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    Clinical Trial Results:
    Sorafenib Long Term Extension Program (STEP)

    Summary
    EudraCT number
    		 2007-002604-17
    Trial protocol
    		 FR   DE   ES   IT   PL   GB   BE   BG  
    Global end of trial date
    24 Sep 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Jul 2022
    First version publication date
    30 Mar 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    12311
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00625378
    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
    Final
    Date of interim/final analysis
    24 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of the program was to enable patients, currently receiving sorafenib (Nexavar) in a Bayer/Onyx sponsored clinical trial, to continue sorafenib treatment after their respective study had met its primary endpoint and/or had reached the end as defined in the original protocol. An additional objective was the assessment of the safety of Nexavar or Nexavar combination treatment.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects/ /legal representatives. Participating subjects/ /legal representatives 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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 26 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 10
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Poland: 70
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    Ukraine: 1
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    204
    EEA total number of subjects
    126
    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)
    109
    From 65 to 84 years
    93
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at multiple centers in 19 countries between 21-Dec-2007 (first subject first visit) and 24-Sep-2021 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 206 subjects were transferred from the feeder studies and have signed informed consent for STEP. Of these 206 subjects, 2 subjects were never treated and 204 subjects received the study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sorafenib monotherapy
    Arm description
    		 Subjects received single-agent sorafenib at the same dose and schedule as in their original Clinical Trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the same dose and schedule as in the subjects' original Clinical Trial

    Arm title
    		 Sorafenib+Erlotinib
    Arm description
    		 Subjects received sorafenib and erlotinib combination at the same dose and schedule as in their original Clinical Trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the same dose and schedule as in the subjects' original Clinical Trial

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the same dose and schedule as in the subjects' original Clinical Trial

    Number of subjects in period 1
    		Sorafenib monotherapy Sorafenib+Erlotinib
    Started
    203
    1
    Completed
    0
    0
    Not completed
    203
    1
         Disease progression, recurrence or relapse
    88
    -
         Non-compliant with study medication
    3
    -
         Adverse event
    22
    -
         Sponsor decision
    1
    -
         Missing
    2
    -
         Multiple toxicities
    1
    -
         New cancer
    1
    -
         PTA program
    2
    -
         Consent withdrawn by subject
    16
    -
         Investigator's decision
    1
    -
         Sponsor's decision to stop the trial
    1
    -
         End of treatment not available
    2
    -
         Death
    38
    -
         Switch to commercial drug
    6
    1
         Medical decision
    1
    -
         Lost to follow-up
    17
    -
         Recurrent rise in amylase and lipase
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib monotherapy
    Reporting group description
    		 Subjects received single-agent sorafenib at the same dose and schedule as in their original Clinical Trial.

    Reporting group title
    Sorafenib+Erlotinib
    Reporting group description
    		 Subjects received sorafenib and erlotinib combination at the same dose and schedule as in their original Clinical Trial.

    Reporting group values
    		 Sorafenib monotherapy Sorafenib+Erlotinib Total
    Number of subjects
    		 203 1 204
    Age Categorical
    Units: Subjects
    Age Continuous
    "99999" denotes that value was not calculated due to the only 1 subject in the group.
    Units: years
        arithmetic mean (standard deviation)
    		 63.5 ( 9.6 ) 20.0 ( 99999 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 63 0 63
        Male
    		 140 1 141
    Race
    Units: Subjects
        Asian
    		 39 1 40
        Hispanic
    		 2 0 2
        Japanese/American
    		 1 0 1
        White
    		 161 0 161
    ECOG performance status
    Eastern cooperative oncology group (ECOG) performance status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours
    Units: Subjects
        ECOG 0
    		 25 1 26
        ECOG 1
    		 16 0 16
        ECOG 2
    		 1 0 1
        Missing
    		 161 0 161

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib monotherapy
    Reporting group description
    		 Subjects received single-agent sorafenib at the same dose and schedule as in their original Clinical Trial.

    Reporting group title
    Sorafenib+Erlotinib
    Reporting group description
    		 Subjects received sorafenib and erlotinib combination at the same dose and schedule as in their original Clinical Trial.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF included all subjects who received at least one dose of study medication.

    Primary: Sorafenib treatment duration within STEP

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    End point title
    		 Sorafenib treatment duration within STEP [1]
    End point description
    Treatment duration was calculated in days as the date of the last dose of any study treatment minus date of the first dose of any study treatment plus one day.
    End point type
    Primary
    End point timeframe
    From the date of the first sorafenib dose until the date of the last sorafenib dose, with a mean duration of 25 months and max duration of 153.8 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [2]
    1 [3]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    15.69 (6.41 to 33.19)
    40.13 (40.13 to 40.13)
    Notes
    [2] - SAF
    [3] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with new treatment-emergent adverse events (TEAEs)

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    End point title
    		 Number of subjects with new treatment-emergent adverse events (TEAEs) [4]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The adverse event did not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death; was life-threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; was a congenital anomaly or birth defect; was an important medical event. A new treatment-emergent adverse event (TEAE) was any AE that had a start date on or after ICF date in STEP and up to 30 days after the last sorafenib dose. A drug-related new TEAE was any new TEAE that had a causal relationship with the study treatment as assessed by the investigator. disc. = discontinuation
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [4] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [5]
    1 [6]
    Units: Subjects
        Any AE
    166
    1
        Serious AE (SAE)
    113
    1
        AE leading to dose modification
    64
    0
        AE leading to study drug discontinuation
    56
    0
        AE leading to death
    37
    0
        Sorafenib-related AE
    117
    1
        Sorafenib-related SAE
    25
    1
        Sorafenib-related AE leading to dose modification
    42
    0
        Sorafenib-related AE leading to study drug disc.
    21
    0
        Sorafenib-related AE leading to death
    2
    0
    Notes
    [5] - SAF
    [6] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with new TEAEs of CTCAE grades 3 or higher by worst CTCAE grade

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    End point title
    		 Number of subjects with new TEAEs of CTCAE grades 3 or higher by worst CTCAE grade [7]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The AE did not necessarily have to have a causal relationship with this treatment. A new treatment-emergent adverse event (TEAE) was any AE that had a start date on or after ICF date in STEP and up to 30 days after the last sorafenib dose. CTCAE: Common Terminology Criteria Adverse Event.
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [7] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [8]
    1 [9]
    Units: Subjects
        Grade 3
    71
    1
        Grade 4
    17
    1
        Grade 5
    37
    0
    Notes
    [8] - SAF
    [9] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with study drug-related new TEAEs of CTCAE grades 3 or higher by worst CTCAE grade

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    End point title
    		 Number of subjects with study drug-related new TEAEs of CTCAE grades 3 or higher by worst CTCAE grade [10]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The AE did not necessarily have to have a causal relationship with this treatment. A new treatment-emergent adverse event (TEAE) was any AE that had a start date on or after ICF date in STEP and up to 30 days after the last sorafenib dose. A drug-related new TEAE was a new TEAE that had a causal relationship with the study treatment as assessed by the investigator. CTCAE: Common Terminology Criteria Adverse Event.
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [10] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [11]
    1 [12]
    Units: Subjects
        Grade 3
    49
    1
        Grade 4
    6
    0
        Grade 5
    2
    0
    Notes
    [11] - SAF
    [12] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with all adverse events

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    End point title
    		 Number of subjects with all adverse events [13]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The AE did not necessarily have to have a causal relationship with this treatment. A drug-related AE was any AE that had a causal relationship with the study treatment as assessed by the investigator. All AEs in STEP were the combination of AEs ongoing from feeder studies and new TEAEs. disc. = discontinuation
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [13] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [14]
    1 [15]
    Units: Subjects
        Any AE
    184
    1
        Serious AE (SAE)
    114
    1
        AE leading to dose modification
    72
    0
        AE leading to study drug discontinuation
    56
    0
        AE leading to death
    37
    0
        Sorafenib-related AE
    159
    1
        Sorafenib-related SAE
    26
    1
        Sorafenib-related AE leading to dose modification
    53
    0
        Sorafenib-related AE leading to study drug disc.
    21
    0
        Sorafenib-related AE leading to death
    2
    0
    Notes
    [14] - SAF
    [15] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with all adverse events of CTCAE grades 3 or higher by worst CTCAE grade

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    End point title
    		 Number of subjects with all adverse events of CTCAE grades 3 or higher by worst CTCAE grade [16]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The AE did not necessarily have to have a causal relationship with this treatment. All AEs in STEP were the combination of AEs ongoing from feeder studies and new TEAEs.
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [16] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [17]
    1 [18]
    Units: Subjects
        Grade 3
    81
    1
        Grade 4
    17
    1
        Grade 5
    37
    0
    Notes
    [17] - SAF
    [18] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with study drug-related all adverse events of CTCAE grades 3 or higher by worst CTCAE

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    End point title
    		 Number of subjects with study drug-related all adverse events of CTCAE grades 3 or higher by worst CTCAE [19]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The AE did not necessarily have to have a causal relationship with this treatment. A drug-related AE was any AE that had a causal relationship with the study treatment as assessed by the investigator. All AEs in STEP was a combination of AEs ongoing from feeder studies and new TEAEs.
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [19] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [20]
    1 [21]
    Units: Subjects
        Grade 3
    65
    1
        Grade 4
    6
    0
        Grade 5
    2
    0
    Notes
    [20] - SAF
    [21] - SAF
    No statistical analyses for this end point

    Primary: Number of deaths with primary cause of death

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    End point title
    		 Number of deaths with primary cause of death [22]
    End point description
    Primary cause of death included: any cause; progressive disease; toxicity due to study treatment (with at least one AE with outcome death); other (unspecified) or missing cause.
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until completion or discontinuation of the study, with a mean duration of 26 months
    Notes
    [22] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [23]
    1 [24]
    Units: Subjects
        Any cause
    62
    0
        Progressive disease
    34
    0
        Toxicity due to study treatment
    3
    0
        Other
    21
    0
        Missing
    4
    0
    Notes
    [23] - SAF
    [24] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with abnormal hematological and biochemical laboratory values by worst CTCAE grade

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    End point title
    		 Number of subjects with abnormal hematological and biochemical laboratory values by worst CTCAE grade [25]
    End point description
    Subjects with a specific laboratory value that were "not graded" are not included in the table. CTCAE grade was set to “not graded” if the reference ranges or other information necessary to derive grades were unavailable or result had a special character (such as > or < ) then the grade. "99999" denotes that value was not countable due to no evaluable data for the subject.
    End point type
    Primary
    End point timeframe
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Notes
    [25] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [26]
    1 [27]
    Units: Subjects
        Neutrophils (n=165;0) - Grade 1
    19
    99999
        Neutrophils (n=165;0) - Grade 2
    7
    99999
        Neutrophils (n=165;0) - Grade 3
    0
    99999
        Neutrophils (n=165;0) - Grade 4
    2
    99999
        Hemoglobin (n=191;1) - Grade 1
    67
    1
        Hemoglobin (n=191;1) - Grade 2
    40
    0
        Hemoglobin (n=191;1) - Grade 3
    13
    0
        Hemoglobin (n=191;1) - Grade 4
    8
    0
        Lymphopenia (n=187;1) - Grade 1
    37
    0
        Lymphopenia (n=187) - Grade 2
    37
    0
        Lymphopenia (n=187;1) - Grade 3
    20
    0
        Lymphopenia (n=187;1) - Grade 4
    4
    1
        Platelets (n=189;1) - Grade 1
    48
    0
        Platelets (n=189;1) - Grade 2
    7
    0
        Platelets (n=189;1) - Grade 3
    7
    0
        Platelets (n=189;1) - Grade 4
    17
    1
        Leukocytes (n=192;1) - Grade 1
    40
    1
        Leukocytes (n=192;1) - Grade 2
    12
    0
        Leukocytes (n=19;1) - Grade 3
    2
    0
        Leukocytes (n=192;1) - Grade 4
    1
    0
        INR (n=82;0) - Grade 1
    17
    99999
        INR (n=82;0) - Grade 2
    1
    99999
        INR (n=82;0) - Grade 3
    11
    99999
        INR (n=82;0) - Grade 4
    0
    99999
        ALT (n=174;1) - Grade 1
    66
    1
        ALT (n=174;1) - Grade 2
    13
    0
        ALT (n=174;1) - Grade 3
    7
    0
        ALT (n=174;1) - Grade 4
    0
    0
        Amylase (n=178;1) - Grade 1
    39
    1
        Amylase (n=178;1) - Grade 2
    12
    0
        Amylase (n=178;1) - Grade 3
    8
    0
        Amylase (n=178;1) - Grade 4
    0
    0
        AST (n=183;1) - Grade 1
    88
    1
        AST (n=183;1) - Grade 2
    19
    0
        AST (n=183;1) - Grade 3
    6
    0
        AST (n=183;1) - Grade 4
    0
    0
        Lipase (n=165;1) - Grade 1
    32
    0
        Lipase (n=165;1) - Grade 2
    11
    1
        Lipase (n=165;1) - Grade 3
    28
    0
        Lipase (n=165;1) - Grade 4
    7
    0
    Notes
    [26] - SAF
    [27] - SAF
    No statistical analyses for this end point

    Primary: Number of subjects with ECOG performance status by 6-months time intervals

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    End point title
    		 Number of subjects with ECOG performance status by 6-months time intervals [28]
    End point description
    Eastern cooperative oncology group (ECOG) performance status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5 = Dead
    End point type
    Primary
    End point timeframe
    Up to 156 months
    Notes
    [28] - 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: Due to the nature of this trial, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified.
    End point values
    		 Sorafenib monotherapy Sorafenib+Erlotinib
    Number of subjects analysed
    203 [29]
    1 [30]
    Units: Subjects
        Months 1-6 (n=42;1) - Missing
    2
    0
        Months 1-6 (n=42;1) - ECOG 0
    28
    1
        Months 1-6 (n=42;1) - ECOG 1
    11
    0
        Months 1-6 (n=42;1) - ECOG 2
    1
    0
        Months 7-12 (n=38;1) - Missing
    3
    0
        Months 7-12 (n=38;1) - ECOG 0
    29
    1
        Months 7-12 (n=38;1) - ECOG 1
    6
    0
        Months 13-18 (n=33;1) - Missing
    2
    0
        Months 13-18 (n=33;1) - ECOG 0
    22
    1
        Months 13-18 (n=33;1) - ECOG 1
    7
    0
        Months 13-18 (n=33;1) - ECOG 2
    1
    0
        Months 13-18 (n=33;1) - ECOG 3
    1
    0
        Months 19-24 (n=28;1) - Missing
    2
    0
        Months 19-24 (n=28;1) - ECOG 0
    15
    1
        Months 19-24 (n=28;1) - ECOG 1
    9
    0
        Months 19-24 (n=28;1) - ECOG 2
    1
    0
        Months 19-24 (N=28;1) - ECOG 5
    1
    0
        Months 25-30 (n=23;1) - Missing
    2
    0
        Months 25-30 (n=23;1) - ECOG 0
    13
    1
        Months 25-30 (n=23;1) - ECOG 1
    7
    0
        Months 25-30 (n=23;1) - ECOG 5
    1
    0
        Months 31-36 (n=19;1) - Missing
    1
    0
        Months 31-36 (n=19;1) - ECOG 0
    9
    1
        Months 31-36 (n=19;1) - ECOG 1
    8
    0
        Months 31-36 (n=19;1) - ECOG 5
    1
    0
        Months 37-42 (n=19;1) - ECOG 0
    10
    1
        Months 37-42 (n=19;1) - ECOG 1
    8
    0
        Months 37-42 (n=19;1) - ECOG 5
    1
    0
        Months 43-48 (n=16;1) - ECOG 0
    9
    0
        Months 43-48 (n=16;1) - ECOG 1
    6
    0
        Months 43-48 (n=16;1) - ECOG 5
    1
    0
        Months 49-54 (n=13;1) - ECOG 0
    7
    0
        Months 49-54 (n=13;1) - ECOG 1
    6
    0
        Months 55-60 (n=19;1) - Missing
    2
    0
        Months 55-60 (n=19;1) - ECOG 0
    11
    0
        Months 55-60 (n=19;1) - ECOG 1
    6
    0
        Months 61-66 (n=15;1) - Missing
    1
    0
        Months 61-66 (n=15;1) - ECOG 0
    8
    0
        Months 61-66 (n=15;1) - ECOG 1
    6
    0
        Months 67-72 (n=14;1) - ECOG 0
    8
    0
        Months 67-72 (n=14;1) - ECOG 1
    6
    0
        Months 73-78 (n=13;1) - ECOG 0
    7
    0
        Months 73-78 (n=13;1) - ECOG 1
    5
    0
        Months 73-78 (n=13;1) - ECOG 2
    1
    0
        Months 79-84 (n=10;1) - ECOG 0
    6
    0
        Months 79-84 (n=10;1) - ECOG 1
    4
    0
        Months 85-90 (n=10;1) - ECOG 0
    4
    0
        Months 85-90 (n=10;1) - ECOG 1
    5
    0
        Months 85-90 (n=10;1) - ECOG 2
    1
    0
        Months 91-96 (n=9;1) - ECOG 0
    5
    0
        Months 91-96 (n=9;1) - ECOG 1
    4
    0
        Months 97-102 (n=8;1) - Missing
    2
    0
        Months 97-102 (n=8;1) - ECOG 0
    4
    0
        Months 97-102 (n=8;1) - ECOG 1
    2
    0
        Months 103-108 (n=5;1) - Missing
    1
    0
        Months 103-108 (n=5;1) - ECOG 0
    1
    0
        Months 103-108 (n=5;1) - ECOG 1
    3
    0
        Months 109-114 (n=3;1) - ECOG 0
    1
    0
        Months 109-114 (n=3;1) - ECOG 1
    2
    0
        Months 115-120 (n=3;1) - ECOG 0
    2
    0
        Months 115-120 (n=3;1) - ECOG 2
    1
    0
        Months 121-126 (n=3;1) - ECOG 0
    1
    0
        Months 121-126 (n=3;1) - ECOG 1
    1
    0
        Months 121-126 (n=3;1) - ECOG 2
    1
    0
        Months 127-132 (n=3;1) - ECOG 0
    1
    0
        Months 127-132 (n=3;1) - ECOG 1
    2
    0
        Months 133-138 (n=3;1) - ECOG 0
    1
    0
        Months 133-138 (n=3;1) - ECOG 1
    2
    0
        Months 139-144 (n=3;1) - ECOG 0
    1
    0
        Months 139-144 (n=3;1) - ECOG 1
    1
    0
        Months 139-144 (n=3;1) - ECOG 2
    1
    0
        Months 145-150 (n=3;1) - ECOG 0
    1
    0
        Months 145-150 (n=3;1) - ECOG 1
    1
    0
        Months 145-150 (n=3;1) - ECOG 2
    1
    0
        Months 151-156 (n=3;1) - ECOG 0
    1
    0
        Months 151-156 (n=3;1) - ECOG 1
    1
    0
        Months 151-156 (n=3;1) - ECOG 2
    1
    0
        Last available value (n=64;1) - Missing
    9
    0
        Last available value (n=64;1) - ECOG 0
    20
    1
        Last available value (n=64;1) - ECOG 1
    25
    0
        Last available value (n=64;1) - ECOG 2
    4
    0
        Last available value (n=64;1) - ECOG 3
    1
    0
        Last available value (n=64;1) - ECOG 5
    5
    0
    Notes
    [29] - SAF
    [30] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the ICF in STEP until 30 days after the last sorafenib dose, with a mean duration of 26 months
    Adverse event reporting additional description
    Adverse event reporting for the numbers of deaths (all causes) considers all deaths that occurred at any time during the study until the end of the follow up (with a mean duration of 26 months); deaths resulting from adverse events considers both adverse events with CTCAE grade 5 and/or adverse events with outcome 'Fatal'.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Sorafenib+Erlotinib
    Reporting group description
    		 Subjects received sorafenib and erlotinib combination at the same dose and schedule as in their original Clinical Trial.

    Reporting group title
    Sorafenib monotherapy
    Reporting group description
    		 Subjects received single-agent sorafenib at the same dose and schedule as in their original Clinical Trial.

    Serious adverse events
    		 Sorafenib+Erlotinib Sorafenib monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    114 / 203 (56.16%)
         number of deaths (all causes)
    0
    62
         number of deaths resulting from adverse events
    0
    39
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone cancer metastatic
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver carcinoma ruptured
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of ampulla of Vater
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm recurrence
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour of the lung metastatic
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Stent placement
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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
    Asthenia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 6
    Disease progression
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Impaired healing
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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
    Apnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Personality change
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Angiocardiogram
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological procedural complication
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basal ganglia infarction
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Migraine
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 203 (3.94%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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 / 1 (0.00%)
    1 / 203 (0.49%)
         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 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatic function abnormal
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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
    Decubitus ulcer
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute kidney injury
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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
    Bone pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck mass
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 203 (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 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 1 (0.00%)
    9 / 203 (4.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Perirectal abscess
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Staphylococcal infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cachexia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypercalcaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 203 (0.49%)
         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: 1%
    Non-serious adverse events
    		 Sorafenib+Erlotinib Sorafenib monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    151 / 203 (74.38%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    7
    Hypertension
         subjects affected / exposed
    1 / 1 (100.00%)
    26 / 203 (12.81%)
         occurrences all number
    2
    26
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    33 / 203 (16.26%)
         occurrences all number
    0
    41
    Asthenia
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences all number
    0
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Dysphonia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences all number
    0
    4
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences all number
    0
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 203 (3.94%)
         occurrences all number
    0
    9
    Lipase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    13 / 203 (6.40%)
         occurrences all number
    0
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 203 (3.94%)
         occurrences all number
    0
    10
    Haemoglobin decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    7 / 203 (3.45%)
         occurrences all number
    0
    9
    Amylase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    9 / 203 (4.43%)
         occurrences all number
    0
    13
    Platelet count decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences all number
    0
    6
    Weight decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    10 / 203 (4.93%)
         occurrences all number
    0
    10
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Lethargy
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Neuropathy peripheral
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    5
    Thrombocytopenia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences all number
    0
    5
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    15 / 203 (7.39%)
         occurrences all number
    0
    16
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    6
    Abdominal pain upper
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    13
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 203 (3.94%)
         occurrences all number
    0
    18
    Ascites
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences all number
    0
    4
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    100 / 203 (49.26%)
         occurrences all number
    0
    147
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    11 / 203 (5.42%)
         occurrences all number
    0
    14
    Stomatitis
         subjects affected / exposed
    0 / 1 (0.00%)
    12 / 203 (5.91%)
         occurrences all number
    0
    15
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences all number
    0
    10
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 203 (0.99%)
         occurrences all number
    1
    3
    Alopecia
         subjects affected / exposed
    0 / 1 (0.00%)
    11 / 203 (5.42%)
         occurrences all number
    0
    12
    Dry skin
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences all number
    0
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 1 (100.00%)
    82 / 203 (40.39%)
         occurrences all number
    1
    96
    Pruritus
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 203 (1.97%)
         occurrences all number
    0
    4
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    16 / 203 (7.88%)
         occurrences all number
    0
    19
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    6
    Proteinuria
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    5
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Arthralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 203 (2.96%)
         occurrences all number
    0
    10
    Muscle spasms
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    7
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 1 (0.00%)
    16 / 203 (7.88%)
         occurrences all number
    0
    16
    Hypocalcaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    0
    8
    Hypophosphataemia
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 203 (1.48%)
         occurrences all number
    0
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Mar 2011
    Global amendment 02 forming integrated protocol Version 3.0 introduced the following changes: An inclusion criterion was added to allow subjects who received combination treatment with sorafenib (Nexavar) and TACE (transarterial chemoembolization) in their originating study to be eligible for this extension study. The exclusion criterion regarding concurrent anti-cancer chemotherapy was, therefore, modified to clarify that the exclusion did not apply to subjects being treated with sorafenib in combination with TACE.
    30 Mar 2012
    Global amendment 03 forming integrated protocol Version 4.0 introduced the following changes: 1. Inclusion of an Evaluation of Overall Survival. 2. Inclusion of safety as a stated objective with the main objective of this program remained unchanged.
    25 Mar 2014
    Global amendment 04 forming integrated protocol Version 5.0 introduced the following changes: 1. Removal of all references to erlotinib. 2. Removal of references to placebo in association with sorafenib administration. 3. Addition of TACE to the permissible anticancer chemotherapies and addition of guidance on Sorafenib dose modification in combination with TACE. 4.Clarification of which CTC version was used for the grading of liver function abnormalities.
    15 May 2018
    Global amendment 07 forming integrated protocol Version 6.0 introduced the following changes: 1. Overall survival (OS) evaluation removed from the study objectives. 2. Safety visits were modified. 3. Laboratory evaluations were modified. 4. Follow-up period was changed.
    26 May 2020
    Global amendment 08 forming integrated protocol Version 7.0 introduced the following changes: 1. Added Post-Trial Access Program. 2. Removal of the instructions for dose modifications for the combination of sorafenib with capecitabine and TACE. 3. Added clarification for continuation on study drug. 4. Added clarification for ending the study. 5. Added clarification on last patient last visit date. 6. The timepoint of the performance of the analyses was corrected, last patient last visit was changed to “after the end of the study”.

    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.
    No primary endpoints were defined specifically for study STEP as the primary purpose of this study was to enable patients to continue sorafenib treatment. The 26-month long-term follow-up duration was the mean follow-up duration for the subjects.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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