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    Clinical Trial Results:
    A Phase 1 Study of XL184 (Cabozantinib, IND# 116059) in Children and Adolescents with Recurrent or Refractory Solid Tumors, Including CNS Tumors

    Summary
    EudraCT number
    		 2018-004591-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    31 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2021
    First version publication date
    27 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADVL1211
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01709435
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    National Cancer Institute Cancer Therapy Evaluation Program (NCI/CTEP)
    Sponsor organisation address
    9609 Medical Center Drive, Bethesda, United States, MD 20892
    Public contact
    Medical Director, Ipsen Innovation, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen Innovation, clinical.trials@ipsen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001143-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives were to identify a maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), to characterise the toxicity profile, and to describe the pharmacokinetics (PK) of XL184 (cabozantinib) in a population of paediatric subjects aged 2 to 18 years (inclusive).
    Protection of trial subjects
    The study was conducted in accordance with National Cancer Institute (NCI) standards, policies and procedures of NCI and the Children’s Oncology Group (COG) and in accordance with applicable laws. COG is an NCI supported National Clinical Trials Network group. The study was conducted according to the ethical principles of the Declaration of Helsinki. This study was conducted in accordance with all applicable regulatory requirements according to the policies and procedures of NCI and COG.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    0
    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)
    18
    Adolescents (12-17 years)
    19
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 1 limited dose-escalation study was conducted in children and adolescent subjects with recurrent or refractory solid tumors including central nervous system tumors at 16 investigational sites in the United States of America that included at least one subject.

    Pre-assignment
    Screening details
    		 Part A: Dose-escalation phase to determine the MTD and/or RP2D; Part B: an evaluation of subjects with medullary thyroid cancer (MTC) at the MTD/RP2D or below; and PK Expansion: for further collection of PK, safety, and efficacy information at 40 mg/m^2. 41 subjects were enrolled into the study, of whom 39 subjects were treated with XL184.

    Period 1
    Period 1 title
    Treatment Assignment to Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 XL184 30 mg/m^2/day
    Arm description
    		 Subjects were assigned to receive XL184 30 milligrams per meter squared per day (mg/m^2/day) administered orally.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 XL184 40 mg/m^2/day
    Arm description
    		 Subjects were assigned to receive XL184 40 mg/m^2/day administered orally.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 XL184 55 mg/m^2/day
    Arm description
    		 Subjects were assigned to receive XL184 55 mg/m^2/day administered orally.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Started
    6
    23
    12
    Completed
    6
    21
    12
    Not completed
    0
    2
    0
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 XL184 30 mg/m^2/day
    Arm description
    		 Subjects received XL184 30 mg/m^2/day administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabozantinib
    Investigational medicinal product code
    XL184
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    XL184 tablets were administered orally at a starting dose of 30 mg/m^2/day (Dose Level 1). Additional dose levels are 23 mg/m^2/day (Dose Level -1), 30 mg/m^2/day (Dose Level 1), 40 mg/m^2/day (Dose Level 2), and 55 mg/m^2/day (Dose Level 3). The dose was escalated using a rolling six design. Doses were not escalated beyond 55 mg/m^2/day.

    Arm title
    		 XL184 40 mg/m^2/day
    Arm description
    		 Subjects received XL184 40 mg/m^2/day administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabozantinib
    Investigational medicinal product code
    XL184
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    XL184 tablets were administered orally at a starting dose of 30 mg/m^2/day (Dose Level 1). Additional dose levels are 23 mg/m^2/day (Dose Level -1), 30 mg/m^2/day (Dose Level 1), 40 mg/m^2/day (Dose Level 2), and 55 mg/m^2/day (Dose Level 3). The dose was escalated using a rolling six design. Doses were not escalated beyond 55 mg/m^2/day.

    Arm title
    		 XL184 55 mg/m^2/day
    Arm description
    		 Subjects received XL184 55 mg/m^2/day administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabozantinib
    Investigational medicinal product code
    XL184
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    XL184 tablets were administered orally at a starting dose of 30 mg/m^2/day (Dose Level 1). Additional dose levels are 23 mg/m^2/day (Dose Level -1), 30 mg/m^2/day (Dose Level 1), 40 mg/m^2/day (Dose Level 2), and 55 mg/m^2/day (Dose Level 3). The dose was escalated using a rolling six design. Doses were not escalated beyond 55 mg/m^2/day.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 presents data for all subjects assigned treatment. Period 2 presents data for all subjects who received the study drug. The baseline characteristics are based on subjects who were assigned treatment and who received the study drug; therefore, Period 2 is the baseline period.
    Number of subjects in period 2 [2]
    		XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Started
    6
    21
    12
    Completed
    0
    1
    0
    Not completed
    6
    20
    12
         Physician decision
    -
    3
    -
         Adverse event, non-fatal
    1
    -
    2
         Subject/Guardian Decision
    -
    2
    5
         Evidence of Progressive Disease
    5
    15
    5
    Notes
    [2] - 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: Period 1 presents data for all subjects assigned treatment. Period 2 presents data for all subjects who received the study drug. The baseline characteristics are based on subjects who were assigned treatment and who received the study drug; therefore, Period 2 is the baseline period.
    Period 3
    Period 3 title
    Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 XL184 30 mg/m^2/day
    Arm description
    		 Subjects received XL184 30 mg/m^2/day administered orally during the treatment period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 XL184 40 mg/m^2/day
    Arm description
    		 Subjects received XL184 40 mg/m^2/day administered orally during the treatment period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 XL184 55 mg/m^2/day
    Arm description
    		 Subjects received XL184 55 mg/m^2/day administered orally during the treatment period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Started
    6
    17
    10
    Completed
    3
    7
    4
    Not completed
    3
    10
    6
         Death
    3
    6
    5
         Ongoing
    -
    1
    -
         Subject/Guardian Decision
    -
    2
    1
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    XL184 30 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 30 mg/m^2/day administered orally.

    Reporting group title
    XL184 40 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 40 mg/m^2/day administered orally.

    Reporting group title
    XL184 55 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 55 mg/m^2/day administered orally.

    Reporting group values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day Total
    Number of subjects
    		 6 21 12 39
    Age categorical
    Units: Subjects
        <12 years
    		 1 11 6 18
        ≥12 years to ≤18 years
    		 5 10 6 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.2 ± 2.79 11.3 ± 4.53 12.6 ± 3.55 -
    Gender categorical
    Units: Subjects
        Female
    		 2 10 7 19
        Male
    		 4 11 5 20
    Race
    Units: Subjects
        White
    		 3 13 9 25
        Black or African American
    		 2 2 3 7
        Asian
    		 0 3 0 3
        American Indian or Alaska Native
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Unknown
    		 1 3 0 4
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 4 21 11 36
        Hispanic or Latino
    		 2 0 1 3
        Unknown
    		 0 0 0 0
    Body Surface Area (BSA)
    Units: Meters^2
        arithmetic mean (standard deviation)
    		 1.468 ± 0.3916 1.303 ± 0.4673 1.278 ± 0.3058 -
    Subject analysis sets

    Subject analysis set title
    Pooled Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Safety population included all subjects who received at least one dose of study drug.

    Subject analysis sets values
    		 Pooled Analysis
    Number of subjects
    39
    Age categorical
    Units: Subjects
        <12 years
    18
        ≥12 years to ≤18 years
    21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    12.3 ± 4.17
    Gender categorical
    Units: Subjects
        Female
    19
        Male
    20
    Race
    Units: Subjects
        White
    25
        Black or African American
    7
        Asian
    3
        American Indian or Alaska Native
    0
        Native Hawaiian or Other Pacific Islander
    0
        Unknown
    4
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    36
        Hispanic or Latino
    3
        Unknown
    0
    Body Surface Area (BSA)
    Units: Meters^2
        arithmetic mean (standard deviation)
    1.321 ± 0.4079

    End points

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    End points reporting groups
    Reporting group title
    XL184 30 mg/m^2/day
    Reporting group description
    		 Subjects were assigned to receive XL184 30 milligrams per meter squared per day (mg/m^2/day) administered orally.

    Reporting group title
    XL184 40 mg/m^2/day
    Reporting group description
    		 Subjects were assigned to receive XL184 40 mg/m^2/day administered orally.

    Reporting group title
    XL184 55 mg/m^2/day
    Reporting group description
    		 Subjects were assigned to receive XL184 55 mg/m^2/day administered orally.
    Reporting group title
    XL184 30 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 30 mg/m^2/day administered orally.

    Reporting group title
    XL184 40 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 40 mg/m^2/day administered orally.

    Reporting group title
    XL184 55 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 55 mg/m^2/day administered orally.
    Reporting group title
    XL184 30 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 30 mg/m^2/day administered orally during the treatment period.

    Reporting group title
    XL184 40 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 40 mg/m^2/day administered orally during the treatment period.

    Reporting group title
    XL184 55 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 55 mg/m^2/day administered orally during the treatment period.

    Subject analysis set title
    Pooled Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Safety population included all subjects who received at least one dose of study drug.

    Primary: MTD of XL184

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    End point title
    		 MTD of XL184 [1]
    End point description
    The MTD was defined as the highest dose at which fewer than one-third of subjects experienced a dose-limiting toxicity (DLT) during Cycle 1 of therapy. '99999' denotes that the MTD was not reached in this study. The Safety population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Cycle 1 Day 28
    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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Pooled Analysis
    Number of subjects analysed
    39
    Units: mg/m^2/day
        number (not applicable)
    99999
    No statistical analyses for this end point

    Primary: RP2D of XL184

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    End point title
    		 RP2D of XL184 [2]
    End point description
    A RP2D was established based on tolerability, pharmacokinetic parameters and response, if applicable. The Safety population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Cycle 1 Day 28
    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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Pooled Analysis
    Number of subjects analysed
    39
    Units: mg/m^2/day
        number (not applicable)
    40
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment Emergent DLTs During Cycle 1

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    End point title
    		 Number of Subjects with Treatment Emergent DLTs During Cycle 1 [3]
    End point description
    DLTs were defined as non-haematological or haematological drug-related treatment-emergent adverse events (TEAEs). TEAEs are defined as events which started or worsened on or after the first dose of study drug administration up to 30 days (gap period) after the last dose of study drug administration. Any TEAE assessed as not drug-related that required a dose reduction in Cycle 1 was also considered a DLT. The Safety population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Cycle 1 Day 28
    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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    21
    12
    Units: Subjects with DLTs during Cycle 1
    0
    5
    3
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of XL184 on Days 1 and 21 of Cycle 1

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    End point title
    		 Maximum Plasma Concentration (Cmax) of XL184 on Days 1 and 21 of Cycle 1 [4]
    End point description
    The PK analysis was performed on subjects who received at least one oral administration of XL184, without major protocol deviation affecting the PK, who did not experience emesis during the dosing interval and who had sufficient number of plasma concentrations to estimate the main PK parameters. 'n' denotes number of subjects analysed for each category.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 (pre-dose and 4 hours post-dose) and Cycle 1 Day 21 (pre-dose and 2, 4, 8, and 24 hours post-dose)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    16
    12
    Units: nanograms per millilitre
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n= 6, 16, 12)
    278 ± 67.6
    350 ± 73.9
    585 ± 39.1
        Cycle 1 Day 21 (n= 6, 13, 9)
    1854 ± 33.4
    1552 ± 53.0
    2160 ± 37.8
    No statistical analyses for this end point

    Primary: Time to Reach Cmax (Tmax) of XL184 on Cycle 1 Day 21

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    End point title
    		 Time to Reach Cmax (Tmax) of XL184 on Cycle 1 Day 21 [5]
    End point description
    The PK analysis was performed on subjects who received at least one oral administration of XL184, without major protocol deviation affecting the PK, who did not experience emesis during the dosing interval and who had sufficient number of plasma concentrations to estimate the main PK parameters.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 21 (pre-dose and 2, 4, 8, and 24 hours post-dose)
    Notes
    [5] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    13
    9
    Units: hours
        median (full range (min-max))
    2.00 (0.00 to 4.00)
    4.00 (1.85 to 24.03)
    2.00 (1.08 to 25.45)
    No statistical analyses for this end point

    Primary: Time of the last observed plasma concentration (Tlast) of XL184 on Cycle 1 Day 21

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    End point title
    		 Time of the last observed plasma concentration (Tlast) of XL184 on Cycle 1 Day 21 [6]
    End point description
    The PK analysis was performed on subjects who received at least one oral administration of XL184, without major protocol deviation affecting the PK, who did not experience emesis during the dosing interval and who had sufficient number of plasma concentrations to estimate the main PK parameters.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 21 (pre-dose and 2, 4, 8, and 24 hours post-dose)
    Notes
    [6] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    13
    9
    Units: hours
        median (full range (min-max))
    23.74 (8.05 to 24.92)
    24.00 (7.98 to 26.83)
    23.92 (7.08 to 25.45)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve from 0 to 24 Hours Post-dose (AUC0-24 hours) of XL184 on Cycle 1 Day 21

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    End point title
    		 Area Under the Plasma Concentration-time Curve from 0 to 24 Hours Post-dose (AUC0-24 hours) of XL184 on Cycle 1 Day 21 [7]
    End point description
    The PK analysis was performed on subjects who received at least one oral administration of XL184, without major protocol deviation affecting the PK, who did not experience emesis during the dosing interval and who had sufficient number of plasma concentrations to estimate the main PK parameters.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 21 (pre-dose and 2, 4, 8, and 24 hours post-dose)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    4
    11
    6
    Units: nanograms*hours per millilitre
        geometric mean (geometric coefficient of variation)
    29872 ± 35.8
    30230 ± 52.1
    37058 ± 29.8
    No statistical analyses for this end point

    Primary: Apparent Total Clearance (CL/F) of XL184 on Cycle 1 Day 21

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    End point title
    		 Apparent Total Clearance (CL/F) of XL184 on Cycle 1 Day 21 [8]
    End point description
    The PK analysis was performed on subjects who received at least one oral administration of XL184, without major protocol deviation affecting the PK, who did not experience emesis during the dosing interval and who had sufficient number of plasma concentrations to estimate the main PK parameters.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 21 (pre-dose and 2, 4, 8, and 24 hours post-dose)
    Notes
    [8] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    4
    11
    6
    Units: Litres per hour (L/ h)
        geometric mean (geometric coefficient of variation)
    1.64 ± 34.8
    2.04 ± 47.4
    2.11 ± 38.9
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR)

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    End point title
    		 Best Overall Response (BOR)
    End point description
    Disease response was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria (Version 1.1) for subjects with solid tumours. BOR was the best post-baseline response recorded from the start of the treatment until disease progression or recurrence. Central review evaluation of BOR for subjects who responded (Complete Response [CR], Partial Response [PR]) to therapy or have long term stable disease (>= 6 cycles) on protocol therapy. The Evaluable population included all subjects who received at least 85% of the prescribed dose or experienced a DLT.
    End point type
    Secondary
    End point timeframe
    Up to the end of the treatment period, approximately 4 years
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    19
    11
    Units: Subjects
        CR
    0
    0
    0
        PR
    0
    2
    2
        Stable Disease
    2
    5
    1
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Disease response was assessed according to RECIST V1.1 criteria for subjects with solid tumours. DoR was measured from when the time measurement criteria were met for CR or PR (whichever was recorded first) that was subsequently confirmed until the first date that progressive disease was objectively documented, date of death, or censoring date. '9999' denotes no subjects had a partial response in that study arm; '99999' denotes standard deviation cannot be calculated when only one is subject analysed; 'n' denotes number of subjects analysed for each category. The Evaluable population included all subjects who received at least 85% of the prescribed dose or experienced a DLT.
    End point type
    Secondary
    End point timeframe
    Up to the end of the treatment period, approximately 4 years
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    19
    11
    Units: days
    arithmetic mean (standard deviation)
        Partial Response or Stable Disease (n= 2, 7, 3)
    195.0 ± 1.41
    457.0 ± 399.46
    340.7 ± 242.71
        Partial Response (n= 0, 2, 2)
    9999 ± 9999
    868.5 ± 617.30
    346.5 ± 342.95
        Stable Disease (n= 2, 5, 1)
    195.0 ± 1.41
    292.4 ± 159.87
    329.0 ± 99999
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Pharmacodynamic Biomarkers on Days 21 and 28 of Cycle 1

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    End point title
    		 Percentage Change from Baseline in Pharmacodynamic Biomarkers on Days 21 and 28 of Cycle 1
    End point description
    Pharmacodynamic biomarkers included hepatocyte growth factor receptor protein (c-MET), vascular endothelial growth factor receptor 2 (VEGF-R2), hepatocyte growth factor (HGF), GAS 6 receptor (AXL), carbonic anhydrase 9 (CA9), erythropoietin (EPO), osteopontin (OPN), placenta growth factor (PIGF), interleukin-6 (IL-6), and tissue inhibitors of metalloproteinase-1 (TIMP-1). Baseline is the last non-missing result prior to first study drug administration, including unscheduled assessments (where applicable). 'n' denotes number of subjects analysed for each category. The Evaluable population included all subjects who received at least 85% of the prescribed dose or experienced a DLT.
    End point type
    Secondary
    End point timeframe
    Baseline; Days 21 and 28 of Cycle 1
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    15
    10
    Units: Percentage change from baseline (%)
    median (full range (min-max))
        AXL: Cycle 1 Day 21 (n= 6, 15, 10)
    23.92 (8.3 to 48.8)
    21.17 (0.0 to 56.9)
    -8.62 (-31.0 to 56.9)
        AXL: Cycle 1 Day 28 (n= 5, 15, 10)
    24.24 (-1.7 to 93.0)
    18.73 (-10.1 to 58.7)
    -1.99 (-26.5 to 81.6)
        CA9: Cycle 1 Day 21 (n= 6, 15, 10)
    163.05 (36.1 to 1234.1)
    128.37 (-58.4 to 1276.0)
    175.19 (-7.5 to 542.5)
        CA9: Cycle 1 Day 28 (n= 5, 15, 10)
    140.21 (21.1 to 865.3)
    205.52 (-33.8 to 1308.4)
    185.01 (-50.1 to 784.4)
        PIGF: Cycle 1 Day 21 (n= 6, 15, 10)
    81.91 (7.4 to 165.9)
    94.37 (-10.3 to 288.8)
    115.29 (-0.2 to 292.1)
        PIGF: Cycle 1 Day 28 (n= 5, 15, 10)
    86.83 (4.8 to 149.3)
    115.07 (26.8 to 219.0)
    91.20 (-2.6 to 938.7)
        OPN: Cycle 1 Day 21 (n= 6, 15, 10)
    -20.43 (-48.6 to -7.3)
    -12.60 (-54.5 to 22.6)
    -19.13 (-76.2 to 42.0)
        OPN: Cycle 1 Day 28 (n= 5, 15, 10)
    -14.02 (-39.7 to 11.4)
    -10.46 (-54.0 to 128.6)
    -22.00 (-58.9 to 59.8)
        TIMP-1: Cycle 1 Day 21 (n= 6, 15, 10)
    -35.79 (-49.3 to 17.3)
    -36.01 (-64.2 to 37.0)
    -15.10 (-59.5 to 17.9)
        TIMP-1: Cycle 1 Day 28 (n= 5, 15, 10)
    -30.07 (-38.9 to 0.4)
    -24.82 (-69.5 to 31.7)
    -19.71 (-41.7 to 1.5)
        VEGF-R2: Cycle 1 Day 21 (n= 6, 15, 10)
    -12.50 (-24.1 to 5.1)
    -16.61 (-29.9 to -3.2)
    -33.49 (-49.9 to -7.9)
        VEGF-R2: Cycle 1 Day 28 (n= 5, 15, 10)
    -13.44 (-17.9 to -4.1)
    -22.96 (-38.4 to -3.8)
    -37.20 (-49.8 to -2.0)
        c-MET: Cycle 1 Day 21 (n= 6, 15, 10)
    14.70 (4.9 to 40.6)
    11.81 (-23.7 to 39.8)
    -1.70 (-33.3 to 64.1)
        c-MET: Cycle 1 Day 28 (n= 5, 15, 10)
    20.36 (5.8 to 55.6)
    10.96 (-13.4 to 25.2)
    2.63 (-20.9 to 29.1)
        EPO: Cycle 1 Day 21 (n= 6, 15, 10)
    85.99 (2.3 to 229.7)
    5.49 (-56.4 to 204.2)
    27.27 (-74.5 to 183.7)
        EPO: Cycle 1 Day 28 (n= 5, 15, 10)
    99.37 (23.1 to 173.9)
    28.61 (-49.9 to 166.8)
    89.16 (-67.9 to 372.2)
        HGF: Cycle 1 Day 21 (n= 6, 15, 10)
    -23.25 (-54.1 to 12.8)
    -17.32 (-64.4 to 123.9)
    -23.57 (-56.2 to 34.3)
        HGF: Cycle 1 Day 28 (n= 5, 15, 10)
    -6.92 (-52.9 to 53.4)
    -10.76 (-86.1 to 149.1)
    -23.67 (-64.5 to 66.4)
        IL-6: Cycle 1 Day 21 (n= 6, 15, 10)
    8.70 (-93.8 to 504.6)
    0.00 (-76.8 to 6653.0)
    -48.78 (-97.2 to 4972.0)
        IL-6: Cycle 1 Day 28 (n= 5, 15, 10)
    5.01 (0.0 to 224.8)
    0.00 (-90.7 to 7660.6)
    -36.30 (-97.2 to 2859.6)
    Statistical analysis title
    		 AXL: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0349
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 AXL: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0245
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 CA9: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 CA9: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 PIGF: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 PIGF: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 OPN: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0039
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 OPN: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0322
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TIMP-1: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 TIMP-1: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 VEGF-R2: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 VEGF-R2: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 c-MET: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7091
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 c-MET: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5472
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 EPO: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2837
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 EPO: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0498
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 HGF: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7872
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 HGF: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.9999
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 IL-6: Change from Baseline at Cycle 1 Day 21
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.9999
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 IL-6: Change from Baseline at Cycle 1 Day 28
    Statistical analysis description
    Testing the null hypothesis of whether the overall median difference between each post-baseline and baseline visit is zero using Wilcoxon signed-rank test adjusted for multiple comparisons using the Bonferroni correction. Number of subjects included in analysis= 30.
    Comparison groups
    XL184 30 mg/m^2/day v XL184 40 mg/m^2/day v XL184 55 mg/m^2/day
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.9999
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The OS was defined as the time from the start of study treatment until death due to any cause. Survival times were censored at the time when the subject was last known to be alive i.e. at the last recorded visit date. '99999' denotes that the value was not calculable (not reached). The Evaluable population included all subjects who received at least 85% of the prescribed dose or experienced a DLT.
    End point type
    Secondary
    End point timeframe
    Up to the end of the follow-up period, a maximum of approximately 8.5 years
    End point values
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Number of subjects analysed
    6
    19
    11
    Units: months
        median (confidence interval 95%)
    18.93 (1.61 to 22.75)
    34.02 (6.28 to 99999)
    8.48 (5.16 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 30 of the follow-up period, approximately 4 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    XL184 30 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 30 mg/m^2/day administered orally.

    Reporting group title
    XL184 40 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 40 mg/m^2/day administered orally.

    Reporting group title
    XL184 55 mg/m^2/day
    Reporting group description
    		 Subjects received XL184 55 mg/m^2/day administered orally.

    Serious adverse events
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    13 / 21 (61.90%)
    6 / 12 (50.00%)
         number of deaths (all causes)
    3
    6
    5
         number of deaths resulting from adverse events
    1
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Urine output decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Mitral valve disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Tricuspid valve disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (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
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Hydrocephalus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Infections and infestations
    Enterocolitis infectious
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Lung infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 12 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 XL184 30 mg/m^2/day XL184 40 mg/m^2/day XL184 55 mg/m^2/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    21 / 21 (100.00%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 6 (33.33%)
    12 / 21 (57.14%)
    6 / 12 (50.00%)
         occurrences all number
    4
    20
    8
    Flushing
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    2
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 6 (50.00%)
    14 / 21 (66.67%)
    7 / 12 (58.33%)
         occurrences all number
    3
    22
    8
    Pyrexia
         subjects affected / exposed
    2 / 6 (33.33%)
    6 / 21 (28.57%)
    7 / 12 (58.33%)
         occurrences all number
    2
    10
    9
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 21 (19.05%)
    1 / 12 (8.33%)
         occurrences all number
    2
    12
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    4 / 12 (33.33%)
         occurrences all number
    0
    4
    5
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    2
    Gait disturbance
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    Face oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Hypothermia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Genital rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Testicular pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
    9 / 21 (42.86%)
    6 / 12 (50.00%)
         occurrences all number
    3
    16
    8
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    7 / 21 (33.33%)
    4 / 12 (33.33%)
         occurrences all number
    0
    9
    6
    Nasal congestion
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 21 (23.81%)
    2 / 12 (16.67%)
         occurrences all number
    3
    8
    2
    Rhinitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 21 (23.81%)
    3 / 12 (25.00%)
         occurrences all number
    3
    5
    4
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 21 (19.05%)
    2 / 12 (16.67%)
         occurrences all number
    0
    4
    2
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    1
    Atelectasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Tachypnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Pneumothorax
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Sinus disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Sinus pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    4
    1
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 21 (19.05%)
    2 / 12 (16.67%)
         occurrences all number
    0
    7
    3
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 21 (23.81%)
    0 / 12 (0.00%)
         occurrences all number
    0
    7
    0
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    1
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Personality change
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 6 (83.33%)
    15 / 21 (71.43%)
    8 / 12 (66.67%)
         occurrences all number
    9
    33
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 6 (50.00%)
    17 / 21 (80.95%)
    8 / 12 (66.67%)
         occurrences all number
    4
    48
    14
    Weight decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    11 / 21 (52.38%)
    8 / 12 (66.67%)
         occurrences all number
    4
    17
    11
    Platelet count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    14 / 21 (66.67%)
    5 / 12 (41.67%)
         occurrences all number
    1
    24
    12
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 6 (50.00%)
    11 / 21 (52.38%)
    5 / 12 (41.67%)
         occurrences all number
    5
    22
    10
    White blood cell count decreased
         subjects affected / exposed
    5 / 6 (83.33%)
    9 / 21 (42.86%)
    5 / 12 (41.67%)
         occurrences all number
    8
    18
    20
    Neutrophil count decreased
         subjects affected / exposed
    3 / 6 (50.00%)
    7 / 21 (33.33%)
    4 / 12 (33.33%)
         occurrences all number
    5
    16
    15
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 6 (50.00%)
    7 / 21 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    6
    11
    3
    Lipase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    5 / 12 (41.67%)
         occurrences all number
    2
    12
    6
    Haemoglobin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    4
    25
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 21 (4.76%)
    3 / 12 (25.00%)
         occurrences all number
    3
    1
    6
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 21 (19.05%)
    2 / 12 (16.67%)
         occurrences all number
    0
    8
    3
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    10
    1
    Blood cholesterol increased
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    Blood urea increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    2
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    3
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    1
    Carbon dioxide increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Blood chloride decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood chloride increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood phosphorus increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood urea decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Glucose urine present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Haptoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Lipase decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Pancreatic enzymes decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Protein total decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Protein total increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 21 (23.81%)
    1 / 12 (8.33%)
         occurrences all number
    0
    7
    1
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Sunburn
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Wound complication
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    7 / 21 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    0
    8
    5
    Sinus bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    13 / 21 (61.90%)
    4 / 12 (33.33%)
         occurrences all number
    4
    30
    4
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 21 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    0
    9
    0
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    4
    1
    Dysarthria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    hydrocephalus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    8 / 21 (38.10%)
    9 / 12 (75.00%)
         occurrences all number
    2
    13
    18
    Haemolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Eye irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Scleral hyperaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 6 (83.33%)
    15 / 21 (71.43%)
    9 / 12 (75.00%)
         occurrences all number
    11
    41
    18
    Vomiting
         subjects affected / exposed
    2 / 6 (33.33%)
    16 / 21 (76.19%)
    7 / 12 (58.33%)
         occurrences all number
    3
    42
    13
    Nausea
         subjects affected / exposed
    4 / 6 (66.67%)
    13 / 21 (61.90%)
    8 / 12 (66.67%)
         occurrences all number
    7
    34
    13
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    10 / 21 (47.62%)
    3 / 12 (25.00%)
         occurrences all number
    2
    18
    6
    Constipation
         subjects affected / exposed
    2 / 6 (33.33%)
    8 / 21 (38.10%)
    4 / 12 (33.33%)
         occurrences all number
    4
    17
    5
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    4 / 12 (33.33%)
         occurrences all number
    0
    3
    4
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 21 (19.05%)
    1 / 12 (8.33%)
         occurrences all number
    0
    7
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    1
    6
    1
    Oral pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    2
    Anal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Cheilitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Eructation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Hair colour changes
         subjects affected / exposed
    2 / 6 (33.33%)
    8 / 21 (38.10%)
    5 / 12 (41.67%)
         occurrences all number
    2
    8
    5
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    8 / 21 (38.10%)
    5 / 12 (41.67%)
         occurrences all number
    1
    21
    6
    Dry skin
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    8
    2
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 21 (23.81%)
    2 / 12 (16.67%)
         occurrences all number
    0
    6
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    7 / 21 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    7
    0
    Skin hypopigmentation
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    3 / 12 (25.00%)
         occurrences all number
    1
    3
    4
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 21 (19.05%)
    1 / 12 (8.33%)
         occurrences all number
    2
    7
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    1
    Skin ulcer
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    0
    Pain of skin
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    1
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Skin irritation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Skin induration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    3 / 6 (50.00%)
    13 / 21 (61.90%)
    9 / 12 (75.00%)
         occurrences all number
    8
    40
    15
    Haematuria
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    3 / 12 (25.00%)
         occurrences all number
    2
    7
    5
    Urinary tract pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    1
    Chromaturia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Haemoglobinuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Micturition urgency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 6 (33.33%)
    12 / 21 (57.14%)
    7 / 12 (58.33%)
         occurrences all number
    3
    15
    10
    Delayed puberty
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 6 (50.00%)
    7 / 21 (33.33%)
    5 / 12 (41.67%)
         occurrences all number
    4
    9
    6
    Pain in extremity
         subjects affected / exposed
    3 / 6 (50.00%)
    9 / 21 (42.86%)
    3 / 12 (25.00%)
         occurrences all number
    5
    22
    6
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    2
    3
    2
    Joint range of motion decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    2
    5
    0
    Neck pain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    2
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    3
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    Bone pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Joint effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Bone lesion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    2
    8
    1
    Skin infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    3
    Enterocolitis infectious
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Mucosal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    2
    5
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Lymph gland infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Penile infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vulvitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    12 / 21 (57.14%)
    7 / 12 (58.33%)
         occurrences all number
    1
    19
    13
    Hypocalcaemia
         subjects affected / exposed
    3 / 6 (50.00%)
    10 / 21 (47.62%)
    7 / 12 (58.33%)
         occurrences all number
    14
    34
    11
    Hyponatraemia
         subjects affected / exposed
    2 / 6 (33.33%)
    10 / 21 (47.62%)
    4 / 12 (33.33%)
         occurrences all number
    2
    16
    8
    Hyperglycaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    8 / 21 (38.10%)
    5 / 12 (41.67%)
         occurrences all number
    2
    21
    12
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    10 / 21 (47.62%)
    4 / 12 (33.33%)
         occurrences all number
    1
    27
    9
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    6 / 12 (50.00%)
         occurrences all number
    1
    18
    10
    Hypophosphataemia
         subjects affected / exposed
    1 / 6 (16.67%)
    10 / 21 (47.62%)
    3 / 12 (25.00%)
         occurrences all number
    1
    20
    4
    Hypoglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    5 / 12 (41.67%)
         occurrences all number
    2
    13
    9
    Hypomagnesaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 21 (23.81%)
    5 / 12 (41.67%)
         occurrences all number
    3
    14
    12
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 21 (23.81%)
    3 / 12 (25.00%)
         occurrences all number
    0
    6
    3
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    4 / 12 (33.33%)
         occurrences all number
    0
    3
    5
    Hypercalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 21 (0.00%)
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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2012
    Added information was given about XL184, that it had been associated with prolonged QTc, and that medications prolonging QTc were prohibited and medications that may prolong QTc should be avoided where possible. Electrocardiogram assessments were added. It was clarified that subjects were to fast for 2 hours before and 1 hour after taking XL184, and informed consent form was updated accordingly. A definition was added for dose-limiting cardiac toxicity based on QT prolongation: “QTc prolongation >500 milliseconds that persists despite correction of serum electrolyte abnormalities”. A statement was added clarifying that corticosteroids “are not routinely recommended on the study unless deemed absolutely necessary or when used in stable or decreasing doses from the time of study enrolment.”. Revised the dosing nomogram to allow for smaller dosing deviations between the calculated and administered doses of XL184 and to reduce the BSA eligibility requirement to 0.35 mg/m^2 for all subjects enroled on Dose Levels 1, 2, or 3.
    23 Apr 2013
    For subjects who were removed from protocol treatment, annual follow-up evaluations for 5 years were added.
    22 May 2013
    Added evaluation of OS from study entry through a 5-year follow-up period as a trial objective. Clarified follow-up evaluations were to be performed 30 days, 6 months, and then annually up to 5 years after receiving the last dose of study drug. Clarified that OS would be analysed using the Kaplan-Meier method.
    21 Jan 2014
    Updated the Comprehensive Adverse Event and Potential Risk and informed consent document risk profile for XL184.
    16 Apr 2014
    The amendment divided the protocol into a PK expansion cohort (Part A) and a separate MTC cohort of Part B. Based on DLTs observed during the dose escalation phase that was already completed before this amendment, the RP2D was determined to be 40 mg/m^2. The Part B MTC subjects were considered as a separate cohort in the toxicity assessment. An expansion cohort was added to acquire additional PK data at Dose Level 2 (40 mg/m^2), the RP2D. Six evaluable subjects were to be enrolled to Part A of the study for a total of 12 evaluable subjects at Dose Level 2 (six subjects < 12 years of age and six subjects ≥ 12 years of age). The PK schedule was updated to collect additional trough samples at pre-Day 1 before Cycle 4 and pre-Day 1 with each disease evaluation.
    06 Aug 2015
    The requirement to collect trough PK samples with each disease assessment and PK samples at the time of a DLT for subjects remaining on study was removed, because adequate PK sample had been obtained and the commercial sponsor support of PK sample evaluation ended.
    02 May 2016
    The Protocol was amended to reflect modified risk information for XL184 and to update the Comprehensive Adverse Events and Potential Risks (CAEPR) list to Version 2.2, 18 December 2015.
    24 Jan 2017
    The Protocol was amended to reflect modified risk information for XL184 and to update the CAEPR list to Version 2.3, 04 October 2016. The amendment was being submitted in response to a Request for Rapid Amendment.
    02 Jun 2017
    The Protocol was amended to modify disease evaluation requirements for the remaining subjects on the study.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Given the limitation of the dosing schedule, PK parameters on Day 21 (AUC, CL/F) may not represent the PK parameters at steady-state.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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