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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects with MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated with One Prior Systemic Therapy

    Summary
    EudraCT number
    2012-003308-10
    Trial protocol
    IT   SE   BE   DE   AT   PT   NL   ES   FR  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Apr 2018
    First version publication date
    19 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARQ197-A-U303
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01755767
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Clinical Trial Information, DAIICHI SANKYO DEVELOPMENT LIMITED, +44 1753482800, info@dsd-eu.com
    Scientific contact
    Clinical Trial Information, DAIICHI SANKYO DEVELOPMENT LIMITED, +44 1753482800, info@dsd-eu.com
    Sponsor organisation name
    ArQule, Inc.
    Sponsor organisation address
    One Wall Street, Burlington, Massachusetts, United States, 01803
    Public contact
    Clinical Trial Information, DAIICHI SANKYO DEVELOPMENT LIMITED, +44 1753482800, info@dsd-eu.com
    Scientific contact
    Clinical Trial Information, DAIICHI SANKYO DEVELOPMENT LIMITED, +44 1753482800, info@dsd-eu.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    28 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Mar 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Evaluate overall survival (OS) among all subjects in the intent-to-treat (ITT) population compared to placebo.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    France: 67
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Italy: 133
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United States: 49
    Worldwide total number of subjects
    383
    EEA total number of subjects
    307
    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)
    164
    From 65 to 84 years
    215
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 383 patients were enrolled in 121 centers throughout Europe, the Americas, and Asia Pacific

    Pre-assignment
    Screening details
    A total of 826 patients were screened but not randomized.

    Period 1
    Period 1 title
    Overall Study (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
    Tivantinib 240 mg BID Cohort
    Arm description
    Patients receive Tivantinib 240 mg, administered as oral tablets twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Tivantinib
    Investigational medicinal product code
    Other name
    ARQ197
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tivantinib tablets for oral administration

    Arm title
    Placebo Matching 240 mg BID Cohort
    Arm description
    Patients receive Placebo, administered as matching oral tablet(s) BID, once in the morning and once in the evening, with food.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets

    Arm title
    Tivantinib 120 mg BID Cohort
    Arm description
    Patients receive Tivantinib 120 mg, administered as oral tablets twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Tivantinib
    Investigational medicinal product code
    Other name
    ARQ197
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tivantinib tablets for oral administration

    Arm title
    Placebo Matching 120 mg BID Cohort
    Arm description
    Patients receive Placebo, administered as matching oral tablet(s) BID, once in the morning and once in the evening, with food.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets

    Number of subjects in period 1
    Tivantinib 240 mg BID Cohort Placebo Matching 240 mg BID Cohort Tivantinib 120 mg BID Cohort Placebo Matching 120 mg BID Cohort
    Started
    28
    15
    226
    114
    Safety Analysis Set
    28
    15
    225
    114
    Intention to Treat Analysis Set
    28
    15
    226
    114
    Efficacy Analysis Set
    0
    0
    226
    114
    Ongoing on the Study Treatment
    0
    0
    5
    2
    Completed
    0
    0
    0
    0
    Not completed
    28
    15
    226
    114
         Patient Decision to Discontinue Treatment
    -
    -
    10
    3
         Progressive disease
    8
    7
    91
    43
         Death
    1
    2
    15
    4
         Radiographic Disease Progression
    9
    4
    44
    27
         Ongoing on the Study Treatment
    -
    -
    5
    2
         Clinical Disease Progression
    4
    2
    29
    20
         Withdrawal of Consent from Treatment and Study
    -
    -
    2
    1
         Adverse event, non-fatal
    6
    -
    28
    11
         Reason Not Provided
    -
    -
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tivantinib 240 mg BID Cohort
    Reporting group description
    Patients receive Tivantinib 240 mg, administered as oral tablets twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.

    Reporting group title
    Placebo Matching 240 mg BID Cohort
    Reporting group description
    Patients receive Placebo, administered as matching oral tablet(s) BID, once in the morning and once in the evening, with food.

    Reporting group title
    Tivantinib 120 mg BID Cohort
    Reporting group description
    Patients receive Tivantinib 120 mg, administered as oral tablets twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg.

    Reporting group title
    Placebo Matching 120 mg BID Cohort
    Reporting group description
    Patients receive Placebo, administered as matching oral tablet(s) BID, once in the morning and once in the evening, with food.

    Reporting group values
    Tivantinib 240 mg BID Cohort Placebo Matching 240 mg BID Cohort Tivantinib 120 mg BID Cohort Placebo Matching 120 mg BID Cohort Total
    Number of subjects
    28 15 226 114 383
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.6 ± 9.34 64.9 ± 7.38 65.6 ± 10.13 64.7 ± 10.23 -
    Gender categorical
    Units: Subjects
        Female
    4 0 27 7 38
        Male
    24 15 199 107 345

    End points

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    End points reporting groups
    Reporting group title
    Tivantinib 240 mg BID Cohort
    Reporting group description
    Patients receive Tivantinib 240 mg, administered as oral tablets twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.

    Reporting group title
    Placebo Matching 240 mg BID Cohort
    Reporting group description
    Patients receive Placebo, administered as matching oral tablet(s) BID, once in the morning and once in the evening, with food.

    Reporting group title
    Tivantinib 120 mg BID Cohort
    Reporting group description
    Patients receive Tivantinib 120 mg, administered as oral tablets twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg.

    Reporting group title
    Placebo Matching 120 mg BID Cohort
    Reporting group description
    Patients receive Placebo, administered as matching oral tablet(s) BID, once in the morning and once in the evening, with food.

    Primary: Rate of Overall Survival (OS) within 36 Months

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    End point title
    Rate of Overall Survival (OS) within 36 Months [1]
    End point description
    OS is defined as the time from randomization to the date of death (i.e., the length of time from the start of treatment that patients are still alive). Rate of OS (Percentage of Patients Still Alive) is determined in the efficacy analysis set (Intent to Treat in the 120 mg BID Cohort) every 3 months for 36 months.
    End point type
    Primary
    End point timeframe
    within 36 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy population includes only patients in the intent to treat 120 mg BID Cohort
    End point values
    Tivantinib 120 mg BID Cohort Placebo Matching 120 mg BID Cohort
    Number of subjects analysed
    226
    114
    Units: Percentage of patients
    number (confidence interval 95%)
        at 3 Months
    86.62 (81.43 to 90.45)
    85.88 (77.99 to 91.10)
        at 6 Months
    61.17 (54.46 to 67.20)
    70.83 (61.51 to 78.29)
        at 9 Months
    46.88 (40.23 to 53.25)
    50.47 (40.93 to 59.24)
        at 12 Months
    36.61 (30.34 to 42.90)
    38.01 (29.11 to 46.86)
        at 15 Months
    30.22 (24.25 to 36.38)
    28.16 (20.04 to 36.82)
        at 18 Months
    25.09 (19.40 to 31.16)
    21.88 (14.29 to 30.51)
        at 21 Months
    21.25 (15.80 to 27.24)
    15.95 (9.11 to 24.51)
        at 24 Months
    16.19 (11.01 to 22.25)
    12.16 (5.91 to 20.79)
        at 27 Months
    13.95 (8.88 to 20.13)
    4.86 (1.05 to 13.44)
        at 30 Months
    13.95 (8.88 to 20.13)
    4.86 (1.05 to 13.44)
        at 33 Months
    13.95 (8.88 to 20.13)
    4.86 (1.05 to 13.44)
        at 36 Months
    0.00 (0.00 to 0.00)
    4.86 (1.05 to 13.44)
    Statistical analysis title
    Unstratified COX Regression Analysis
    Comparison groups
    Tivantinib 120 mg BID Cohort v Placebo Matching 120 mg BID Cohort
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7246 [2]
    Method
    Logrank
    Parameter type
    Unstratified COX Regression Analysis
    Point estimate
    0.9555
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.744
         upper limit
    1.2271
    Notes
    [2] - Unstratified

    Secondary: Rate of Progression Free Survival (PFS) within 10 months

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    End point title
    Rate of Progression Free Survival (PFS) within 10 months [3]
    End point description
    PFS is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause. Rate of PFS (Percentage of Patients Still Alive without Disease Progression) is determined in the efficacy analysis set (Intent to Treat in the 120 mg BID Cohort) every 2 months for 10 months.
    End point type
    Secondary
    End point timeframe
    within 10 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy population includes only patients in the intent to treat 120 mg BID Cohort
    End point values
    Tivantinib 120 mg BID Cohort Placebo Matching 120 mg BID Cohort
    Number of subjects analysed
    221
    114
    Units: percentage of patients
    number (confidence interval 95%)
        at 2 Months
    50.02 (43.20 to 56.45)
    49.23 (39.51 to 58.22)
        at 4 Months
    27.21 (21.41 to 33.32)
    27.99 (19.78 to 36.77)
        at 6 Months
    13.86 (9.56 to 18.95)
    12.50 (6.92 to 19.80)
        at 8 Months
    8.78 (5.39 to 13.18)
    5.21 (1.95 to 10.88)
        at 10 Months
    4.96 (2.50 to 8.67)
    5.21 (1.95 to 10.88)
    Statistical analysis title
    Unstratified COX Regression Analysis
    Comparison groups
    Tivantinib 120 mg BID Cohort v Placebo Matching 120 mg BID Cohort
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8044 [4]
    Method
    Logrank
    Parameter type
    Hazard Ratio Relative to Placebo
    Point estimate
    0.9675
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7634
         upper limit
    1.2263
    Notes
    [4] - Unstratified

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent Adverse Events (TEAEs) are collected from the first day of treatment until the end of treatment plus a 30-day Safety Follow-up, for a total of 1519 days for Serious Adverse Events and 1489 days for non-serious adverse events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Tivantinib
    Reporting group description
    Tivantinib administered by oral tablet

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo administered by oral tablet

    Serious adverse events
    Tivantinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    120 / 253 (47.43%)
    61 / 129 (47.29%)
         number of deaths (all causes)
    208
    108
         number of deaths resulting from adverse events
    51
    12
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver carcinoma ruptured
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour embolism
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 253 (1.19%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 253 (0.79%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    11 / 253 (4.35%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 2
         deaths causally related to treatment / all
    0 / 8
    0 / 1
    Implant site haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Adrenal gland injury
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic enzyme increased
         subjects affected / exposed
    3 / 253 (1.19%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    6 / 253 (2.37%)
    3 / 129 (2.33%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 253 (1.58%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 253 (1.58%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 253 (0.40%)
    3 / 129 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    4 / 253 (1.58%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 253 (1.58%)
    3 / 129 (2.33%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 253 (1.19%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    9 / 253 (3.56%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (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
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord paralysis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 253 (1.19%)
    4 / 129 (3.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    7 / 253 (2.77%)
    5 / 129 (3.88%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    3 / 129 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    9 / 253 (3.56%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    1 / 13
    1 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    7 / 253 (2.77%)
    5 / 129 (3.88%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 253 (1.19%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic failure
         subjects affected / exposed
    6 / 253 (2.37%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    Hepatorenal failure
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hepatotoxicity
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Liver injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure acute
         subjects affected / exposed
    4 / 253 (1.58%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    Renal impairment
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral meatus stenosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         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
    Arthralgia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 129 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolic acidosis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 253 (2.77%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 253 (0.79%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tivantinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    224 / 253 (88.54%)
    111 / 129 (86.05%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 253 (7.51%)
    6 / 129 (4.65%)
         occurrences all number
    22
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    55 / 253 (21.74%)
    27 / 129 (20.93%)
         occurrences all number
    77
    37
    Fatigue
         subjects affected / exposed
    58 / 253 (22.92%)
    34 / 129 (26.36%)
         occurrences all number
    74
    46
    Oedema peripheral
         subjects affected / exposed
    61 / 253 (24.11%)
    20 / 129 (15.50%)
         occurrences all number
    85
    23
    Pyrexia
         subjects affected / exposed
    34 / 253 (13.44%)
    14 / 129 (10.85%)
         occurrences all number
    47
    28
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 253 (3.95%)
    7 / 129 (5.43%)
         occurrences all number
    10
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 253 (3.56%)
    9 / 129 (6.98%)
         occurrences all number
    12
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 253 (5.93%)
    13 / 129 (10.08%)
         occurrences all number
    18
    13
    Blood bilirubin increased
         subjects affected / exposed
    13 / 253 (5.14%)
    5 / 129 (3.88%)
         occurrences all number
    14
    5
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    33 / 253 (13.04%)
    0 / 129 (0.00%)
         occurrences all number
    34
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    50 / 253 (19.76%)
    17 / 129 (13.18%)
         occurrences all number
    73
    28
    Neutropenia
         subjects affected / exposed
    42 / 253 (16.60%)
    7 / 129 (5.43%)
         occurrences all number
    94
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    37 / 253 (14.62%)
    11 / 129 (8.53%)
         occurrences all number
    40
    12
    Dyspnoea
         subjects affected / exposed
    22 / 253 (8.70%)
    7 / 129 (5.43%)
         occurrences all number
    27
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 253 (6.32%)
    4 / 129 (3.10%)
         occurrences all number
    22
    4
    Headache
         subjects affected / exposed
    13 / 253 (5.14%)
    3 / 129 (2.33%)
         occurrences all number
    14
    4
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    11 / 253 (4.35%)
    8 / 129 (6.20%)
         occurrences all number
    13
    9
    Abdominal pain
         subjects affected / exposed
    47 / 253 (18.58%)
    32 / 129 (24.81%)
         occurrences all number
    64
    38
    Abdominal pain upper
         subjects affected / exposed
    29 / 253 (11.46%)
    16 / 129 (12.40%)
         occurrences all number
    39
    17
    Ascites
         subjects affected / exposed
    51 / 253 (20.16%)
    29 / 129 (22.48%)
         occurrences all number
    66
    39
    Constipation
         subjects affected / exposed
    29 / 253 (11.46%)
    15 / 129 (11.63%)
         occurrences all number
    38
    17
    Diarrhoea
         subjects affected / exposed
    53 / 253 (20.95%)
    19 / 129 (14.73%)
         occurrences all number
    72
    24
    Dyspepsia
         subjects affected / exposed
    14 / 253 (5.53%)
    9 / 129 (6.98%)
         occurrences all number
    16
    11
    Nausea
         subjects affected / exposed
    54 / 253 (21.34%)
    14 / 129 (10.85%)
         occurrences all number
    73
    16
    Vomiting
         subjects affected / exposed
    28 / 253 (11.07%)
    13 / 129 (10.08%)
         occurrences all number
    52
    17
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    26 / 253 (10.28%)
    23 / 129 (17.83%)
         occurrences all number
    34
    30
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 253 (7.51%)
    6 / 129 (4.65%)
         occurrences all number
    24
    9
    Back pain
         subjects affected / exposed
    20 / 253 (7.91%)
    13 / 129 (10.08%)
         occurrences all number
    20
    13
    Musculoskeletal pain
         subjects affected / exposed
    9 / 253 (3.56%)
    9 / 129 (6.98%)
         occurrences all number
    13
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    38 / 253 (15.02%)
    24 / 129 (18.60%)
         occurrences all number
    45
    34
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 253 (3.56%)
    7 / 129 (5.43%)
         occurrences all number
    9
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2013
    Changed frequency of hematology testing and dose reduction requirements following recommendations from Data Monitoring Committee (DMC). Clarified in synopsis minimum requirement for regional lymph node to be considered involved (previously clarification was only in body of protocol). Corrected language that remained in error in the original protocol regarding stopping rules for subject treatment. Protocol now was consistent throughout with existing details in Section 4.2.1, Table 4.1. Updated to reflect the fact that the LabCorp IHC assay now has IDE approval for investigational use in this study and that assay has CE mark in EU. .Revised minimum number of tissue slides required per current lab manual. Revised language to account for the fact that some sites have a single consent form for the entire study while others had separate consent forms for various portions of the study. Corrected discrepancy in protocol regarding timing of PK on Cycle 1 Day 22. Protocol now was consistent throughout with existing details in Section 8.1. Following multiple queries, added clarification on use, storage and destruction of tissue samples for this study. Corrected typo (symbol for ≤ corrected to ≥) and added clarity on Hy’s Law definition.
    29 Aug 2013
    Added exclusion criterion number 14 to exclude subjects with pleural effusion or clinically evident (visible or palpable) ascites following recommendations from Data Monitoring Committee (DMC). Such subjects may have been more susceptible to infections and more at risk if they were to develop neutropenia. Reduced starting dose from 240 mg BID to 120 mg BID following recommendations from DMC as higher than expected rate of severe neutropenia was seen at original starting dose of 240 mg BID and exposure was noted to be higherthan it was in the phase 2 HCC study. Updated clinical experience section and study rationale section to distinguish which prior studies used capsule formulation and which used tablet formulation and to clarify that in this study tablet formulation was used. Updated dose modifications section to allow one lower level dose reduction given that starting dose had been reduced following recommendations from DMC. Changed visit schedule to increase frequency of hematology testing during Cycle 1 following recommendations from DMC. Hematology must have now been performed every 2 days during cycle 1. This would help more closely monitor any changes in neutrophil values and take action more quickly if necessary. Updated contact information for CRO physician to generic contact as named physician was terminating employment. The updated contact information was valid even if the assigned CRO physician changed again in the future.
    13 Sep 2013
    Added description and rationale for the change of study design (eg, reduced dose) and subject grouping (2 cohorts: 120 mg cohort and 240 mg cohort) for statistical analyses. Updated study design due to reduced dose. Updated synopsis and statistical methods section to reflect that the efficacy analyses was to be performed only for the 120 mg cohort as 120 mg BID was the intended dose regimen for approval. Updated statistical methods section to reflect that the safety analyses and summary of disposition, demographic and baseline characteristics, and exposure were to be performed separately for the 120 mg and 240 mg cohorts. Updated the section of Risks and Benefits for Study Subjects to incorporate additional DMC review for the 120 mg cohort based on the DMC recommendation. An administrative update to make protocol PK and ECG schedule consistent with section 6.5.2. Editorial changes
    17 Dec 2013
    Updated to confirm enrollment could continue per new recommendations from the DMC after complete review of neutrophil count data on 15 November, 2013. For consistency, updated protocol so that retesting of hematology through resolution of AE was consistent regardless of whether neutropenia was grade 2, 3 or 4. Reduced frequency of hematology monitoring during the first cycle. Of the 29 subjects treated at 120 mg BID by 15 November 2013, 26 were treated from between 1 and 2½ months and 3 were treated for at least 3 weeks. After reviewing the Absolute Neutrophil Count (ANC) data provided on 15 November 2013, the DMC advised that the frequency of hematology monitoring during the first cycle could be reduced from every 2 days to every 4 days. Re-wrote sections regarding re-screening of subjects to more clearly distinguish between subjects requiring full re-screening and those who needed to send in fresh biopsy after MET low result initially received. Protocol section 4.2.3 and 6.1 were now consistent with footnote 6 in Appendix 17.1. Furthermore we clarified the timeframe between notification of MET-high status and initiation of screening procedures. Corrected typographical error in Section 5.1.2. Following suggestions from some regulatory agencies, modified the frequency of hematology testing post Cycle 1 to allow for a more gradual decrease in frequency of hematology testing between Cycle 1 and subsequent cycles. Instead of testing hematology twice a month in Cycle 2, it would be tested on weekly basis during Cycle 2 before reverting to twice a month testing in subsequent cycles.
    17 Mar 2016
    Updated current address of ArQule, Inc. co-sponsor of the study. Changed sponsor representative who signs the protocol approval page. In the event of a positive study showing significant difference favoring tivantinib over placebo, updated various sections in the protocol to allow for the possibility of subjects randomized to placebo to receive active treatment with tivantinib. This would occur after database lock and unblinding. The protocol was amended also to specify the safety eligibility criteria such patients would have to meet in order to receive active treatment. Added a definition of “end of trial” to the protocol. Added a sentence to clarify that after database lock, additional data will be reviewed via listings. Clarified that subjects unblinded before database lock would have to discontinue treatment immediately. Added updated standardized language to the protocol regarding drug accountability (which matches the process being followed to-date). Removed language requiring that MRI be used exclusively in certain countries. Listed safety procedures that are required at the time they start tivantinib for any subjects randomized to placebo who then receives tivantinib after database lock and unblinding (if the study is positive). Corrected typo to clarify that Alpha Fetoprotein (AFP) is collected at screening and not on Day 1. This is now consistent throughout all sections of the protocol. Added clarification language to one sentence in the statistical section. Updated wording in Child Pugh appendix to make consistent with wording in the body of the protocol.

    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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