Notes
    [23] - FAS
    [24] - FAS
    No statistical analyses for this end point

    Other pre-specified: Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score

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    End point title
    Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score
    End point description
    The EQ-5D was a generic QoL preference based instrument and has been validated in the cancer populations. VAS was generated from 0 (worst imaginable health state) to 100 (best imaginable health state). This VAS score was referred to as the EQ-5D self-reported health status score. The results on ANCOVA of time-adjusted AUC were reported. Only subjects with a baseline assessment and at least one post-baseline assessment during the study were used for the AUC-based analyses. Please find the statistical analyses in the attachment below.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, and EOT (21 days after last dose of study drug)
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    235 [25]
    244 [26]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    67.532 (65.87 to 69.19)
    69.228 (67.6 to 70.86)
    Attachments
    Statistical Analyses_Other_EQ-5D-VAS
    Notes
    [25] - FAS
    [26] - FAS
    No statistical analyses for this end point

    Other pre-specified: Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil

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    End point title
    Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil
    End point description
    Maximum observed drug concentration, directly taken from analytical data. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In the listed categories below, 'N' signifies the number of evaluable subjects for the drug administered. Please find the statistical analyses in the attachments below.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    78 [27]
    104 [28]
    Units: milligram per liter
    geometric mean (geometric coefficient of variation)
        Capecitabine (N=56, 84)
    6.05 ± 79
    4.68 ± 72
        5-fluorouracil (N=51, 84)
    0.434 ± 105
    0.382 ± 67
    Attachments
    12444_Statistical Analyses_Other_Cmax of 5-FU
    12444_Statistical Analyses_Other_Cmax of Cape
    Notes
    [27] - PKS
    [28] - PKS
    No statistical analyses for this end point

    Other pre-specified: Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil

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    End point title
    Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil
    End point description
    AUC(0-tlast) is defined as AUC from time 0 to the last data point, calculated up by linear trapezoidal rule, down by logarithmic trapezoidal rule. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In the listed categories below, 'N' signifies the number of evaluable subjects for the drug administered. Please find the statistical analyses in the attachments below.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    78 [29]
    104 [30]
    Units: milligram*hour per liter
    geometric mean (geometric coefficient of variation)
        Capecitabine (N=56, 84)
    7.12 ± 50
    5.13 ± 48
        5-fluorouracil (N=51, 84)
    0.621 ± 71
    0.557 ± 47
    Attachments
    12444_Statistical Analyses_Other_AUC(0-tlast) 5-FU
    12444_Statistical Analyses_Other_AUC(0-tlast) of C
    Notes
    [29] - PKS
    [30] - PKS
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities

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    End point title
    Number of Subjects With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities
    End point description
    Hematological (anemia, hemoglobin, international normalized ratio [INR], lymphocyte, neutrophil, platelet, white blood cell [WBC]), biochemical (ALT [alanine aminotransferase], AST [aspartate aminotransferase], GGT [gamma-glutamyl-transferase], lipase, hypoalbuminemia, hypocalcemia, hyperglycemia, hyperuricemia) evaluations were done. Common terminology criteria for adverse events (CTCAE) version 4-Grade 3: Severe or medically significant; hospitalization or prolongation of hospitalization and CTCAE version 4-Grade 4: life-threatening consequences; urgent intervention were indicated. '99999' in the below table indicates that the lab parameter has no grade 4 (hemoglobin) or grade 3 (uric acid).
    End point type
    Other pre-specified
    End point timeframe
    From the start of study treatment up to 30 days after the last dose
    End point values
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    260 [31]
    267 [32]
    Units: Subjects
        Anemia (grade 3)
    12
    7
        Hemoglobin increased (grade 3)
    0
    3
        INR increased (grade 3)
    9
    9
        Lymphocyte count decreased (grade 3)
    20
    17
        Neutrophil count decreased (grade 3)
    11
    19
        Platelet count decreased (grade 3)
    6
    2
        WBC decreased (grade 3)
    15
    13
        ALT increased (grade 3)
    4
    5
        AST increased (grade 3)
    10
    5
        Alkaline phosphatase increased (grade 3)
    12
    13
        Bilirubin increased (grade 3)
    9
    1
        GGT increased (grade 3)
    22
    21
        Lipase increased (grade 3)
    19
    12
        Serum amylase increased (grade 3)
    8
    4
        Hypoalbuminemia (grade 3)
    4
    2
        Hypocalcemia (grade 3)
    9
    6
        Hypokalemia (grade 3)
    20
    11
        Hyponatremia (grade 3)
    9
    7
        Hypophosphatemia (grade 3)
    47
    15
        Hyperglycemia (grade 3)
    9
    10
        Lymphocyte count decreased (grade 4)
    3
    2
        Neutrophil count decreased (grade 4)
    7
    7
        Platelet count decreased (grade 4)
    1
    7
        WBC decreased (grade 4)
    2
    3
        ALT increased (grade 4)
    3
    0
        GGT increased (grade 4)
    6
    2
        Lipase increased (grade 4)
    5
    1
        Hypokalemia (grade 4)
    2
    4
        Hyponatremia (grade 4)
    4
    0
        Hypophosphatemia (grade 4)
    5
    0
        Hyperuricemia (grade 4)
    5
    0
    Notes
    [31] - Safety Analysis Set (SAF)
    [32] - Safety Analysis Set (SAF)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration until 30 days after the last dose of study medication intake.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine
    Reporting group description
    Sorafenib tablets were administered orally continuously at a total daily dose of 600 mg (200 mg in the morning, 400 mg in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m^2 (1,000 mg/m^2 twice daily, 12 hours apart). If tolerability criteria were met for a subject, capecitabine dose was escalated to 2,500 mg/m^2 total daily dose (1,250 mg/m^2 twice daily) and sorafenib dose to a total daily dose of 800 mg for that subject.

    Reporting group title
    Placebo + Capecitabine
    Reporting group description
    Placebo tablets matching with sorafenib were administered orally continuously (1 tablet in the morning, 2 tablets in the evening) in a 3-week cycle. Capecitabine was administered orally at a total daily dose of 2,000 mg/m^2 (1,000 mg/m^2 twice daily, 12 hours apart). If tolerability criteria were met for a subject, capecitabine dose was escalated to 2,500 mg/m^2 total daily dose (1,250 mg/m^2 twice daily) and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.

    Serious adverse events
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 260 (30.77%)
    71 / 267 (26.59%)
         number of deaths (all causes)
    159
    154
         number of deaths resulting from adverse events
    16
    12
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurodesis
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatectomy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Axillary lymphadenectomy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer surgery
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour associated fever
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cancer pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 260 (1.15%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy lung
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 260 (0.00%)
    5 / 267 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 260 (3.08%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 260 (2.31%)
    11 / 267 (4.12%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary microemboli
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Tracheal obstruction extrinsic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lethargy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system mass
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytotoxic oedema
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye symptom
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 260 (1.15%)
    8 / 267 (3.00%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 260 (2.69%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (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
    Arthralgia
         subjects affected / exposed
    3 / 260 (1.15%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus enterocolitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sorafenib (Nexavar, BAY43-9006) + Capecitabine Placebo + Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    256 / 260 (98.46%)
    248 / 267 (92.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    69 / 260 (26.54%)
    16 / 267 (5.99%)
         occurrences all number
    92
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    49 / 260 (18.85%)
    51 / 267 (19.10%)
         occurrences all number
    67
    69
    Fatigue
         subjects affected / exposed
    79 / 260 (30.38%)
    81 / 267 (30.34%)
         occurrences all number
    101
    102
    Influenza like illness
         subjects affected / exposed
    5 / 260 (1.92%)
    15 / 267 (5.62%)
         occurrences all number
    9
    19
    Mucosal inflammation
         subjects affected / exposed
    39 / 260 (15.00%)
    19 / 267 (7.12%)
         occurrences all number
    49
    20
    Oedema peripheral
         subjects affected / exposed
    9 / 260 (3.46%)
    23 / 267 (8.61%)
         occurrences all number
    10
    29
    Pyrexia
         subjects affected / exposed
    28 / 260 (10.77%)
    32 / 267 (11.99%)
         occurrences all number
    31
    39
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 260 (7.31%)
    12 / 267 (4.49%)
         occurrences all number
    19
    12
    Insomnia
         subjects affected / exposed
    16 / 260 (6.15%)
    12 / 267 (4.49%)
         occurrences all number
    16
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    27 / 260 (10.38%)
    21 / 267 (7.87%)
         occurrences all number
    34
    24
    Aspartate aminotransferase increased
         subjects affected / exposed
    27 / 260 (10.38%)
    23 / 267 (8.61%)
         occurrences all number
    32
    26
    Blood bilirubin increased
         subjects affected / exposed
    19 / 260 (7.31%)
    17 / 267 (6.37%)
         occurrences all number
    27
    26
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    14 / 260 (5.38%)
    4 / 267 (1.50%)
         occurrences all number
    14
    4
    Lipase increased
         subjects affected / exposed
    13 / 260 (5.00%)
    5 / 267 (1.87%)
         occurrences all number
    15
    5
    Neutrophil count decreased
         subjects affected / exposed
    14 / 260 (5.38%)
    10 / 267 (3.75%)
         occurrences all number
    27
    22
    Weight decreased
         subjects affected / exposed
    28 / 260 (10.77%)
    12 / 267 (4.49%)
         occurrences all number
    28
    13
    White blood cell count decreased
         subjects affected / exposed
    17 / 260 (6.54%)
    12 / 267 (4.49%)
         occurrences all number
    23
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 260 (11.92%)
    32 / 267 (11.99%)
         occurrences all number
    37
    37
    Neutropenia
         subjects affected / exposed
    12 / 260 (4.62%)
    24 / 267 (8.99%)
         occurrences all number
    22
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 260 (9.62%)
    23 / 267 (8.61%)
         occurrences all number
    25
    25
    Dyspnoea
         subjects affected / exposed
    32 / 260 (12.31%)
    41 / 267 (15.36%)
         occurrences all number
    34
    47
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 260 (8.08%)
    22 / 267 (8.24%)
         occurrences all number
    26
    26
    Dysgeusia
         subjects affected / exposed
    12 / 260 (4.62%)
    20 / 267 (7.49%)
         occurrences all number
    13
    20
    Headache
         subjects affected / exposed
    35 / 260 (13.46%)
    36 / 267 (13.48%)
         occurrences all number
    49
    45
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 260 (0.00%)
    16 / 267 (5.99%)
         occurrences all number
    0
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    33 / 260 (12.69%)
    28 / 267 (10.49%)
         occurrences all number
    40
    41
    Abdominal pain upper
         subjects affected / exposed
    35 / 260 (13.46%)
    19 / 267 (7.12%)
         occurrences all number
    44
    22
    Constipation
         subjects affected / exposed
    53 / 260 (20.38%)
    33 / 267 (12.36%)
         occurrences all number
    67
    36
    Diarrhoea
         subjects affected / exposed
    123 / 260 (47.31%)
    98 / 267 (36.70%)
         occurrences all number
    291
    190
    Dyspepsia
         subjects affected / exposed
    16 / 260 (6.15%)
    25 / 267 (9.36%)
         occurrences all number
    19
    31
    Nausea
         subjects affected / exposed
    101 / 260 (38.85%)
    97 / 267 (36.33%)
         occurrences all number
    166
    150
    Stomatitis
         subjects affected / exposed
    45 / 260 (17.31%)
    24 / 267 (8.99%)
         occurrences all number
    54
    29
    Vomiting
         subjects affected / exposed
    65 / 260 (25.00%)
    53 / 267 (19.85%)
         occurrences all number
    118
    83
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    44 / 260 (16.92%)
    6 / 267 (2.25%)
         occurrences all number
    49
    6
    Dry skin
         subjects affected / exposed
    19 / 260 (7.31%)
    17 / 267 (6.37%)
         occurrences all number
    23
    19
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    206 / 260 (79.23%)
    158 / 267 (59.18%)
         occurrences all number
    288
    228
    Rash
         subjects affected / exposed
    48 / 260 (18.46%)
    22 / 267 (8.24%)
         occurrences all number
    58
    29
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    35 / 260 (13.46%)
    27 / 267 (10.11%)
         occurrences all number
    54
    33
    Back pain
         subjects affected / exposed
    33 / 260 (12.69%)
    33 / 267 (12.36%)
         occurrences all number
    39
    34
    Muscle spasms
         subjects affected / exposed
    17 / 260 (6.54%)
    6 / 267 (2.25%)
         occurrences all number
    24
    6
    Musculoskeletal pain
         subjects affected / exposed
    9 / 260 (3.46%)
    17 / 267 (6.37%)
         occurrences all number
    9
    21
    Pain in extremity
         subjects affected / exposed
    23 / 260 (8.85%)
    21 / 267 (7.87%)
         occurrences all number
    32
    28
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    22 / 260 (8.46%)
    15 / 267 (5.62%)
         occurrences all number
    24
    19
    Hypophosphataemia
         subjects affected / exposed
    16 / 260 (6.15%)
    4 / 267 (1.50%)
         occurrences all number
    22
    5
    Decreased appetite
         subjects affected / exposed
    53 / 260 (20.38%)
    38 / 267 (14.23%)
         occurrences all number
    63
    40
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 260 (9.23%)
    23 / 267 (8.61%)
         occurrences all number
    35
    28
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 260 (5.77%)
    11 / 267 (4.12%)
         occurrences all number
    15
    12
    Urinary tract infection
         subjects affected / exposed
    16 / 260 (6.15%)
    15 / 267 (5.62%)
         occurrences all number
    21
    16

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Dec 2010
    1. Several changes were made to the inclusion criterion concerning subjects who were (1) resistant to or failed prior taxane and an anthracycline OR (2) resistant to or failed prior taxane and for whom further anthracycline therapy was not indicated 2. Clarification of Consent to Long-Term Follow-up as information on overall survival (a secondary study objective) must be collected for all subjects 3. Subjects in the Long-term Follow-up Period should have regular computed tomography (CT) scans/magnetic resonance images (MRIs) until disease progression is documented 4. The IVRS used in this study has a built-in 3-day time period for the screening phase 5. Participation in the pharmacokinetics part of the study is not mandatory 6. To allow collection of pharmacokinetic samples at the scheduled Day 15 visit of appropriate cycles rather than Day 14 to enhance subject convenience by eliminating the need for this additional Day-14 visit 7. Anti-cancer drugs or device therapy for the treatment of breast cancer was prohibited within 4 weeks (28 days) or 5 half-lives, whichever was longer, prior to randomization 8. Allowed for the use of hematopoietic growth factor (only cycles subsequent to Cycle 1) in study subjects at the discretion of the investigator 9. To emphasize that a subject may decline to participate in the optional genetic biomarker study and yet still participate in the study trial.
    03 May 2011
    1. Clarifications on inclusion criteria regarding radiological evaluations, dose range of doxorubicin equivalents, eligibility following taxane and anthracycline therapy, discontinuation of prior chemotherapy, and pregnancy test 2. Clarifications on exclusion criteria regarding testing of subjects with unknown HER2 status, breast cancer types, subjects with brain metastases, baseline infections, prior radiation, excluded therapies, hemorrhage/bleeding events 3. To allow dose re-escalation of sorafenib/placebo only under the specific circumstances that are clearly defined in protocol 4. Included detailed guidelines on dose modifications, dose interruptions, and criteria for reintroduction of study medications in response to hematologic toxicities 5. To allow subjects for collection of pharmacokinetic samples, to attend their weekly clinic visit scheduled for Cycle 2/Day 15 to be conducted on Cycle 2/Day 14 6. To state that, if 10 slides are not available, fewer slides may be accepted for formalin-fixed paraffin embedded biopsy after discussion and agreement with the sponsor 7. In the interest of increasing the subject safety the protocol was modified to specify that subjects should undergo electrocardiograms (ECGs) on Day 1 of each cycle in addition to previously specified baseline, end-of-treatment, and as-required ECGs 8. The text on excluded concurrent therapies was clarified for consistency with the remainder of the protocol 9. The inclusion criterion regarding cancer-evaluation imaging at baseline was amended to allow a bone scan to be conducted up to 8 weeks before randomization to be used as the baseline scan 10. Screening study assessments should be performed within specified time periods relative to randomization 11. The instructions regarding HER2 status determination were changed in order to reflect the current practices regarding laboratory accreditation and usage of testing kits.
    26 Jan 2012
    Amendment 6 modified inclusion criteria defining the specification for prior treatment with taxane and anthracycline therapy in subjects who relapsed over 12 months following the end of treatment and clarifications were made. 1. The inclusion criterion regarding baseline cancer evaluation imaging was amended to allow the baseline bone scan to have been conducted up to 12 weeks before randomization 2. Detailed guidelines on baseline criteria for laboratory evaluations were provided. 3. Re-screening was permitted in cases in which the subject’s eligibility for the study depended on the completion of further treatment, or to allow protocol compliant time lines for assessment or washout periods 4. Detailed guidelines on dose modifications, dose interruptions, and criteria for re-introduction of study medications in response to hematologic toxicities based on the CTCAE v4.0 grade of events
    03 Sep 2013
    1. The original assumption of a 1-sided alpha of 0.025, power of 98% and a randomization ratio of 1:1 between treatments for 363 PFS events (for progression events based on central radiology review) to detect a 66.7% increase in PFS was amended to an assumption of a 1-sided alpha of 0.025, power of 92.8% and a randomization ratio of 1:1 between treatments for 250 PFS events (including progression events based on central radiology review and death, if death occurs before disease progression) to detect a 66.7% increase in PFS 2. The following statement: “assuming a median OS of 12 months for the control group, approximately 270 deaths would be expected at the time of the PFS analysis. For the final analysis of OS, 405 deaths are projected to occur by approximately 43.3 months after the first subject is randomized” was amended to “assuming a median of 12 months for the control group, approximately 270 deaths would be expected at the time of the PFS analysis. However, at the time approximately 250 PFS events are reached, if the observed number of deaths is less than approximately 270, the trial will continue and remain blinded until approximately 270 deaths are observed. In such a case, the analysis of PFS will include all PFS data up to the later data cutoff date for approximately 270 deaths. For the final analysis of OS, and based on actual events, 405 deaths are projected to occur by approximately 56.2 months after the first subject was randomized.” 3. DCR was added as a secondary end-point.

    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.
    Results of exploratory analysis of biomarkers are anticipated in the month of February, 2016. Occurrence of "±” in relation with geometric CV (%) is auto-generated and cannot be deleted.
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