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    Clinical Trial Results:
    A Randomized, Placebo-Controlled, Phase 1/2 Study of ARQ 197 in Combination with Irinotecan and Cetuximab in Subjects with Metastatic Colorectal Cancer with Wild-Type KRAS Who Have Received Front-Line Systemic Therapy

    Summary
    EudraCT number
    2009-016025-34
    Trial protocol
    DE   IT  
    Global end of trial date
    16 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Sep 2016
    First version publication date
    16 Sep 2016
    Other versions
    Summary report(s)
    Report Synopsis for ARQ197-A-U252

    Trial information

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    Trial identification
    Sponsor protocol code
    ARQ197-A-U252
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01075048
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Pharma Development
    Sponsor organisation address
    399 Thornall Street, Edison, United States, New Jersey 08837
    Public contact
    Jason Mann, Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, United States, +001 732 5905011, jamann@dsi.com
    Scientific contact
    Jason Mann, Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, United States, +001 732 5905011, jamann@dsi.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
    16 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the safety and tolerability of ARQ197 when administered with irinotecan and cetuximab in subjects who had received front-line systemic therapy, to define the Recommended Phase 2 dose (RP2D) study in combination with irinotecan and cetuximab, to estimate the difference in progression-free survival (PFS) between the study and control arms in subjects with Colorectal cancer (CRC) with wild-type k-ras oncogene (KRAS) who have received front-line systemic therapy.
    Protection of trial subjects
    The safety assessments included adverse events, clinical laboratory evaluations, coagulation, vital signs, 12-Lead eElectrocardiogram (ECG), physical examination, and Urinalysis.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jan 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    United States: 76
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    131
    EEA total number of subjects
    16
    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)
    91
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study period: 26 Jan 2010 (First subject first visit) to 16 Dec 2014 (Last subject last visit)

    Pre-assignment
    Screening details
    Overall, 131 subjects were enrolled in the study, with 9 subjects enrolled into the Phase 1 cohort and 122 subjects randomly assigned to ARQ197 or placebo treatment in Phase 2. In Phase 2, 1 (1.7%) enrolled subject in the placebo group did not receive study drug and therefore was not included in the safety analysis set.

    Period 1
    Period 1 title
    Phase 1
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Phase 1
    Arm description
    Subjects were administered with an oral dose of ARQ197 capsules twice daily (BID) with a meal, in escalating doses of 120 milligram (mg), 240 mg, and 360 mg to 3 separate cohorts on Day 1 of Cycle 1 and Cycle 2. Cetuximab 500 milligram per square meter (mg/m^2) intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed by 60 minutes with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    ARQ197
    Investigational medicinal product code
    ARQ197
    Other name
    Tivantinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with an oral dose of ARQ197 capsules twice daily (BID) with a meal, in escalating doses of 120 milligram (mg), 240 mg, and 360 mg to 3 separate cohorts on Day 1 of Cycle 1 and 2.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Cetuximab 500 mg/m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles on Day 1 and Day 15 of each 28 day cycle.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes on Day 1 and Day 15 of each 28 day cycle.

    Number of subjects in period 1 [1]
    Phase 1
    Started
    9
    Completed
    0
    Not completed
    9
         Death
    4
         start of other or new therapy
    4
         Consent withdrawn by subject
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: As baseline period included only for the Phase 1 subjects. Hence, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.
    Period 2
    Period 2 title
    Phase 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo
    Arm description
    Subjects received placebo twice daily with Cetuximab and Irinotecan until disease progression, unacceptable toxicity or other discontinuation. Cetuximab 500 mg/ m^2 intravenous infusion over 120 minutes, then over 60 minutes at subsequent cycles. Followed 60 minutes later with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with placebo twice daily until disease progression, unacceptable toxicity or other discontinuation.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Cetuximab 500 mg/m^2 intravenous infusion until disease progression, unacceptable toxicity or other discontinuation.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Irinotecan 180 mg/m^2 intravenous infusion until disease progression, unacceptable toxicity or other discontinuation.

    Arm title
    ARQ197
    Arm description
    Subject received ARQ197 (recommended Phase 2 dose of 720 mg) daily with Cetuximab and Irinotecan until disease progression, unacceptable toxicity or other discontinuation. Cetuximab 500 mg/m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed 60 minutes later with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Cetuximab 500 mg/m^2 intravenous infusion until disease progression, unacceptable toxicity or other discontinuation.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with Irinotecan 180 mg/m^2 intravenous infusion until disease progression, unacceptable toxicity or other discontinuation.

    Investigational medicinal product name
    ARQ 197
    Investigational medicinal product code
    ARQ 197
    Other name
    Tivantinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with an oral dose of ARQ 197 capsules twice daily (BID) with a meal, until disease progression, unacceptable toxicity or other discontinuation.

    Number of subjects in period 2
    Placebo ARQ197
    Started
    60
    62
    Completed
    0
    0
    Not completed
    60
    62
         Death
    17
    12
         start of other or new therapy
    36
    46
         Consent withdrawn by subject
    6
    3
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    Subjects were administered with an oral dose of ARQ197 capsules twice daily (BID) with a meal, in escalating doses of 120 milligram (mg), 240 mg, and 360 mg to 3 separate cohorts on Day 1 of Cycle 1 and Cycle 2. Cetuximab 500 milligram per square meter (mg/m^2) intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed by 60 minutes with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.

    Reporting group values
    Phase 1 Total
    Number of subjects
    9 9
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    6 6
        From 65-84 years
    3 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.2 ± 14.69 -
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    7 7

    End points

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    End points reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    Subjects were administered with an oral dose of ARQ197 capsules twice daily (BID) with a meal, in escalating doses of 120 milligram (mg), 240 mg, and 360 mg to 3 separate cohorts on Day 1 of Cycle 1 and Cycle 2. Cetuximab 500 milligram per square meter (mg/m^2) intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed by 60 minutes with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo twice daily with Cetuximab and Irinotecan until disease progression, unacceptable toxicity or other discontinuation. Cetuximab 500 mg/ m^2 intravenous infusion over 120 minutes, then over 60 minutes at subsequent cycles. Followed 60 minutes later with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.

    Reporting group title
    ARQ197
    Reporting group description
    Subject received ARQ197 (recommended Phase 2 dose of 720 mg) daily with Cetuximab and Irinotecan until disease progression, unacceptable toxicity or other discontinuation. Cetuximab 500 mg/m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed 60 minutes later with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESEAs)

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    End point title
    Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESEAs) [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which did not necessarily have to have a causal relationship with that treatment. A TEAE was defined as an AE that Had an onset date on or after the first dose of Study Drug, cetuximab, or irinotecan up to and including 30 days after the last dose of any study drug, or Worsened in severity after the first dose of Study Drug relative to the pre-treatment state. Safety population included all subjects who received any amount of study drug and had at least one safety assessment.
    End point type
    Primary
    End point timeframe
    Screening up to End of the Treatment (30 Days After Last Dose)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Phase 1 Placebo ARQ197
    Number of subjects analysed
    9
    59
    62
    Units: Subjects
        TEAEs
    9
    59
    62
        TESAEs
    3
    17
    13
    No statistical analyses for this end point

    Primary: Recommended Phase 2 Dose (RP2D) of ARQ 197

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    End point title
    Recommended Phase 2 Dose (RP2D) of ARQ 197 [2]
    End point description
    RP2D of ARQ 197 was identified when administered along with irinotecan and cetuximab in Phase 1. All enrolled subjects received study drug and were included in the safety analysis set.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Phase 1
    Number of subjects analysed
    9
    Units: milligram
        number (not applicable)
    720
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Progression-Free Survival (PFS)

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    End point title
    Percentage of Subjects With Progression-Free Survival (PFS) [3]
    End point description
    Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. Full analysis set (FAS) included all subjects who were randomized in the Phase 2 portion of the study, received at least one dose of study drug, and had at least one assessment for the efficacy variable. Here '99999' indicates the parameter was not evaluated at that time point.
    End point type
    Primary
    End point timeframe
    Up to 80 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Placebo ARQ197
    Number of subjects analysed
    57
    60
    Units: Months
        median (confidence interval 95%)
    7.3 (5.3 to 9)
    8.3 (5.6 to 10.8)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Best Overall Response and Objective Response Rate

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    End point title
    Number of Subjects With Best Overall Response and Objective Response Rate
    End point description
    Best overall tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria assessed by CT/MRI. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30 percent (%) decrease in the longest diameter of target lesions; Overall Response (OR), CR+PR. All enrolled subjects received study drug and were included in the safety analysis set.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Placebo ARQ197
    Number of subjects analysed
    57
    60
    Units: Subjects
    number (not applicable)
        Complete Response
    0
    0
        Partial Response
    19
    27
        Stable Disease
    22
    22
        Progressive Disease
    13
    9
        Objective Response (CR + PR)
    19
    27
        Inevaluable
    3
    2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Survival (OS)

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    End point title
    Percentage of Subjects With Overall Survival (OS)
    End point description
    Overall survival is defined as the time from randomization date to the date of death. Full analysis set (FAS) included all subjects who were randomized in the Phase 2 portion of the study, received at least one dose of study drug, and had at least one assessment for the efficacy variable. Here '99999' indicates the parameter was not evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Up to 3.8 years
    End point values
    Placebo ARQ197
    Number of subjects analysed
    57
    60
    Units: months
        median (confidence interval 95%)
    16.3 (11.6 to 20.4)
    22.3 (15.4 to 27)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to End of the Treatment (30 Days After Last Dose)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    Subjects were administered with an oral dose of ARQ 197 capsules twice daily (BID) with a meal, in escalating doses of 120 milligram (mg), 240 mg, and 360 mg to 3 separate cohorts on Day 1 of Cycle 1 and 2. Cetuximab 500 milligram per square meter (mg/m^2) intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed by 60 minutes with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo twice daily with Cetuximab and Irinotecan until disease progression, unacceptable toxicity or other discontinuation. Cetuximab 500 mg/m^2 intravenous infusion over 120 minutes, then over 60 minutes at subsequent cycles. Followed 60 minutes later with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.

    Reporting group title
    ARQ197
    Reporting group description
    Subject received ARQ197 (recommended Phase 2 dose of 720 mg) daily with Cetuximab and Irinotecan until disease progression, unacceptable toxicity or other discontinuation. Cetuximab 500 mg/m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Followed 60 minutes later with Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Cetuximab and Irinotecan are administered on Day 1 and Day 15 of each 28 day cycle.

    Serious adverse events
    Phase 1 Placebo ARQ197
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    17 / 59 (28.81%)
    13 / 62 (20.97%)
         number of deaths (all causes)
    0
    3
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena caval occlusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Metastases to bone
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumatosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 59 (6.78%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Phase 1 Placebo ARQ197
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    59 / 59 (100.00%)
    62 / 62 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Flushing
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    1
    1
    2
    Hot flush
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    3
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    2 / 62 (3.23%)
         occurrences all number
    0
    3
    3
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphostasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Varicose vein
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Contrast media allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    3
    Seasonal allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 9 (0.00%)
    6 / 59 (10.17%)
    8 / 62 (12.90%)
         occurrences all number
    0
    19
    12
    Chest discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Chills
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 59 (5.08%)
    2 / 62 (3.23%)
         occurrences all number
    4
    4
    2
    Fatigue
         subjects affected / exposed
    7 / 9 (77.78%)
    21 / 59 (35.59%)
    26 / 62 (41.94%)
         occurrences all number
    14
    35
    44
    Feeling hot
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    0
    3
    2
    Hyperthermia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    4 / 62 (6.45%)
         occurrences all number
    0
    2
    4
    Inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    3
    Infusion site oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Local swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Mucosal dryness
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 59 (5.08%)
    5 / 62 (8.06%)
         occurrences all number
    2
    3
    6
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 9 (22.22%)
    5 / 59 (8.47%)
    4 / 62 (6.45%)
         occurrences all number
    3
    14
    5
    Pain
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    2
    2
    0
    Performance status decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    2 / 9 (22.22%)
    7 / 59 (11.86%)
    4 / 62 (6.45%)
         occurrences all number
    3
    15
    4
    Xerosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Agitation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    1
    2
    1
    Confusional state
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    2 / 9 (22.22%)
    4 / 59 (6.78%)
    3 / 62 (4.84%)
         occurrences all number
    2
    4
    5
    Eating disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 59 (6.78%)
    7 / 62 (11.29%)
         occurrences all number
    1
    4
    11
    Reproductive system and breast disorders
    Vulvovaginal erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Excoriation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Incision site pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Joint sprain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Postoperative hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    0
    Road traffic accident
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Seroma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    2
    Skin laceration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Wound secretion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 59 (5.08%)
    2 / 62 (3.23%)
         occurrences all number
    0
    6
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Blood chloride increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    3
    Blood magnesium decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    3 / 62 (4.84%)
         occurrences all number
    0
    2
    4
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    2
    Cortisol free urine decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    5 / 62 (8.06%)
         occurrences all number
    0
    1
    10
    Heart rate irregular
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 59 (5.08%)
    6 / 62 (9.68%)
         occurrences all number
    0
    3
    10
    Platelet count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Pulse abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 9 (22.22%)
    6 / 59 (10.17%)
    3 / 62 (4.84%)
         occurrences all number
    2
    7
    3
    Weight increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    4 / 62 (6.45%)
         occurrences all number
    1
    1
    6
    Blood calcium decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    3
    Cardiac disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    3
    Sinus tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    4 / 9 (44.44%)
    7 / 59 (11.86%)
    7 / 62 (11.29%)
         occurrences all number
    4
    8
    7
    Dry throat
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    1
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    7 / 59 (11.86%)
    3 / 62 (4.84%)
         occurrences all number
    1
    9
    6
    Dyspnoea exertional
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 59 (3.39%)
    2 / 62 (3.23%)
         occurrences all number
    1
    3
    2
    Hiccups
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Hyperventilation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    2
    3
    0
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    1
    2
    1
    Pleural effusion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Postnasal drip
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Pulmonary congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Rales
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis seasonal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Sinus congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    19 / 59 (32.20%)
    7 / 62 (11.29%)
         occurrences all number
    4
    26
    8
    Febrile neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 59 (5.08%)
    5 / 62 (8.06%)
         occurrences all number
    5
    10
    13
    Lymphopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    3
    Neutropenia
         subjects affected / exposed
    4 / 9 (44.44%)
    13 / 59 (22.03%)
    17 / 62 (27.42%)
         occurrences all number
    12
    26
    35
    Pancytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    5 / 62 (8.06%)
         occurrences all number
    0
    2
    6
    Thrombocytosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Aphasia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 59 (6.78%)
    2 / 62 (3.23%)
         occurrences all number
    1
    5
    2
    Dysarthria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Grand mal convulsion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 9 (22.22%)
    4 / 59 (6.78%)
    7 / 62 (11.29%)
         occurrences all number
    3
    4
    11
    Hypoaesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Hypotonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    2
    Neuropathy peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    3
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Parosmia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Polyneuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Radiculopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Sinus headache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Conjunctival irritation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    3
    Ectropion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Eye allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Growth of eyelashes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    1
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Photophobia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Visual acuity reduced
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Eye disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    3 / 9 (33.33%)
    16 / 59 (27.12%)
    12 / 62 (19.35%)
         occurrences all number
    6
    23
    14
    Abdominal pain lower
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 59 (6.78%)
    7 / 62 (11.29%)
         occurrences all number
    2
    10
    9
    Cheilitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    2
    Colonic fistula
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    11 / 59 (18.64%)
    10 / 62 (16.13%)
         occurrences all number
    1
    19
    20
    Diarrhoea
         subjects affected / exposed
    5 / 9 (55.56%)
    30 / 59 (50.85%)
    33 / 62 (53.23%)
         occurrences all number
    13
    87
    88
    Dry mouth
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    1
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 59 (5.08%)
    3 / 62 (4.84%)
         occurrences all number
    2
    4
    3
    Dysphagia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 59 (8.47%)
    2 / 62 (3.23%)
         occurrences all number
    0
    6
    2
    Gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    0
    6
    Gingival pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    1
    0
    3
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Lip dry
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Lip exfoliation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Lip ulceration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    3
    Nausea
         subjects affected / exposed
    6 / 9 (66.67%)
    27 / 59 (45.76%)
    28 / 62 (45.16%)
         occurrences all number
    22
    59
    68
    Oral pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    1
    Rectal discharge
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 59 (6.78%)
    7 / 62 (11.29%)
         occurrences all number
    3
    7
    14
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    4 / 9 (44.44%)
    17 / 59 (28.81%)
    22 / 62 (35.48%)
         occurrences all number
    6
    33
    42
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Haematuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    0
    Pollakiuria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    7
    Renal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Urinary tract pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatitis toxic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Jaundice
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    3
    Actinic elastosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Alopecia
         subjects affected / exposed
    5 / 9 (55.56%)
    14 / 59 (23.73%)
    17 / 62 (27.42%)
         occurrences all number
    5
    14
    19
    Alopecia totalis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    4
    0
    Dermatitis acneiform
         subjects affected / exposed
    4 / 9 (44.44%)
    9 / 59 (15.25%)
    8 / 62 (12.90%)
         occurrences all number
    5
    17
    20
    Dry skin
         subjects affected / exposed
    4 / 9 (44.44%)
    10 / 59 (16.95%)
    11 / 62 (17.74%)
         occurrences all number
    5
    10
    14
    Erythema
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    2
    6
    1
    Hair colour changes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    Hypertrichosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    2
    Ichthyosis acquired
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Nail bed inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Nail disorder
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    10
    0
    2
    Night sweats
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Onychalgia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    0
    Onychoclasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    0
    10
    Photosensitivity reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 59 (6.78%)
    6 / 62 (9.68%)
         occurrences all number
    1
    5
    6
    Purpura
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    6 / 9 (66.67%)
    34 / 59 (57.63%)
    36 / 62 (58.06%)
         occurrences all number
    14
    69
    69
    Rash generalised
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 59 (1.69%)
    6 / 62 (9.68%)
         occurrences all number
    4
    1
    10
    Rash maculo-papular
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    4 / 62 (6.45%)
         occurrences all number
    1
    1
    8
    Rash pruritic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Rash vesicular
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Scab
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Skin atrophy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Skin disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    3 / 9 (33.33%)
    3 / 59 (5.08%)
    5 / 62 (8.06%)
         occurrences all number
    3
    4
    7
    Skin lesion
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    1
    1
    2
    Skin ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    3 / 62 (4.84%)
         occurrences all number
    0
    6
    4
    Xeroderma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    4
    Arthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Back pain
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 59 (5.08%)
    3 / 62 (4.84%)
         occurrences all number
    1
    5
    4
    Bone pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Exostosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Flank pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    1
    1
    3
    Muscular weakness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    3 / 62 (4.84%)
         occurrences all number
    0
    1
    3
    Pain in jaw
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    2 / 9 (22.22%)
    7 / 59 (11.86%)
    11 / 62 (17.74%)
         occurrences all number
    2
    11
    14
    Dehydration
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 59 (10.17%)
    6 / 62 (9.68%)
         occurrences all number
    1
    9
    6
    Hyperglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    7 / 59 (11.86%)
    4 / 62 (6.45%)
         occurrences all number
    0
    9
    4
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 59 (5.08%)
    0 / 62 (0.00%)
         occurrences all number
    0
    4
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 59 (8.47%)
    3 / 62 (4.84%)
         occurrences all number
    0
    6
    3
    Hypomagnesaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    6 / 59 (10.17%)
    6 / 62 (9.68%)
         occurrences all number
    2
    6
    10
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    2
    Hypophosphataemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Hypouricaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Polydipsia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Abscess neck
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Acute sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    3 / 62 (4.84%)
         occurrences all number
    0
    1
    3
    Candidiasis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    1
    1
    2
    Cystitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Device related infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Eye infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Folliculitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    1
    Herpes simplex
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Herpes zoster
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Hordeolum
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 59 (5.08%)
    1 / 62 (1.61%)
         occurrences all number
    0
    6
    1
    Kidney infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Labyrinthitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    5
    Localised infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Nail infection
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    2
    Oral pustule
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 59 (8.47%)
    6 / 62 (9.68%)
         occurrences all number
    0
    9
    16
    Pharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 59 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Pyoderma
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    1 / 62 (1.61%)
         occurrences all number
    0
    5
    1
    Rash pustular
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    6
    Rhinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    4
    0
    Sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    3
    Skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    2
    Tooth abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    Tooth infection
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 59 (3.39%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    0
    Tracheitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 59 (1.69%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 59 (5.08%)
    1 / 62 (1.61%)
         occurrences all number
    0
    3
    1
    Viral infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 59 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2009
    The amendment was included to clarify the administration of ARQ 197 was changed to be with a meal. A summary of results of a food-effect study (ARQ197-A-U151) was added. Tumor re-evaluation was clarified. The schedule of events was updated to be consistent with changes made to the protocol body text. The entry for the functional assessment of cancer therapy-colorectal (FACT-C) questionnaire in the schedule of assessments was annotated to clarify the testing schedule. Population pharmacokinetic (PK) analysis was changed to population PK/pharmacodynamic analysis.
    20 Apr 2011
    The amendment was included to address changed the last possible study follow-up contact from “12 months after the end of treatment visit” to “12 months after the end of treatment visit for the last subject on the study.” Number of study sites was increased from 25 to 40. Clarified inclusion criteria from “Subjects with surgically unresectable locally advanced or metastatic disease who have received one prior line of chemotherapy. (The Phase 1 portion of the study will be open for enrollment for subjects who received 1 or more prior therapies). Both relapsed and refractory Colorectal cancer (CRC) are allowed.” to “Subjects with surgically unresectable locally advanced or metastatic disease who have received one prior line of chemotherapy, including irinotecan-based chemotherapy. Subjects who received only adjuvant treatment will be eligible if disease progressed less than 6 months after completion of adjuvant therapy. (The Phase 1 portion of the study will be open for enrollment for subjects who received 1 or more prior therapies). Both relapsed and refractory CRC are allowed. Subjects must have radiologically documented disease progression prior to enrollment”. Clarified Exclusion Criteria from “Previous administration of ARQ 197.” to “Previous administration of ARQ 197 (or other known c-MET inhibitor)”. Added the PK analysis of irinotecan and SN-38.

    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.
    Descriptive statistics on PK parameters were not performed. The original sample size was reduced after early termination of enrollment.
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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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