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    Clinical Trial Results:
    A Phase III randomized, placebo controlled, double blind trial of Sorafenib plus Erlotinib vs. Sorafenib plus placebo as First Line systemic treatment for Hepatocellular Carcinoma (HCC)

    Summary
    EudraCT number
    		 2008-006021-14
    Trial protocol
    		 DE   ES   GB   BE   FR   IT   BG   AT   GR  
    Global end of trial date
    23 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2019
    First version publication date
    01 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY43-9006/12917
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00901901
    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
    23 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective: Overall Survival (OS) Secondary objectives:  -Time to radiographic tumor progression (TTP)  -Disease control rate (DCR) (proportion of subjects who had a best response rating of complete response [CR], partial response [PR], or stable disease [SD] according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria, that was maintained for at least 28 days from the first demonstration of that rating)  -Safety  -Health Related Quality of Life (HRQoL) and utility values as measured by the European Quality of life scale (5 dimensions) (EQ-5D)
    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 Council for Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 May 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Bulgaria: 23
    Country: Number of subjects enrolled
    Brazil: 59
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Chile: 12
    Country: Number of subjects enrolled
    China: 49
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Germany: 53
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    France: 76
    Country: Number of subjects enrolled
    United Kingdom: 52
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hong Kong: 11
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 49
    Country: Number of subjects enrolled
    New Zealand: 21
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Russian Federation: 32
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Taiwan: 26
    Country: Number of subjects enrolled
    United States: 88
    Country: Number of subjects enrolled
    South Africa: 10
    Worldwide total number of subjects
    720
    EEA total number of subjects
    308
    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)
    440
    From 65 to 84 years
    279
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 128 study centers in 26 countries in North America, South America, Europe, Africa, and Asia.

    Pre-assignment
    Screening details
    		 Of the 962 screened participants, 242 were screen failures and were excluded from participated in the study. A total of 720 participants were randomized to study arms: 358 participants in the sorafenib + placebo group and 362 participants in the sorafenib + erlotinib group.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva)
    Arm description
    		 Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose was 150 mg once daily

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY 43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose was 400 mg twice a day

    Arm title
    		 Sorafenib (Nexavar, BAY43-9006) + Placebo
    Arm description
    		 Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose was 150 mg once daily

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY 43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose was 400 mg twice a day

    Number of subjects in period 1
    		Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY43-9006) + Placebo
    Started
    362
    358
    Participants received treatment
    362
    355
    Completed
    193
    181
    Not completed
    169
    177
         Consent withdrawn by subject
    26
    24
         Physician decision
    2
    2
         Adverse event, non-fatal
    120
    128
         Protocol driven decision point
    -
    2
         Switch to commercial drug
    1
    1
         Study terminated by sponsor
    2
    -
         Noncompliance with study medication
    4
    1
         Transfer to treatment continuation study
    5
    2
         Never treated
    -
    3
         Lost to follow-up
    3
    5
         Missing
    1
    -
         Protocol deviation
    5
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva)
    Reporting group description
    		 Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd)

    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Placebo
    Reporting group description
    		 Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd)

    Reporting group values
    		 Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY43-9006) + Placebo Total
    Number of subjects
    		 362 358 720
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.3 ( 11.8 ) 59.5 ( 13.0 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 67 72 139
        Male
    		 295 286 581
    Smoking status
    Units: Subjects
        non-smoker
    		 112 107 219
        former smoker
    		 132 128 260
        current smoker
    		 118 123 241
    ECOG stratification group
    Eastern Cooperative Oncology Group (ECOG) grade 0 = fully active; grade 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
    Units: Subjects
        Grade 0
    		 222 216 438
        Grade 1
    		 140 142 282
    Macroscopic vascular invasion
    Units: Subjects
        Macroscopic vascular invasion: Yes
    		 138 153 291
        Macroscopic vascular invasion: No
    		 224 205 429
    Extrahepatic spread
    Units: Subjects
        Extrahepatic spread: Yes
    		 205 219 424
        Extrahepatic spread: No
    		 157 139 296
    Subject analysis sets

    Subject analysis set title
    Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd)

    Subject analysis set title
    Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd)

    Subject analysis sets values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects
    362
    358
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    60.3 ( 11.8 )
    59.5 ( 13.0 )
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Smoking status
    Units: Subjects
        non-smoker
        former smoker
        current smoker
    ECOG stratification group
    Eastern Cooperative Oncology Group (ECOG) grade 0 = fully active; grade 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
    Units: Subjects
        Grade 0
        Grade 1
    Macroscopic vascular invasion
    Units: Subjects
        Macroscopic vascular invasion: Yes
        Macroscopic vascular invasion: No
    Extrahepatic spread
    Units: Subjects
        Extrahepatic spread: Yes
        Extrahepatic spread: No

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva)
    Reporting group description
    		 Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd)

    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Placebo
    Reporting group description
    		 Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd)

    Subject analysis set title
    Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd)

    Subject analysis set title
    Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd)

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall Survival (OS) was defined as the time from date of randomization to death due to any cause.
    End point type
    Primary
    End point timeframe
    From randomization of the first patient until 34 months or date of death of any cause whichever came first
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    362
    358
    Units: Days
        median (confidence interval 95%)
    289 (250 to 321)
    259 (226 to 322)
    Statistical analysis title
    		 Log rank test
    Statistical analysis description
    A one-sided log-rank test stratified by tumor burden, region, and ECOG at baseline was conducted.
    Comparison groups
    Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) v Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects included in analysis
    720
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.204
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9292
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7805
         upper limit
    		 1.1061

    Secondary: Time to radiological tumor progression (TTP)

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    End point title
    		 Time to radiological tumor progression (TTP)
    End point description
    TTP was the time from randomization to radiological tumor progression. Participants without radiological tumor progression at the time of analysis were censored at their last date of tumor evaluation. Progressive disease (PD) was defined using Response Evaluation Criteria in Solid Tumors (RECIST version 1.0), as at least a 20% increase in the sum of longest diameter (LD) of measured lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Appearance of new lesions also constituted PD.
    End point type
    Secondary
    End point timeframe
    From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    362
    358
    Units: Days
        median (confidence interval 95%)
    97 (82 to 126)
    122 (88 to 136)
    No statistical analyses for this end point

    Secondary: Disease control

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    End point title
    		 Disease control
    End point description
    Disease control was defined as the number of participants who had a best response rating of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST assessed by magnetic resonance imaging (MRI) that was confirmed at least 28 days from the first demonstration of that rating. CR: disappearance of all clinical and radiological evidence of target and non-target tumors. PR: at least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. SD: steady state of disease. Neither sufficient shrinkage for PR nor sufficient increase for PD.
    End point type
    Secondary
    End point timeframe
    From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    362
    358
    Units: Participants
    159
    188
    No statistical analyses for this end point

    Secondary: Health-related quality of life and utility values as measured by EQ-5D - Index

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    End point title
    		 Health-related quality of life and utility values as measured by EQ-5D - Index
    End point description
    The European quality of life scale (5 dimensions) (EQ-5D) questionnaire was given to the participants at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 ‘no problems’; 2 ‘some problems’; 3 ‘extreme problems’). The 5 health dimensions are summarized into a single score, the EQ-5D index score. The EQ-5D index score has a range of 0 and 1 with 0 representing death and 1 representing perfect health.
    End point type
    Secondary
    End point timeframe
    The EQ-5D was administered at the beginning of the visit prior to seeing the investigator. Questionnaires were to be completed every 6 weeks (Day 1 of each cycle) for subsequent cycles and at the end of treatment visit.
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    362
    358
    Units: Scores on a scale
    least squares mean (confidence interval 95%)
        cycle1
    0.777 (0.760 to 0.795)
    0.774 (0.757 to 0.790)
        cycle2
    0.753 (0.735 to 0.771)
    0.749 (0.732 to 0.766)
        cycle3
    0.728 (0.708 to 0.748)
    0.724 (0.706 to 0.743)
        cycle4
    0.704 (0.681 to 0.726)
    0.700 (0.678 to 0.721)
        cycle5
    0.679 (0.653 to 0.705)
    0.675 (0.650 to 0.700)
        cycle6
    0.654 (0.625 to 0.684)
    0.651 (0.622 to 0.679)
    No statistical analyses for this end point

    Secondary: Health-related quality of life and utility values as measured by EQ-5D - VAS

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    End point title
    		 Health-related quality of life and utility values as measured by EQ-5D - VAS
    End point description
    Participants indicated on a scale of 0 (worst) to 100 (best) how good or bad their health state was on that particular day.
    End point type
    Secondary
    End point timeframe
    The EQ-5D VAS was administered at the beginning of the visit prior to seeing the investigator. Questionnaires were to be completed every 6 weeks (Day 1 of each cycle) for subsequent cycles and at the end of treatment visit.
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    362
    358
    Units: Scores on a scale
    least squares mean (confidence interval 95%)
        cycle1
    74.397 (73.219 to 75.576)
    74.656 (73.504 to 75.808)
        cycle2
    72.649 (71.420 to 73.877)
    72.907 (71.735 to 74.080)
        cycle3
    70.900 (69.518 to 72.281)
    71.158 (69.854 to 72.462)
        cycle4
    69.151 (67.542 to 70.759)
    69.409 (67.891 to 70.927)
        cycle5
    67.402 (65.520 to 69.283)
    67.660 (65.875 to 69.445)
        cycle6
    65.653 (63.468 to 67.837)
    65.911 (63.827 to 67.996)
    No statistical analyses for this end point

    Other pre-specified: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of response - RECIST: number of days from the date that CR or PR is first documented to date that PD is first objectively documented or to death before progression. Note: the relevant date is that of the first documentation, not the confirmation date (if participant progressed or died then censored=no) or to last observation if participant did not progress or die then censored=yes note: this last observation date should be the same as that used for time to progression.
    End point type
    Other pre-specified
    End point timeframe
    From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    24
    14 [1]
    Units: Days
        median (confidence interval 95%)
    297 (100 to 427)
    168 (90 to 99999)
    Notes
    [1] - For below CI: 99999 indicates that the upper bound of the CI was not available due to censored data.
    No statistical analyses for this end point

    Other pre-specified: Time to response

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    End point title
    		 Time to response
    End point description
    Time to response was the number of days from randomization to the date the CR or PR was documented (with confirmation) (Note: the relevant date is that of the first documentation, not the confirmation date).
    End point type
    Other pre-specified
    End point timeframe
    From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    24
    14
    Units: Days
        median (confidence interval 95%)
    84.5 (47 to 122)
    83.5 (39 to 331)
    No statistical analyses for this end point

    Other pre-specified: Tumor response

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    End point title
    		 Tumor response
    End point description
    Tumor response was the proportion of participants with the best tumor response (ie, achieving either a confirmed complete response [CR] or partial response [PR], according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria).
    End point type
    Other pre-specified
    End point timeframe
    From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
    End point values
    		 Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) Sorafenib (Nexavar, BAY 43-9006) + Placebo
    Number of subjects analysed
    362
    358
    Units: Participants
    24
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment up to 30 days after the last dose of study medication
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Placebo
    Reporting group description
    		 Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd).

    Reporting group title
    Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva)
    Reporting group description
    		 Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd).

    Serious adverse events
    		 Sorafenib (Nexavar, BAY43-9006) + Placebo Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    198 / 355 (55.77%)
    214 / 362 (59.12%)
         number of deaths (all causes)
    271
    258
         number of deaths resulting from adverse events
    73
    83
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary Malignancy (possibly related to cancer treatment)
         subjects affected / exposed
    2 / 355 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    CNS hemorrhage
         subjects affected / exposed
    2 / 355 (0.56%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Hematoma
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage - Other
         subjects affected / exposed
    4 / 355 (1.13%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Hemorrhage pulmonary, Bronchopulmonary NOS
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hemorrhage pulmonary, Nose
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage pulmonary, Respiratory tract NOS
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI, Abdomen NOS
         subjects affected / exposed
    8 / 355 (2.25%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    1 / 10
    3 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hemorrhage with surgery
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hemorrhage, GI, Anus
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI, Colon
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI, Duodenum
         subjects affected / exposed
    2 / 355 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI, Liver
         subjects affected / exposed
    1 / 355 (0.28%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Hemorrhage, GI, Esophagus
         subjects affected / exposed
    4 / 355 (1.13%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hemorrhage, GI, Lower GI NOS
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI, Oral cavity
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI, Stomach
         subjects affected / exposed
    4 / 355 (1.13%)
    6 / 362 (1.66%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hemorrhage, GI, Upper GI NOS
         subjects affected / exposed
    7 / 355 (1.97%)
    11 / 362 (3.04%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Hemorrhage, GI, Varices (esophageal)
         subjects affected / exposed
    11 / 355 (3.10%)
    6 / 362 (1.66%)
         occurrences causally related to treatment / all
    6 / 18
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Hemorrhage, GI, Varices (rectal)
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hemorrhage, GU, Urinary NOS
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial ischemia
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis/embolism (vascular access)
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visceral arterial ischemia
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular - Other
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    5 / 355 (1.41%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Constitutional Symptoms - Other
         subjects affected / exposed
    19 / 355 (5.35%)
    11 / 362 (3.04%)
         occurrences causally related to treatment / all
    6 / 23
    3 / 15
         deaths causally related to treatment / all
    1 / 12
    0 / 7
    Death not associated with CTCAE term, Death NOS
         subjects affected / exposed
    1 / 355 (0.28%)
    7 / 362 (1.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 7
    Death not associated with CTCAE term, Disease Progression NOS
         subjects affected / exposed
    17 / 355 (4.79%)
    18 / 362 (4.97%)
         occurrences causally related to treatment / all
    1 / 17
    0 / 18
         deaths causally related to treatment / all
    1 / 17
    0 / 18
    Death not associated with CTCAE term, Multi-Organ Failure
         subjects affected / exposed
    3 / 355 (0.85%)
    5 / 362 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 3
    1 / 5
    Fatigue
         subjects affected / exposed
    8 / 355 (2.25%)
    11 / 362 (3.04%)
         occurrences causally related to treatment / all
    12 / 15
    9 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    11 / 355 (3.10%)
    12 / 362 (3.31%)
         occurrences causally related to treatment / all
    4 / 13
    7 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu-like syndrome
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    No Code In CTCAE
         subjects affected / exposed
    10 / 355 (2.82%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain, Abdomen NOS
         subjects affected / exposed
    15 / 355 (4.23%)
    12 / 362 (3.31%)
         occurrences causally related to treatment / all
    3 / 15
    1 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Back
         subjects affected / exposed
    3 / 355 (0.85%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Bone
         subjects affected / exposed
    2 / 355 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Chest wall
         subjects affected / exposed
    0 / 355 (0.00%)
    5 / 362 (1.38%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Chest/thorax NOS
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Extremity - limb
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Joint
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Other (Specify)
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Muscle
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Pain NOS
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Scrotum
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Stomach
         subjects affected / exposed
    0 / 355 (0.00%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain, Tumor pain
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syndromes - Other
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight gain
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight loss
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea (shortness of breath)
         subjects affected / exposed
    4 / 355 (1.13%)
    7 / 362 (1.93%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pleural effusion
         subjects affected / exposed
    7 / 355 (1.97%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 355 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary - Other
         subjects affected / exposed
    2 / 355 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Intraop injury, Lung
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac General - Other
         subjects affected / exposed
    3 / 355 (0.85%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac ischemia/infarction
         subjects affected / exposed
    4 / 355 (1.13%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Conduction abnormality, asystole
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 355 (0.56%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SupraVentricular arrhythmia, Atrial fibrillation
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SupraVentricular arrhythmia, Sinus bradycardia
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SupraVentricular arrhythmia, Sinus tachycardia
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia, Bigeminy
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS ischemia
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disturbance
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood Alteration, Agitation
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusion
         subjects affected / exposed
    6 / 355 (1.69%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    6 / 355 (1.69%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    5 / 8
    7 / 16
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neuropathy: Cranial, CN V Motor-jaw muscles; Sensory-facial
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurology - Other
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood Alteration, Depression
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy: motor
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy: sensory
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 355 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope (fainting)
         subjects affected / exposed
    3 / 355 (0.85%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood - Other
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema: Limb
         subjects affected / exposed
    4 / 355 (1.13%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemoglobin
         subjects affected / exposed
    9 / 355 (2.54%)
    8 / 362 (2.21%)
         occurrences causally related to treatment / all
    8 / 15
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INR
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophils
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelets
         subjects affected / exposed
    2 / 355 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ocular - Other
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    1 / 355 (0.28%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    13 / 355 (3.66%)
    14 / 362 (3.87%)
         occurrences causally related to treatment / all
    7 / 21
    4 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 355 (1.41%)
    12 / 362 (3.31%)
         occurrences causally related to treatment / all
    1 / 5
    6 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diarrhea
         subjects affected / exposed
    3 / 355 (0.85%)
    15 / 362 (4.14%)
         occurrences causally related to treatment / all
    4 / 4
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distension
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula, GI, Abdomen NOS
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula, GI, Anus
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula, GI, Stomach
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GI - Other
         subjects affected / exposed
    4 / 355 (1.13%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heartburn
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhoids
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis (clinical exam), Large bowel
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis (functional/symptomatic), Oral cavity
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis, GI, Colon/cecum/appendix
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction, GI, Colon
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction, GI, Gallbladder
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforation, GI, Colon
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Perforation, GI, Duodenum
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Perforation, GI, Stomach
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Stricture, GI, Biliary tree
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer, GI, Duodenum
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer, GI, Stomach
         subjects affected / exposed
    1 / 355 (0.28%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 355 (0.85%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary - Other
         subjects affected / exposed
    8 / 355 (2.25%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver dysfunction
         subjects affected / exposed
    30 / 355 (8.45%)
    36 / 362 (9.94%)
         occurrences causally related to treatment / all
    10 / 37
    5 / 44
         deaths causally related to treatment / all
    4 / 18
    2 / 21
    Pancreatitis
         subjects affected / exposed
    2 / 355 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 355 (0.00%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bruising
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burn
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatology - Other
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand-foot skin reaction
         subjects affected / exposed
    3 / 355 (0.85%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Injection Site Reaction
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash/desquamation
         subjects affected / exposed
    1 / 355 (0.28%)
    6 / 362 (1.66%)
         occurrences causally related to treatment / all
    0 / 4
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulceration
         subjects affected / exposed
    0 / 355 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal - Other
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    8 / 355 (2.25%)
    10 / 362 (2.76%)
         occurrences causally related to treatment / all
    1 / 13
    3 / 12
         deaths causally related to treatment / all
    1 / 3
    0 / 4
    Urinary retention
         subjects affected / exposed
    0 / 355 (0.00%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    0 / 355 (0.00%)
    6 / 362 (1.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness, Extremity - lower
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness, Whole body/generalized
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal - Other
         subjects affected / exposed
    2 / 355 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Colitis, infectious
         subjects affected / exposed
    0 / 355 (0.00%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection (Documented clinically), Biliary tree
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection (Documented clinically), Bladder (urinary)
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection (Documented clinically), Blood
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection (Documented clinically), Peritoneal Cavity
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection (Documented clinically), Lung (pneumonia)
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection (Documented clinically), Skin (cellulitis)
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection - Other
         subjects affected / exposed
    7 / 355 (1.97%)
    5 / 362 (1.38%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Infection with normal ANC, Abdomen NOS
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Blood
         subjects affected / exposed
    3 / 355 (0.85%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Infection with normal ANC, Anal/perianal
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Bronchus
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Catheter-related
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Heart (Endocarditis)
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Kidney
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Lung (pneumonia)
         subjects affected / exposed
    1 / 355 (0.28%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Infection with normal ANC, Penis
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Peritoneal cavity
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infection with normal ANC, Skin (cellulitis)
         subjects affected / exposed
    3 / 355 (0.85%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC, Upper airway NOS
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection with normal ANC, Urinary tract NOS
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC, Abdomen NOS
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC, Anal/perianal
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC, Biliary tree
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC, Blood
         subjects affected / exposed
    1 / 355 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infection with unknown ANC, Cornea
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC, Duodenum
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection with unknown ANC, Lung (pneumonia)
         subjects affected / exposed
    2 / 355 (0.56%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Infection with unknown ANC, Peritoneal Cavity
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral hepatitis
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    ALT
         subjects affected / exposed
    0 / 355 (0.00%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bilirubin (hyperbilirubinemia)
         subjects affected / exposed
    5 / 355 (1.41%)
    12 / 362 (3.31%)
         occurrences causally related to treatment / all
    4 / 9
    11 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AST
         subjects affected / exposed
    2 / 355 (0.56%)
    6 / 362 (1.66%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    2 / 355 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CPK
         subjects affected / exposed
    1 / 355 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    3 / 355 (0.85%)
    4 / 362 (1.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    2 / 355 (0.56%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    1 / 355 (0.28%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycemia
         subjects affected / exposed
    2 / 355 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphatemia
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic/Lab - Other
         subjects affected / exposed
    0 / 355 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sorafenib (Nexavar, BAY43-9006) + Placebo Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    349 / 355 (98.31%)
    353 / 362 (97.51%)
    Vascular disorders
    Hemorrhage pulmonary, Nose
         subjects affected / exposed
    25 / 355 (7.04%)
    63 / 362 (17.40%)
         occurrences all number
    48
    123
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    86 / 355 (24.23%)
    72 / 362 (19.89%)
         occurrences all number
    336
    339
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    25 / 355 (7.04%)
    18 / 362 (4.97%)
         occurrences all number
    45
    52
    Mood Alteration, Depression
         subjects affected / exposed
    23 / 355 (6.48%)
    15 / 362 (4.14%)
         occurrences all number
    119
    35
    Blood and lymphatic system disorders
    INR
         subjects affected / exposed
    18 / 355 (5.07%)
    19 / 362 (5.25%)
         occurrences all number
    56
    36
    Hemoglobin
         subjects affected / exposed
    49 / 355 (13.80%)
    65 / 362 (17.96%)
         occurrences all number
    129
    200
    Edema: Limb
         subjects affected / exposed
    74 / 355 (20.85%)
    82 / 362 (22.65%)
         occurrences all number
    150
    176
    Leukocytes
         subjects affected / exposed
    20 / 355 (5.63%)
    17 / 362 (4.70%)
         occurrences all number
    41
    48
    Platelets
         subjects affected / exposed
    50 / 355 (14.08%)
    45 / 362 (12.43%)
         occurrences all number
    186
    156
    General disorders and administration site conditions
    Constitutional Symptoms - Other
         subjects affected / exposed
    25 / 355 (7.04%)
    21 / 362 (5.80%)
         occurrences all number
    53
    33
    Fatigue
         subjects affected / exposed
    192 / 355 (54.08%)
    184 / 362 (50.83%)
         occurrences all number
    779
    676
    Insomnia
         subjects affected / exposed
    43 / 355 (12.11%)
    36 / 362 (9.94%)
         occurrences all number
    105
    151
    Fever
         subjects affected / exposed
    64 / 355 (18.03%)
    71 / 362 (19.61%)
         occurrences all number
    107
    112
    Pain, Abdomen NOS
         subjects affected / exposed
    112 / 355 (31.55%)
    112 / 362 (30.94%)
         occurrences all number
    312
    339
    Pain, Back
         subjects affected / exposed
    48 / 355 (13.52%)
    40 / 362 (11.05%)
         occurrences all number
    110
    132
    Pain, Extremity - limb
         subjects affected / exposed
    23 / 355 (6.48%)
    15 / 362 (4.14%)
         occurrences all number
    74
    46
    Pain, Chest/thorax NOS
         subjects affected / exposed
    25 / 355 (7.04%)
    10 / 362 (2.76%)
         occurrences all number
    47
    15
    Pain, Head/headache
         subjects affected / exposed
    51 / 355 (14.37%)
    31 / 362 (8.56%)
         occurrences all number
    117
    60
    Pain, Joint
         subjects affected / exposed
    19 / 355 (5.35%)
    24 / 362 (6.63%)
         occurrences all number
    48
    56
    Weight loss
         subjects affected / exposed
    111 / 355 (31.27%)
    127 / 362 (35.08%)
         occurrences all number
    465
    552
    Pain, Other (Specify)
         subjects affected / exposed
    25 / 355 (7.04%)
    20 / 362 (5.52%)
         occurrences all number
    51
    28
    Pain, Muscle
         subjects affected / exposed
    19 / 355 (5.35%)
    21 / 362 (5.80%)
         occurrences all number
    54
    78
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    86 / 355 (24.23%)
    76 / 362 (20.99%)
         occurrences all number
    205
    192
    Anorexia
         subjects affected / exposed
    135 / 355 (38.03%)
    153 / 362 (42.27%)
         occurrences all number
    383
    479
    Constipation
         subjects affected / exposed
    72 / 355 (20.28%)
    46 / 362 (12.71%)
         occurrences all number
    145
    77
    Dehydration
         subjects affected / exposed
    8 / 355 (2.25%)
    21 / 362 (5.80%)
         occurrences all number
    9
    30
    Diarrhea
         subjects affected / exposed
    211 / 355 (59.44%)
    273 / 362 (75.41%)
         occurrences all number
    784
    1079
    Flatulence
         subjects affected / exposed
    19 / 355 (5.35%)
    24 / 362 (6.63%)
         occurrences all number
    51
    63
    Dry mouth
         subjects affected / exposed
    24 / 355 (6.76%)
    13 / 362 (3.59%)
         occurrences all number
    105
    33
    Distension
         subjects affected / exposed
    22 / 355 (6.20%)
    26 / 362 (7.18%)
         occurrences all number
    61
    98
    GI - Other
         subjects affected / exposed
    29 / 355 (8.17%)
    31 / 362 (8.56%)
         occurrences all number
    81
    120
    Gastritis
         subjects affected / exposed
    13 / 355 (3.66%)
    24 / 362 (6.63%)
         occurrences all number
    32
    53
    Heartburn
         subjects affected / exposed
    21 / 355 (5.92%)
    28 / 362 (7.73%)
         occurrences all number
    47
    111
    Mucositis (functional/symptomatic), Oral cavity
         subjects affected / exposed
    53 / 355 (14.93%)
    72 / 362 (19.89%)
         occurrences all number
    134
    176
    Nausea
         subjects affected / exposed
    109 / 355 (30.70%)
    90 / 362 (24.86%)
         occurrences all number
    259
    212
    Taste Alteration
         subjects affected / exposed
    10 / 355 (2.82%)
    20 / 362 (5.52%)
         occurrences all number
    33
    82
    Vomiting
         subjects affected / exposed
    78 / 355 (21.97%)
    82 / 362 (22.65%)
         occurrences all number
    150
    140
    Hepatobiliary disorders
    Liver dysfunction
         subjects affected / exposed
    21 / 355 (5.92%)
    21 / 362 (5.80%)
         occurrences all number
    39
    35
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    60 / 355 (16.90%)
    41 / 362 (11.33%)
         occurrences all number
    111
    138
    Dyspnea (shortness of breath)
         subjects affected / exposed
    40 / 355 (11.27%)
    35 / 362 (9.67%)
         occurrences all number
    74
    79
    Pulmonary - Other
         subjects affected / exposed
    20 / 355 (5.63%)
    13 / 362 (3.59%)
         occurrences all number
    41
    32
    Voice changes
         subjects affected / exposed
    31 / 355 (8.73%)
    31 / 362 (8.56%)
         occurrences all number
    116
    120
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    13 / 355 (3.66%)
    53 / 362 (14.64%)
         occurrences all number
    46
    210
    Alopecia
         subjects affected / exposed
    84 / 355 (23.66%)
    46 / 362 (12.71%)
         occurrences all number
    352
    222
    Dermatology - Other
         subjects affected / exposed
    39 / 355 (10.99%)
    55 / 362 (15.19%)
         occurrences all number
    142
    184
    Rash/desquamation
         subjects affected / exposed
    141 / 355 (39.72%)
    186 / 362 (51.38%)
         occurrences all number
    536
    785
    Pruritus
         subjects affected / exposed
    44 / 355 (12.39%)
    42 / 362 (11.60%)
         occurrences all number
    101
    83
    Hand-foot skin reaction
         subjects affected / exposed
    169 / 355 (47.61%)
    136 / 362 (37.57%)
         occurrences all number
    805
    723
    Dry skin
         subjects affected / exposed
    33 / 355 (9.30%)
    36 / 362 (9.94%)
         occurrences all number
    114
    122
    Musculoskeletal and connective tissue disorders
    Musculoskeletal - Other
         subjects affected / exposed
    28 / 355 (7.89%)
    25 / 362 (6.91%)
         occurrences all number
    139
    92
    Infections and infestations
    Infection - Other
         subjects affected / exposed
    25 / 355 (7.04%)
    12 / 362 (3.31%)
         occurrences all number
    43
    19
    Metabolism and nutrition disorders
    ALT
         subjects affected / exposed
    39 / 355 (10.99%)
    43 / 362 (11.88%)
         occurrences all number
    92
    159
    AST
         subjects affected / exposed
    74 / 355 (20.85%)
    76 / 362 (20.99%)
         occurrences all number
    217
    259
    Alkaline phosphatase
         subjects affected / exposed
    24 / 355 (6.76%)
    19 / 362 (5.25%)
         occurrences all number
    66
    67
    Hypokalemia
         subjects affected / exposed
    21 / 355 (5.92%)
    31 / 362 (8.56%)
         occurrences all number
    41
    64
    Hypocalcemia
         subjects affected / exposed
    24 / 355 (6.76%)
    21 / 362 (5.80%)
         occurrences all number
    67
    66
    Hypoalbuminemia
         subjects affected / exposed
    27 / 355 (7.61%)
    34 / 362 (9.39%)
         occurrences all number
    50
    50
    Hyponatremia
         subjects affected / exposed
    21 / 355 (5.92%)
    18 / 362 (4.97%)
         occurrences all number
    35
    22
    Bilirubin (hyperbilirubinemia)
         subjects affected / exposed
    74 / 355 (20.85%)
    59 / 362 (16.30%)
         occurrences all number
    166
    131
    Metabolic/Lab - Other
         subjects affected / exposed
    20 / 355 (5.63%)
    26 / 362 (7.18%)
         occurrences all number
    53
    52
    Lipase
         subjects affected / exposed
    13 / 355 (3.66%)
    20 / 362 (5.52%)
         occurrences all number
    24
    57
    Hypophosphatemia
         subjects affected / exposed
    38 / 355 (10.70%)
    39 / 362 (10.77%)
         occurrences all number
    89
    135

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2009
    • Study design and plan: local ablation was deleted as a potentially curative intervention and transplant was added). • Exclusion criteria: Uncontrolled hypertension was defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management and clinically significant peripheral vascular disease was defined as symptomatic. • Removal of subjects from study • Administration of erlotinib and sorafenib was revised • Dose modification was revised • Permissible Concomitant Medications and Therapies were revised • Adverse Event Documentation was clarified for death and nonfatal serious adverse event (SAE) reporting • Detailed information for the genetic biomarker sampling were provided.
    06 Aug 2010
    • Revisions were made to relevant sections of the protocol to include South Africa in the stratification plan for randomization. • For HCC subjects without cirrhosis, the inclusion criterion was revised to add that the mandatory confirmation may also include cytological confirmation. • The use of the IWRS was added to all applicable sections. • Revisions were made to the section on the selection and timing of dose for each subject. • At 3 time points during the treatment period, the provisions under which additional cycles of therapy could be administered were revised to delete the requirements of ANC > 1000/µL and platelets > 50,000/µL. • Clarification was added to the prothrombin time for the calculation of the Child-Pugh score. • A note that strong inhibitors and inducers of CYP3A4 enzyme should be avoided during the study was added. • Statements were added to allow additional assessments to evaluate the status/activity of the hepatitis virus

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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
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