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    Clinical Trial Results:
    Phase 1, Open Label, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of CP-751,871 in Patients with Advanced Solid Tumours

    Summary
    EudraCT number
    2005-001224-36
    Trial protocol
    GB  
    Global end of trial date
    26 Oct 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    26 Mar 2016
    First version publication date
    02 Aug 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Reporting periods and duplicate AEs in their data
    Summary report(s)
    A4021010 EU Posting

    Trial information

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    Trial identification
    Sponsor protocol code
    A4021010
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00474760
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001800 718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001800 718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 May 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To define the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of CP-751,871 in patients with advanced solid tumors.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Aug 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 38
    Worldwide total number of subjects
    65
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    57
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A Total 65 subjects from two countries received the study drug. The duration of the study was 01 August 2005 to 26 October 2012 and no enrollments were made after 03 September 2008 .

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Figitumumab 3 mg/kg
    Arm description
    Figitumumab 3 milligram per kilogram (mg/kg) administered as an intravenous (IV) infusion on Day 1 of each cycle for dose escalation cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 3 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration).

    Arm title
    Figitumumab 6 mg/kg
    Arm description
    Figitumumab 6 mg/kg administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 6 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration).

    Arm title
    Figitumumab 10 mg/kg
    Arm description
    Figitumumab 10 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 10 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration).

    Arm title
    Figitumumab 20 mg/kg
    Arm description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    CP- 751,871
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration).

    Arm title
    Figitumumab 20 mg/kg RP2D
    Arm description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for recommended Phase 2 dose [RP2D] extension cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration).

    Arm title
    Figitumumab 20 mg/kg RP2D ACC+Sarcoma
    Arm description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for RP2D adrenocortical carcinoma [ACC] and sarcoma extension cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration).

    Arm title
    Figitumumab 20 mg/kg RP2D ESFT
    Arm description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (4 weeks in duration) for RP2D Ewing’s sarcoma family of tumors [ESFT] extension cohort.
    Arm type
    Experimental

    Investigational medicinal product name
    Figitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (4 weeks in duration).

    Number of subjects in period 1
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D Figitumumab 20 mg/kg RP2D ACC+Sarcoma Figitumumab 20 mg/kg RP2D ESFT
    Started
    3
    3
    3
    3
    13
    29
    11
    Completed
    0
    0
    0
    0
    1
    0
    1
    Not completed
    3
    3
    3
    3
    12
    29
    10
         Death
    -
    -
    -
    -
    2
    -
    -
         Withdrawal by Subject
    -
    -
    -
    1
    -
    1
    1
         Terminated by sponsor
    -
    -
    -
    -
    -
    -
    2
         Laboratory abnormality
    -
    -
    -
    -
    -
    1
    -
         Progressive disease
    3
    2
    3
    2
    8
    20
    7
         Unspecified
    -
    1
    -
    -
    1
    -
    -
         Adverse Event
    -
    -
    -
    -
    1
    7
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Figitumumab 3 mg/kg
    Reporting group description
    Figitumumab 3 milligram per kilogram (mg/kg) administered as an intravenous (IV) infusion on Day 1 of each cycle for dose escalation cohort.

    Reporting group title
    Figitumumab 6 mg/kg
    Reporting group description
    Figitumumab 6 mg/kg administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    Figitumumab 10 mg/kg
    Reporting group description
    Figitumumab 10 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    Figitumumab 20 mg/kg
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    Figitumumab 20 mg/kg RP2D
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for recommended Phase 2 dose [RP2D] extension cohort.

    Reporting group title
    Figitumumab 20 mg/kg RP2D ACC+Sarcoma
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for RP2D adrenocortical carcinoma [ACC] and sarcoma extension cohort.

    Reporting group title
    Figitumumab 20 mg/kg RP2D ESFT
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (4 weeks in duration) for RP2D Ewing’s sarcoma family of tumors [ESFT] extension cohort.

    Reporting group values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D Figitumumab 20 mg/kg RP2D ACC+Sarcoma Figitumumab 20 mg/kg RP2D ESFT Total
    Number of subjects
    3 3 3 3 13 29 11 65
    Age categorical
    Units: Subjects
        Less than (<) 70 years
    3 3 3 3 13 28 11 64
        Equal to or greater than (>=) 70 years
    0 0 0 0 0 1 0 1
    Gender categorical
    Units: Subjects
        Female
    1 2 1 0 1 13 3 21
        Male
    2 1 2 3 12 16 8 44

    End points

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    End points reporting groups
    Reporting group title
    Figitumumab 3 mg/kg
    Reporting group description
    Figitumumab 3 milligram per kilogram (mg/kg) administered as an intravenous (IV) infusion on Day 1 of each cycle for dose escalation cohort.

    Reporting group title
    Figitumumab 6 mg/kg
    Reporting group description
    Figitumumab 6 mg/kg administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    Figitumumab 10 mg/kg
    Reporting group description
    Figitumumab 10 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    Figitumumab 20 mg/kg
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    Figitumumab 20 mg/kg RP2D
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for recommended Phase 2 dose [RP2D] extension cohort.

    Reporting group title
    Figitumumab 20 mg/kg RP2D ACC+Sarcoma
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (3 weeks in duration) for RP2D adrenocortical carcinoma [ACC] and sarcoma extension cohort.

    Reporting group title
    Figitumumab 20 mg/kg RP2D ESFT
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion on Day 1 of each cycle (4 weeks in duration) for RP2D Ewing’s sarcoma family of tumors [ESFT] extension cohort.

    Subject analysis set title
    Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for RP2D, and RP2D ACC and sarcoma extension cohorts.

    Primary: Number of Subjecs With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjecs With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE was any untoward medical occurrence in a subjects who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 150 days after last dose that were absent before treatment or that worsened relative to pretreatment state. All enrolled subjects who started treatment.
    End point type
    Primary
    End point timeframe
    Baseline up to 150 days after the last administration of study drug
    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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D Figitumumab 20 mg/kg RP2D ACC+Sarcoma Figitumumab 20 mg/kg RP2D ESFT
    Number of subjects analysed
    3
    3
    3
    3
    13
    29
    11
    Units: subjects
        AEs
    3
    3
    3
    3
    13
    29
    11
        SAEs
    2
    1
    3
    1
    5
    17
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Dose Limiting Toxicities (DLTs)

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    End point title
    Number of Subjects With Dose Limiting Toxicities (DLTs) [2] [3]
    End point description
    DLTs were defined as any 1 of the following adverse events (AEs) that occurred in Cycle 1 following treatment with figitumumab and was considered related to the drug: Any National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version (v) 3.0 (CTCAE) Grade greater than equal to (>=4) treatment-related hematologic AEs (that lasted greater than (>)7 days) and/or required therapy, Any CTCAE Grade >=3 treatment-related non-hematologic AEs despite optimal supportive care, Grade 2 or greater allergic reaction or infusion reaction (required therapy but responded promptly to symptomatic treatment) that affected vital organs and Mitral valve regurgitation > mild. Safety Population
    End point type
    Primary
    End point timeframe
    Baseline up to Day 28 (end of cycle 1)
    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: DLTs was analysed in all subjects.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: DLTs was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg , 10 mg/kg , 20 mg/kg , reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    Units: subjects
        number (not applicable)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) in Cycle 1

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    End point title
    Maximum Observed Plasma Concentration (Cmax) in Cycle 1 [4]
    End point description
    All subjects treated who had at least 1 of the pharmacokinetic (PK) parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Cmax in Cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg , 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [5]
    3 [6]
    3 [7]
    3 [8]
    9 [9]
    34 [10]
    Units: milligram/liter (mg/L)
        arithmetic mean (standard deviation)
    57.77 ± 2.658
    134.7 ± 31.754
    211 ± 59.808
    463 ± 97.964
    392 ± 90.308
    457.5 ± 135.68
    Notes
    [5] - N=number of subjects evaluable for the outcome measure.
    [6] - N=number of subjects evaluable for the outcome measure.
    [7] - N=number of subjects evaluable for the outcome measure.
    [8] - N=number of subjects evaluable for the outcome measure.
    [9] - N=number of subjects evaluable for the outcome measure.
    [10] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) in Cycle 4

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    End point title
    Maximum Observed Plasma Concentration (Cmax) in Cycle 4 [11]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Cmax in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    6 [12]
    16 [13]
    Units: mg/L
        arithmetic mean (standard deviation)
    650.8 ± 169.92
    697.2 ± 165.4
    Notes
    [12] - N=number of subjects evaluable for the outcome measure.
    [13] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) in Cycle 1

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax) in Cycle 1 [14]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tmax in cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg, 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [15]
    3 [16]
    3 [17]
    3 [18]
    9 [19]
    34 [20]
    Units: Hours
        arithmetic mean (standard deviation)
    8.361 ± 13.552
    1.147 ± 0.117
    1.043 ± 0.075
    0.678 ± 0.558
    3.441 ± 7.718
    9.394 ± 28.527
    Notes
    [15] - N=number of subjects evaluable for the outcome measure.
    [16] - N=number of subjects evaluable for the outcome measure.
    [17] - N=number of subjects evaluable for the outcome measure.
    [18] - N=number of subjects evaluable for the outcome measure.
    [19] - N=number of subjects evaluable for the outcome measure.
    [20] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) in Cycle 4

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax) in Cycle 4 [21]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tmax in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only. 
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    6 [22]
    16 [23]
    Units: Hours
        arithmetic mean (standard deviation)
    4.84 ± 9.436
    7.541 ± 16.343
    Notes
    [22] - N=number of subjects evaluable for the outcome measure.
    [23] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Plasma Decay Half-Life (t1/2) in Cycle 1

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    End point title
    Plasma Decay Half-Life (t1/2) in Cycle 1 [24]
    End point description
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks. Here "99999" in the standard deviation signifies not available (NA). Standard deviation was not calculated as only 1 subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: t1/2 in Cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg, 6 mg/kg, 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D) and 20 mg/kg (RP2D ESFT) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D Figitumumab 20 mg/kg RP2D ESFT
    Number of subjects analysed
    2 [25]
    1 [26]
    3 [27]
    1 [28]
    8 [29]
    2 [30]
    Units: Hours
        arithmetic mean (standard deviation)
    203 ± 7.071
    226 ± 99999
    252.3 ± 56.713
    227 ± 99999
    259.6 ± 80.5
    319 ± 8.485
    Notes
    [25] - N=number of subjects evaluable for the outcome measure.
    [26] - N=number of subjects evaluable for the outcome measure.
    [27] - N=number of subjects evaluable for the outcome measure.
    [28] - N=number of subjects evaluable for the outcome measure.
    [29] - N=number of subjects evaluable for the outcome measure.
    [30] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Plasma Decay Half-Life (t1/2) in Cycle 4

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    End point title
    Plasma Decay Half-Life (t1/2) in Cycle 4 [31]
    End point description
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: t1/2 in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [32]
    5 [33]
    Units: Hours
        arithmetic mean (standard deviation)
    479.7 ± 163.59
    386 ± 172.16
    Notes
    [32] - N=number of subjects evaluable for the outcome measure.
    [33] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Last Quantifiable Concentration (Tlast) in Cycle 1

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    End point title
    Time to Reach Last Quantifiable Concentration (Tlast) in Cycle 1 [34]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tlast in Cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg, 6 mg/kg, 10 mg/kg, 20 mg/kg, 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [35]
    3 [36]
    3 [37]
    3 [38]
    9 [39]
    34 [40]
    Units: Hours
        arithmetic mean (standard deviation)
    501 ± 4.583
    443 ± 96.995
    523.7 ± 41.041
    498.3 ± 1.155
    666.7 ± 3.082
    509.5 ± 100.13
    Notes
    [35] - N=number of subjects evaluable for the outcome measure.
    [36] - N=number of subjects evaluable for the outcome measure.
    [37] - N=number of subjects evaluable for the outcome measure.
    [38] - N=number of subjects evaluable for the outcome measure.
    [39] - N=number of subjects evaluable for the outcome measure.
    [40] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Last Quantifiable Concentration (Tlast) in Cycle 4

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    End point title
    Time to Reach Last Quantifiable Concentration (Tlast) in Cycle 4 [41]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tlast in cycle was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    6 [42]
    16 [43]
    Units: Hours
        arithmetic mean (standard deviation)
    743.7 ± 100.81
    418.7 ± 227.37
    Notes
    [42] - N=number of subjects evaluable for the outcome measure.
    [43] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Systemic Clearance (CL) in Cycle 1

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    End point title
    Systemic Clearance (CL) in Cycle 1 [44]
    End point description
    CL is a quantitative measure of the rate at which a drug substance is removed from the body. All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks. Here "99999" in the standard deviation signifies not available (NA). Standard deviation was not calculated as only 1 subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Systemic CL in Cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg , 10 mg /kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    2 [45]
    1 [46]
    3 [47]
    1 [48]
    2 [49]
    7 [50]
    Units: milliliter/day/kilogram (mL/day/kg)
        arithmetic mean (standard deviation)
    6.435 ± 2.199
    3.6 ± 99999
    4.807 ± 2.059
    4.99 ± 99999
    3.155 ± 0.559
    3.846 ± 1.101
    Notes
    [45] - N=number of subjects evaluable for the outcome measure.
    [46] - N=number of subjects evaluable for the outcome measure.
    [47] - N=number of subjects evaluable for the outcome measure.
    [48] - N=number of subjects evaluable for the outcome measure.
    [49] - N=number of subjects evaluable for the outcome measure.
    [50] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Systemic Clearance (CL) in Cycle 4

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    End point title
    Systemic Clearance (CL) in Cycle 4 [51]
    End point description
    CL is a quantitative measure of the rate at which a drug substance is removed from the body. All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: CL in cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    6 [52]
    6 [53]
    Units: mL/day/kg
        arithmetic mean (standard deviation)
    2.612 ± 1.112
    2.576 ± 0.484
    Notes
    [52] - N=number of subjects evaluable for the outcome measure.
    [53] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Concentration at End of Infusion (Cendinf) in Cycle 1

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    End point title
    Concentration at End of Infusion (Cendinf) in Cycle 1 [54]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Cendinf in cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/k g , 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [55]
    3 [56]
    3 [57]
    3 [58]
    9 [59]
    33 [60]
    Units: mg/L
        arithmetic mean (standard deviation)
    57.5 ± 3.081
    134.7 ± 31.754
    211 ± 59.808
    463 ± 97.964
    386.3 ± 96.496
    434.3 ± 94.278
    Notes
    [55] - N=number of subjects evaluable for the outcome measure.
    [56] - N=number of subjects evaluable for the outcome measure.
    [57] - N=number of subjects evaluable for the outcome measure.
    [58] - N=number of subjects evaluable for the outcome measure.
    [59] - N=number of subjects evaluable for the outcome measure.
    [60] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Concentration at End of Infusion (Cendinf) in Cycle 4

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    End point title
    Concentration at End of Infusion (Cendinf) in Cycle 4 [61]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Cendinf in cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    6 [62]
    16 [63]
    Units: mg/L
        arithmetic mean (standard deviation)
    650.3 ± 170.8
    685 ± 167.15
    Notes
    [62] - N=number of subjects evaluable for the outcome measure.
    [63] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Volume of Distribution (Vz) in Cycle 1

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    End point title
    Volume of Distribution (Vz) in Cycle 1 [64]
    End point description
    Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.Here "99999" in the standard deviation signifies not available (NA). Standard deviation was not calculated as only 1 subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Vz in cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg , 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    2 [65]
    1 [66]
    3 [67]
    1 [68]
    2 [69]
    7 [70]
    Units: milliliter/kilogram (mL/kg)
        arithmetic mean (standard deviation)
    78 ± 24.183
    49 ± 99999
    70.47 ± 25.733
    68.1 ± 99999
    60.35 ± 9.122
    59.34 ± 14.36
    Notes
    [65] - N=number of subjects evaluable for the outcome measure.
    [66] - N=number of subjects evaluable for the outcome measure.
    [67] - N=number of subjects evaluable for the outcome measure.
    [68] - N=number of subjects evaluable for the outcome measure.
    [69] - N=number of subjects evaluable for the outcome measure.
    [70] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Volume of Distribution (Vz) in Cycle 4

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    End point title
    Volume of Distribution (Vz) in Cycle 4 [71]
    End point description
    Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Vz in cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [72]
    5 [73]
    Units: mL/kg
        arithmetic mean (standard deviation)
    89.17 ± 47.461
    61.98 ± 20.741
    Notes
    [72] - N=number of subjects evaluable for the outcome measure.
    [73] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) in Cycle 1

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    End point title
    Volume of Distribution at Steady State (Vss) in Cycle 1 [74]
    End point description
    Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the Vz at steady-state. All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks. Here "99999" in the standard deviation signifies not available (NA). Standard deviation was not calculated as only 1 subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Vss in Cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg , 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only. 
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    2 [75]
    1 [76]
    3 [77]
    1 [78]
    2 [79]
    7 [80]
    Units: mL/kg
        arithmetic mean (standard deviation)
    75.05 ± 20.011
    47.9 ± 99999
    68.8 ± 23.477
    66.9 ± 99999
    61.65 ± 6.435
    59.27 ± 14.765
    Notes
    [75] - N=number of subjects evaluable for the outcome measure.
    [76] - N=number of subjects evaluable for the outcome measure.
    [77] - N=number of subjects evaluable for the outcome measure.
    [78] - N=number of subjects evaluable for the outcome measure.
    [79] - N=number of subjects evaluable for the outcome measure.
    [80] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) in Cycle 4

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    End point title
    Volume of Distribution at Steady State (Vss) in Cycle 4 [81]
    End point description
    Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the Vz at steady-state. All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Vss in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [82]
    5 [83]
    Units: mL/kg
        arithmetic mean (standard deviation)
    86.07 ± 42.133
    60.84 ± 19.694
    Notes
    [82] - N=number of subjects evaluable for the outcome measure.
    [83] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) in Cycle 1

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    End point title
    Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) in Cycle 1 [84]
    End point description
    Area under the plasma concentration time-curve from zero to the last measured concentration. All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [84] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for AUClast in cycle 1 was analyzed in subjects in Figitumumab 3 mg/kg , 6 mg/kg , 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [85]
    2 [86]
    3 [87]
    3 [88]
    9 [89]
    31 [90]
    Units: milligram*hour/liter (mg*hr/L)
        arithmetic mean (standard deviation)
    10900 ± 3005
    27500 ± 5656.9
    43900 ± 19630
    89430 ± 11904
    102700 ± 25300
    107900 ± 36398
    Notes
    [85] - N=number of subjects evaluable for the outcome measure.
    [86] - N=number of subjects evaluable for the outcome measure.
    [87] - N=number of subjects evaluable for the outcome measure.
    [88] - N=number of subjects evaluable for the outcome measure.
    [89] - N=number of subjects evaluable for the outcome measure.
    [90] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) in Cycle 4

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    End point title
    Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) in Cycle 4 [91]
    End point description
    Area under the plasma concentration time-curve from zero to the last measured concentration. All subjects treated who had at least 1 of the PK parameters of primary interest in extension cohorts. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [91] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: AUClast in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg (RP2D ESFT) and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only. 
    End point values
    Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    6 [92]
    16 [93]
    Units: mg*hr/L
        arithmetic mean (standard deviation)
    214500 ± 67592
    166500 ± 77400
    Notes
    [92] - N=number of subjects evaluable for the outcome measure.
    [93] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] in Cycle 1

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    End point title
    Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] in Cycle 1 [94]
    End point description
    Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). All subjects treated who had at least 1 of the PK parameters of primary interest. Summaries for figitumumab 20 mg/kg RP2D, and figitumumab 20 mg/kg RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: figitumumab 20 mg/kg RP2D every 3 weeks. Here "99999" in the standard deviation signifies not available (NA). Standard deviation was not calculated as only 1 subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [94] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: AUC (0-∞) in Cycle 1 was analyzed in subjects of Figitumumab 3 mg/kg , 6 mg/kg , 10 mg/kg , 20 mg/kg , 20 mg/kg (RP2D ESFT), 20 mg/kg (RP2D Every 3 Weeks) reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D ESFT Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    2 [95]
    1 [96]
    3 [97]
    1 [98]
    2 [99]
    7 [100]
    Units: mg*hr/L
        arithmetic mean (standard deviation)
    11910 ± 4094.1
    40000 ± 99999
    57770 ± 28167
    96300 ± 99999
    154500 ± 27577
    136000 ± 47622
    Notes
    [95] - N=number of subjects evaluable for the outcome measure.
    [96] - N=number of subjects evaluable for the outcome measure.
    [97] - N=number of subjects evaluable for the outcome measure.
    [98] - N=number of subjects evaluable for the outcome measure.
    [99] - N=number of subjects evaluable for the outcome measure.
    [100] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Profile From Time 0 to 504 Hours (21 Days) (AUC504) in Cycle 1

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    End point title
    Area Under the Plasma Concentration-time Profile From Time 0 to 504 Hours (21 Days) (AUC504) in Cycle 1 [101]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in all cohorts except ESFT extension cohort. Summaries for figitumumab 20 mg/kg RP2D, and RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [101] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: AUC 504 in Cycle 1 was analyzed in subjects of Figitumumab 3, 6, 10, 20 mg/kg and 20 mg/kg (RP2D Every 3 Weeks) reporting arms only. 
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    3 [102]
    2 [103]
    3 [104]
    3 [105]
    31 [106]
    Units: mg*hr/L
        arithmetic mean (standard deviation)
    10900 ± 3005
    27500 ± 5656.9
    43170 ± 20124
    89430 ± 11904
    104000 ± 32547
    Notes
    [102] - N=number of subjects evaluable for the outcome measure.
    [103] - N=number of subjects evaluable for the outcome measure.
    [104] - N=number of subjects evaluable for the outcome measure.
    [105] - N=number of subjects evaluable for the outcome measure.
    [106] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Profile From Time 0 to 504 Hours (21 Days) (AUC504) in Cycle 4

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    End point title
    Area Under the Plasma Concentration-time Profile From Time 0 to 504 Hours (21 Days) (AUC504) in Cycle 4
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in all cohorts except ESFT extension cohort. Summaries for figitumumab 20 mg/kg RP2D, and RP2D ACC and sarcoma extension cohorts were combined into 1 reporting group: 20 mg/kg RP2D every 3 weeks.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    End point values
    Figitumumab 20 mg/kg RP2D Every 3 Weeks
    Number of subjects analysed
    9 [107]
    Units: mg*hr/L
        arithmetic mean (standard deviation)
    193100 ± 40001
    Notes
    [107] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Profile From Time 0 to 672 Hours (28 Days) (AUC672) in Cycle 1

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    End point title
    Area Under the Plasma Concentration-time Profile From Time 0 to 672 Hours (28 Days) (AUC672) in Cycle 1 [108]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in RP2D ESFT extension cohort.
    End point type
    Secondary
    End point timeframe
    Cycle 1: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [108] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tmax in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg RP2D ESFT reporting arm only. 
    End point values
    Figitumumab 20 mg/kg RP2D ESFT
    Number of subjects analysed
    9 [109]
    Units: mg*hr/L
        arithmetic mean (standard deviation)
    102400 ± 25227
    Notes
    [109] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Profile From Time 0 to 672 Hours (28 Days) (AUC672) in Cycle 4

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    End point title
    Area Under the Plasma Concentration-time Profile From Time 0 to 672 Hours (28 Days) (AUC672) in Cycle 4 [110]
    End point description
    All subjects treated who had at least 1 of the PK parameters of primary interest in RP2D ESFT extension cohort.
    End point type
    Secondary
    End point timeframe
    Cycle 4: 0 (predose), 1, 24 and 72 hours, 7 and 14 days postdose
    Notes
    [110] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tmax in Cycle 4 was analyzed in subjects of Figitumumab 20 mg/kg RP2D ESFT reporting arm only. 
    End point values
    Figitumumab 20 mg/kg RP2D ESFT
    Number of subjects analysed
    6 [111]
    Units: mg*hr/L
        arithmetic mean (standard deviation)
    207200 ± 72334
    Notes
    [111] - N=number of subjects evaluable for the outcome measure.
    No statistical analyses for this end point

    Secondary: Human Anti-human Antibodies (HAHA) Levels

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    End point title
    Human Anti-human Antibodies (HAHA) Levels [112]
    End point description
    HAHA were indicators of immunogenicity to figitumumab. Per protocol, the presence of HAHA would only be evaluated for those samples with plasma figitumumab concentrations below the limit of quantification (BLQ). Since none of the postdose samples in the study had figitumumab concentrations BLQ, therefore no sample was analyzed for HAHA.
    End point type
    Secondary
    End point timeframe
    30 minutes predose in Cycles 1 up to 61, and last scheduled follow-up visit (up to 150 days from the last dose of study drug)
    Notes
    [112] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification:  HAHA levels were analyzed in subjects of Figitumumab 3, 6, 10, 20 mg/kg reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg
    Number of subjects analysed
    0 [113]
    0 [114]
    0 [115]
    0 [116]
    Units: subjects
        number (not applicable)
    Notes
    [113] - No sample in the study had figitumumab concentrations BLQ therefore no sample was analyzed for HAHA.
    [114] - No sample in the study had figitumumab concentrations BLQ therefore no sample was analyzed for HAHA.
    [115] - No sample in the study had figitumumab concentrations BLQ therefore no sample was analyzed for HAHA.
    [116] - No sample in the study had figitumumab concentrations BLQ therefore no sample was analyzed for HAHA.
    No statistical analyses for this end point

    Secondary: Number of Circulating Tumor Cells (CTCs)

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    End point title
    Number of Circulating Tumor Cells (CTCs) [117]
    End point description
    Quantification of CTCs using an automated microscope system. Pretreatment CTCs were detected in an insufficient number of subjects to analyze for any treatment effect on this pharmacodynamic biomarker.
    End point type
    Secondary
    End point timeframe
    30 minutes predose in all cycles (up to 17); 1, 3, 7, and 14 days postdose in Cycle 1 for dose escalation and RP2D extension cohorts; and also 1 day postdose in Cycle 4 for RP2D extension cohort
    Notes
    [117] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Number of CTCs was analyzed in subjects of Figitumumab 3, 6, 10 and 20 mg/kg reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg
    Number of subjects analysed
    0 [118]
    0 [119]
    0 [120]
    0 [121]
    Units: subjects
        number (not applicable)
    Notes
    [118] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    [119] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    [120] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    [121] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    No statistical analyses for this end point

    Secondary: Number of Insulin-like Growth Factor 1 Receptor (IGF-1R) Positive CTCs

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    End point title
    Number of Insulin-like Growth Factor 1 Receptor (IGF-1R) Positive CTCs [122]
    End point description
    Quantification of IGF-IR positive CTCs using an automated microscope system. Pretreatment IGF-1R positive CTCs were detected in an insufficient number of subjects to analyze for any treatment effect on this pharmacodynamic biomarker.
    End point type
    Secondary
    End point timeframe
    30 minutes predose in all cycles (up to 17); 1, 3, 7, and 14 days postdose in Cycle 1 for dose escalation and RP2D extension cohorts; and also 1 day postdose in Cycle 4 for RP2D extension cohort
    Notes
    [122] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: IGF­-1R Positive CTCs was analyzed in subjects of Figitumumab 3, 6, 10, 20 mg/kg reporting arms only.
    End point values
    Figitumumab 3 mg/kg Figitumumab 6 mg/kg Figitumumab 10 mg/kg Figitumumab 20 mg/kg
    Number of subjects analysed
    0 [123]
    0 [124]
    0 [125]
    0 [126]
    Units: subjects
        number (not applicable)
    Notes
    [123] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    [124] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    [125] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    [126] - Insufficient number of subjects to analyze for treatment effect on this pharmacodynamic biomarker.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events are reported from time of first dose of study treatment up to 150 days after last dose of study treatment .
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    10MG/KG
    Reporting group description
    Figitumumab 3 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    20MG/KG
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    20MG/KG RP2D
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for RP2D extension cohort.

    Reporting group title
    20MG/KG RP2D ACC+SARCOMA
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for RP2D ACC and sarcoma extension cohort.

    Reporting group title
    20MG/KG RP2D ESFT
    Reporting group description
    Figitumumab 20 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (4 weeks in duration) for RP2D ESFT extension cohort.

    Reporting group title
    3MG/KG
    Reporting group description
    Figitumumab 3 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Reporting group title
    6MG/KG
    Reporting group description
    Figitumumab 6 mg/kg was supplied as a liquid solution administered as an IV infusion over 2.5 hours (plus or minus 15 minutes) on Day 1 of each cycle (3 weeks in duration) for dose escalation cohort.

    Serious adverse events
    10MG/KG 20MG/KG 20MG/KG RP2D 20MG/KG RP2D ACC+SARCOMA 20MG/KG RP2D ESFT 3MG/KG 6MG/KG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    5 / 13 (38.46%)
    17 / 29 (58.62%)
    5 / 11 (45.45%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    3
    1
    3
    8
    4
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Superior vena cava occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood culture positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumomediastinum
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    2 / 13 (15.38%)
    8 / 29 (27.59%)
    3 / 11 (27.27%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 6
    0 / 13
    0 / 5
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 8
    0 / 3
    0 / 1
    0 / 1
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    10MG/KG 20MG/KG 20MG/KG RP2D 20MG/KG RP2D ACC+SARCOMA 20MG/KG RP2D ESFT 3MG/KG 6MG/KG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    13 / 13 (100.00%)
    28 / 29 (96.55%)
    11 / 11 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    4 / 29 (13.79%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    8
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Pallor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tooth repair
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    4 / 29 (13.79%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    6
    2
    0
    0
    Catheter site related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Crepitations
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Disease progression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 3 (100.00%)
    6 / 13 (46.15%)
    12 / 29 (41.38%)
    7 / 11 (63.64%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    5
    8
    21
    13
    0
    1
    Feeling abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    4
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Mass
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    1
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    3 / 11 (27.27%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 29 (3.45%)
    4 / 11 (36.36%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    1
    4
    0
    1
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    2
    0
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Scrotal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Scratch
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Wound dehiscence
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 13 (38.46%)
    6 / 29 (20.69%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    10
    12
    2
    0
    0
    Activated partial thromboplastin time abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    2
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    7 / 13 (53.85%)
    7 / 29 (24.14%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    0
    8
    10
    1
    0
    1
    Bacterial test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    4 / 29 (13.79%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    7
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    4 / 29 (13.79%)
    1 / 11 (9.09%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    7
    3
    2
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    Blood magnesium increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 13 (23.08%)
    5 / 29 (17.24%)
    1 / 11 (9.09%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    5
    5
    1
    1
    1
    Body temperature
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood urea increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    Fungal test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    5 / 13 (38.46%)
    7 / 29 (24.14%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    7
    11
    1
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    3
    1
    0
    2
    International normalised ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    0
    Pulse abnormal
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    3 / 29 (10.34%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    8
    3
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Urine leukocyte esterase positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    3 / 29 (10.34%)
    5 / 11 (45.45%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    3
    13
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    4 / 29 (13.79%)
    5 / 11 (45.45%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    3
    5
    8
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    4 / 11 (36.36%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    1
    5
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 29 (6.90%)
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    2
    14
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    7
    1
    2
    0
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    4 / 29 (13.79%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    5
    4
    1
    0
    1
    Dizziness postural
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    2
    0
    0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    6 / 29 (20.69%)
    4 / 11 (36.36%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    2
    8
    27
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Hyporeflexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Paralysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Sinus headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Phantom pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Miosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    0
    1
    10
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    9 / 29 (31.03%)
    4 / 11 (36.36%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    11
    7
    2
    0
    Cheilitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    6 / 13 (46.15%)
    5 / 29 (17.24%)
    7 / 11 (63.64%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    1
    7
    5
    14
    0
    3
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    4 / 29 (13.79%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    4
    0
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    3 / 29 (10.34%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    8 / 13 (61.54%)
    13 / 29 (44.83%)
    4 / 11 (36.36%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    0
    14
    17
    16
    0
    3
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Oesophageal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    3 / 29 (10.34%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    4
    0
    1
    0
    Sensitivity of teeth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    6 / 13 (46.15%)
    6 / 29 (20.69%)
    7 / 11 (63.64%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    9
    6
    20
    1
    0
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    0
    Tooth disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    6
    1
    0
    Microalbuminuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    3 / 29 (10.34%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    0
    0
    Renal impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    2
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    3 / 29 (10.34%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    3
    0
    0
    0
    Alopecia totalis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood blister
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blister
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    1
    3
    0
    0
    Dermal cyst
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Onychoclasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    0
    2
    3
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Skin discolouration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin mass
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Skin irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    7 / 29 (24.14%)
    4 / 11 (36.36%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    3
    10
    20
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    5 / 11 (45.45%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    18
    2
    0
    Limb discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    5 / 29 (17.24%)
    6 / 11 (54.55%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    3
    6
    30
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    4 / 29 (13.79%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 29 (6.90%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    3 / 29 (10.34%)
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    5
    3
    5
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    6 / 29 (20.69%)
    1 / 11 (9.09%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    9
    2
    1
    0
    Trismus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Endocrine disorders
    Delayed puberty
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Goitre
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    5 / 13 (38.46%)
    14 / 29 (48.28%)
    6 / 11 (54.55%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
         occurrences all number
    3
    2
    9
    19
    10
    2
    2
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 3 (100.00%)
    5 / 13 (38.46%)
    8 / 29 (27.59%)
    2 / 11 (18.18%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
         occurrences all number
    0
    5
    15
    16
    6
    7
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 13 (15.38%)
    6 / 29 (20.69%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    2
    8
    2
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 29 (6.90%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    5 / 29 (17.24%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    7
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 29 (3.45%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Eye infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    3 / 11 (27.27%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    6
    0
    0
    Nail infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Skin infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    2 / 29 (6.90%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    5
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    2 / 11 (18.18%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tinea pedis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    0 / 11 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 29 (3.45%)
    0 / 11 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 29 (0.00%)
    1 / 11 (9.09%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2007
    A4021010 was amended to allow for the testing of the safety and tolerability of CP-751,871 in a RP2D Extension Cohort of 12 Ewing’s sarcoma patients aged 9 years or older.
    12 Dec 2010
    The protocol was amended to provide guidance on data reporting and follow-up of patients receiving CP-751,871 for more than 1 year. Also, guidance for evaluation and reportability of potential cases of liver injury has been added. Only AE, SAE and dosing information will be reported in the CRF.

    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.
    The study was completed and 2 subjects in figitumumab 20 mg/kg RP2D ESFT group were transitioned to compassionate figitumumab treatment as investigators judged they were receiving benefit from the protocol therapy.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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