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    Clinical Trial Results:
    A Study to Determine the Activity of Robatumumab (SCH 717454) in Participants With Osteosarcoma or Ewing’s Sarcoma That Has Relapsed After Standard Systemic Therapy

    The data reported in v3 is not correct and has been removed from public view
    Summary
    EudraCT number
    2007-005341-38
    Trial protocol
    DE   FR   ES   SE   NO   NL   IT   CZ   PT   HU   GB  
    Global end of trial date
    31 Aug 2013

    Results information
    Results version number
    v4(current)
    This version publication date
    30 Apr 2016
    First version publication date
    13 Jun 2015
    Other versions
    v1 , v2 , v3 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    P04720
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00617890
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    MK-7454-002: Merck study number
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    31 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Group 1-Determine tumor cell proliferation response after dosing with SCH 717454 in subjects with resectable osteosarcoma that has relapsed after standard systemic therapy compared to the subject’s historical tumor cell proliferation. Group 2-Determine the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST)-defined radiological response rate to SCH 717454 in subjects with unresectable osteosarcoma refractory to standard therapy. Group 3-Determine the WHO and RECIST-defined radiological response rate to SCH 717454 in subjects with Ewing’s sarcoma refractory to standard therapy. The study was prematurely terminated for strategic reasons, not for a safety concern; analyses of some efficacy endpoints were not performed due to large number of incomplete or uncleaned data which occurred as a result of the early termination. Participants could continue on drug per usual standard of care as long as receiving clinical benefit per Investigator discretion.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statues and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Feb 2008
    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
    Canada: 8
    Country: Number of subjects enrolled
    Brazil: 10
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Peru: 3
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 115
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Guatemala: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    219
    EEA total number of subjects
    57
    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)
    14
    Adolescents (12-17 years)
    56
    Adults (18-64 years)
    147
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study enrolled both adult and child participants with relapsed resectable osteosarcoma after definitive treatment, participants with relapsed unresectable osteosarcoma refractory to prior chemotherapy, and participants with Ewing's sarcoma refractory to prior treatment.

    Pre-assignment
    Screening details
    Participants were to have a minimum life expectancy of >=8 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Group 1 participants were given randomized assignment to a dose of 0.3 mg/kg or 10 mg/kg of robatumumab; Group 1 was blinded (investigator and participant) but not controlled.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1: 0.3 mg/kg
    Arm description
    Participants received robatumumab 0.3 mg/kg intravenously (IV) as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 0.3 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.
    Arm type
    Experimental

    Investigational medicinal product name
    robatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Robatumumab was supplied as a concentrated solution for infusion.

    Arm title
    Group 1: 10 mg/kg
    Arm description
    Participants received robatumumab 10 mg/kg IV as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 10 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.
    Arm type
    Experimental

    Investigational medicinal product name
    robatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Robatumumab was supplied as a concentrated solution for infusion.

    Arm title
    Group 2: 10 mg/kg
    Arm description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with relapsed and unresectable osteosarcoma refractory to prior chemotherapy with a platinum- and doxorubicin-containing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    robatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Robatumumab was supplied as a concentrated solution for infusion.

    Arm title
    Group 3: 10 mg/kg
    Arm description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing's sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine.
    Arm type
    Experimental

    Investigational medicinal product name
    robatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Robatumumab was supplied as a concentrated solution for infusion.

    Number of subjects in period 1
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg Group 2: 10 mg/kg Group 3: 10 mg/kg
    Started
    35
    33
    35
    116
    Received treatment
    34
    33
    34
    115
    Completed
    4
    5
    0
    1
    Not completed
    31
    28
    35
    115
         Protocol deviation
    2
    1
    -
    -
         Treatment ongoing at data cut-off
    -
    -
    -
    5
         Lack of efficacy
    23
    26
    30
    97
         Adverse event, non-fatal
    1
    -
    3
    8
         Consent withdrawn by subject
    4
    1
    -
    2
         Lost to follow-up
    -
    -
    1
    2
         Not treated
    1
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: 0.3 mg/kg
    Reporting group description
    Participants received robatumumab 0.3 mg/kg intravenously (IV) as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 0.3 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.

    Reporting group title
    Group 1: 10 mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 10 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.

    Reporting group title
    Group 2: 10 mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with relapsed and unresectable osteosarcoma refractory to prior chemotherapy with a platinum- and doxorubicin-containing regimen.

    Reporting group title
    Group 3: 10 mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing's sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine.

    Reporting group values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg Group 2: 10 mg/kg Group 3: 10 mg/kg Total
    Number of subjects
    35 33 35 116 219
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    23.7 ± 15.5 20.1 ± 10.3 27.5 ± 15.3 24.6 ± 11.4 -
    Gender categorical
    Units: Subjects
        Female
    14 13 11 43 81
        Male
    21 20 24 73 138

    End points

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    End points reporting groups
    Reporting group title
    Group 1: 0.3 mg/kg
    Reporting group description
    Participants received robatumumab 0.3 mg/kg intravenously (IV) as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 0.3 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.

    Reporting group title
    Group 1: 10 mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 10 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.

    Reporting group title
    Group 2: 10 mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with relapsed and unresectable osteosarcoma refractory to prior chemotherapy with a platinum- and doxorubicin-containing regimen.

    Reporting group title
    Group 3: 10 mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing's sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine.

    Primary: Number of Participants Achieving a Complete Response or Partial Response (Group 3 Only)

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    End point title
    Number of Participants Achieving a Complete Response or Partial Response (Group 3 Only) [1] [2]
    End point description
    This is a measure of the number of participants with a complete response (CR) or partial response (PR) to therapy, confirmed by central review. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria.
    End point type
    Primary
    End point timeframe
    Up to 1 year following the start of study therapy
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was done for this endpoint due to early termination.
    [2] - 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: This analysis was only planned for Group 3 participants.
    End point values
    Group 3: 10 mg/kg
    Number of subjects analysed
    84 [3]
    Units: Participants
    6
    Notes
    [3] - Participants with evaluable data
    No statistical analyses for this end point

    Primary: Number of Participants Achieving a Complete Response, a Partial Response, or Stable Disease (Group 2 Only)

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    End point title
    Number of Participants Achieving a Complete Response, a Partial Response, or Stable Disease (Group 2 Only) [4] [5]
    End point description
    Responses to treatment (complete response, partial response, or stable disease) confirmed by central review for participants in Group 2. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria.
    End point type
    Primary
    End point timeframe
    Up to 1 year following the start of study therapy
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was done for this endpoint due to early termination.
    [5] - 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: This analysis was only planned for Group 2 participants.
    End point values
    Group 2: 10 mg/kg
    Number of subjects analysed
    29 [6]
    Units: Participants
    6
    Notes
    [6] - Accrual to this arm was stopped due to no responses.
    No statistical analyses for this end point

    Primary: Number of Participants With >= 25% Change in Tumor Proliferation After Exposure to Robatumumab (Group 1 Only)

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    End point title
    Number of Participants With >= 25% Change in Tumor Proliferation After Exposure to Robatumumab (Group 1 Only) [7] [8]
    End point description
    Tumor proliferation was measured using Ki-67 levels. Ki-67 is nuclear protein associated with cellular proliferation.
    End point type
    Primary
    End point timeframe
    Approximately 14 days
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint could not be analysed due to early study termination.
    [8] - 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: This analysis was only planned for Group 1 participants.
    End point values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Participants
    Notes
    [9] - This endpoint was not evaluated due to early termination of the study.
    [10] - This endpoint was not evaluated due to early termination of the study.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    The endpoint is defined as the number of participants known to be alive at the time of data analysis for the study.
    End point type
    Secondary
    End point timeframe
    From start of treatment until death or data analysis cut off (Up to 3.4 years)
    End point values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg Group 2: 10 mg/kg Group 3: 10 mg/kg
    Number of subjects analysed
    35
    33
    35
    116
    Units: Participants
    17
    16
    7
    28
    No statistical analyses for this end point

    Secondary: Time Until Tumor Relapse (Group 1 Only)

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    End point title
    Time Until Tumor Relapse (Group 1 Only) [11]
    End point description
    This is a measure of the time from the start of the study to documented relapse of disease (up to 3.4 years).
    End point type
    Secondary
    End point timeframe
    From start of treatment until relapse or data analysis cut off (Up to 3.4 years)
    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: This analysis was only planned for Group 1 participants.
    End point values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [12] - This endpoint was not evaluated due to early termination of the study
    [13] - This endpoint was not evaluated due to early termination of the study
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve (AUC) of Serum Levels of Robatumumab (Group 1 Only)

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    End point title
    Area Under the Concentration-time Curve (AUC) of Serum Levels of Robatumumab (Group 1 Only) [14]
    End point description
    End point type
    Secondary
    End point timeframe
    End of infusion on Day 1, and then prior to surgery, before and after the 2nd, 3rd, and 8th doses (up to 20 weeks)
    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: This analysis was only planned for Group 1 participants.
    End point values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: μg*day/mL
        geometric mean (geometric coefficient of variation)
    ±
    ±
    Notes
    [15] - This endpoint was not evaluated due to early termination of the study
    [16] - This endpoint was not evaluated due to early termination of the study
    No statistical analyses for this end point

    Secondary: Incidence of Anti-robatumumab Antibodies

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    End point title
    Incidence of Anti-robatumumab Antibodies
    End point description
    For biological agents, it is possible for the host (participant) to develop antibodies to the agent. This endpoint was planned to find out the number of participants who developed the antibodies after treatment with robatumumab.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg Group 2: 10 mg/kg Group 3: 10 mg/kg
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    0 [20]
    Units: Percent of Participants
    Notes
    [17] - This endpoint was not evaluated due to early termination of the study
    [18] - This endpoint was not evaluated due to early termination of the study
    [19] - This endpoint was not evaluated due to early termination of the study
    [20] - This endpoint was not evaluated due to early termination of the study
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Treatment-Emergent Adverse Events

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    End point title
    Number of Participants Experiencing Treatment-Emergent Adverse Events
    End point description
    An adverse event is any unfavorable and unintended change in the structure, function, or chemistry of the body whether or not considered related to the study treatment. Treatment-emergent adverse events are those that occur after participants have received study treatment, or existing adverse events that occurred during screening that increase in severity after study treatment. Adverse events in the Group 1: 0.3 mg/kg arm that occurred after switching to the 10 mg/kg dose are displayed under the originally assigned treatment.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Group 1: 0.3 mg/kg Group 1: 10 mg/kg Group 2: 10 mg/kg Group 3: 10 mg/kg
    Number of subjects analysed
    34
    33
    34
    115
    Units: Participants
    31
    30
    31
    112
    No statistical analyses for this end point

    Secondary: Time to Disease Progression (Groups 2 and 3 Only)

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    End point title
    Time to Disease Progression (Groups 2 and 3 Only) [21]
    End point description
    This is a measure of the time from the start of the study to the time of documented disease progression.
    End point type
    Secondary
    End point timeframe
    From the start of treatment until disease progression or data analysis cut off (Up to 3.4 years)
    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: This analysis was only planned for Group 2 and 3 participants.
    End point values
    Group 2: 10 mg/kg Group 3: 10 mg/kg
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [22] - This endpoint was not evaluated due to early termination of the study
    [23] - This endpoint was not evaluated due to early termination of the study
    No statistical analyses for this end point

    Secondary: Duration of Response (Groups 2 and 3 Only)

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    End point title
    Duration of Response (Groups 2 and 3 Only) [24]
    End point description
    This is a measure of the amount of time in which the tumor responded to therapy.
    End point type
    Secondary
    End point timeframe
    From time of documented response until disease progression or data analysis cut off (Up to 3.4 years)
    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: This analysis was only planned for Group 2 and 3 participants.
    End point values
    Group 2: 10 mg/kg Group 3: 10 mg/kg
    Number of subjects analysed
    0 [25]
    0 [26]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [25] - This endpoint was not evaluated due to early termination of the study
    [26] - This endpoint was not evaluated due to early termination of the study
    No statistical analyses for this end point

    Secondary: Overall Survival (Groups 2 and 3 Only)

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    End point title
    Overall Survival (Groups 2 and 3 Only) [27]
    End point description
    This is a measure of the time of survival from first dose to documentation of death
    End point type
    Secondary
    End point timeframe
    From start of treatment until death or data analysis cut off (Up to 3.4 years)
    Notes
    [27] - 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: This analysis was only planned for Group 2 and 3 participants.
    End point values
    Group 2: 10 mg/kg Group 3: 10 mg/kg
    Number of subjects analysed
    35
    116
    Units: months
        median (confidence interval 95%)
    8.18 (2.96 to 10.58)
    6.93 (4.93 to 11.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from enrollment up to 5 weeks after the end of treatment (up to 2 years).
    Adverse event reporting additional description
    All treated participants; adverse events in the Group 1: 0.3 mg/kg arm that occurred after switching to the 10 mg/kg dose are displayed under the originally assigned treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Group 1: 0.3mg/kg
    Reporting group description
    Participants received robatumumab 0.3 mg/kg intravenously (IV) as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 0.3 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.

    Reporting group title
    Group 2: 10mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with relapsed and unresectable osteosarcoma refractory to prior chemotherapy with a platinum- and doxorubicin-containing regimen.

    Reporting group title
    Group 3: 10mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing's sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine.

    Reporting group title
    Group 1: 10mg/kg
    Reporting group description
    Participants received robatumumab 10 mg/kg IV as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 10 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin.

    Serious adverse events
    Group 1: 0.3mg/kg Group 2: 10mg/kg Group 3: 10mg/kg Group 1: 10mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 34 (50.00%)
    12 / 34 (35.29%)
    57 / 115 (49.57%)
    8 / 33 (24.24%)
         number of deaths (all causes)
    6
    1
    14
    1
         number of deaths resulting from adverse events
    1
    0
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock Haemorrhagic
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Leg Amputation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical Device Removal
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracotomy
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Pleural Effusion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteosarcoma Recurrent
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases To Lung
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Tumour Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    4 / 115 (3.48%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Dislocation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Condition Aggravated
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Withdrawal Syndrome
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    11 / 115 (9.57%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    7 / 115 (6.09%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional State
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain Herniation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Respiratory Distress
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Hypotension
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity To Various Agents
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Necrosis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Biopsy Bone Abnormal
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Potassium Decreased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Bronchial Disorder
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea At Rest
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Toxicity
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    6 / 115 (5.22%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
    5 / 115 (4.35%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 5
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    4 / 115 (3.48%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered State Of Consciousness
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Headache
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Encephalopathy
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningeal Disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve Compression
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic Encephalopathy
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness Unilateral
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision Blurred
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal Haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercreatinaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central Nervous System Infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1: 0.3mg/kg Group 2: 10mg/kg Group 3: 10mg/kg Group 1: 10mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 34 (82.35%)
    29 / 34 (85.29%)
    104 / 115 (90.43%)
    30 / 33 (90.91%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 34 (5.88%)
    6 / 115 (5.22%)
    1 / 33 (3.03%)
         occurrences all number
    2
    2
    6
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
    8 / 115 (6.96%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    11
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    13 / 115 (11.30%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    18
    4
    Fatigue
         subjects affected / exposed
    7 / 34 (20.59%)
    7 / 34 (20.59%)
    23 / 115 (20.00%)
    7 / 33 (21.21%)
         occurrences all number
    10
    7
    28
    8
    Chest Pain
         subjects affected / exposed
    7 / 34 (20.59%)
    3 / 34 (8.82%)
    10 / 115 (8.70%)
    3 / 33 (9.09%)
         occurrences all number
    8
    3
    12
    3
    Mucosal Inflammation
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    7
    Oedema Peripheral
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 34 (8.82%)
    4 / 115 (3.48%)
    2 / 33 (6.06%)
         occurrences all number
    2
    3
    4
    2
    Pain
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 34 (5.88%)
    9 / 115 (7.83%)
    4 / 33 (12.12%)
         occurrences all number
    4
    2
    11
    4
    Pyrexia
         subjects affected / exposed
    9 / 34 (26.47%)
    6 / 34 (17.65%)
    21 / 115 (18.26%)
    11 / 33 (33.33%)
         occurrences all number
    11
    7
    37
    13
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 34 (8.82%)
    18 / 115 (15.65%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    24
    3
    Insomnia
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 34 (5.88%)
    20 / 115 (17.39%)
    3 / 33 (9.09%)
         occurrences all number
    4
    2
    20
    4
    Depression
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
    4 / 115 (3.48%)
    3 / 33 (9.09%)
         occurrences all number
    1
    2
    4
    4
    Injury, poisoning and procedural complications
    Incision Site Pain
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 34 (2.94%)
    2 / 115 (1.74%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    3
    2
    Procedural Pain
         subjects affected / exposed
    13 / 34 (38.24%)
    1 / 34 (2.94%)
    2 / 115 (1.74%)
    6 / 33 (18.18%)
         occurrences all number
    16
    1
    2
    7
    Post Procedural Haemorrhage
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    0
    0
    1
    Post-Thoracotomy Pain Syndrome
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    0
    1
    Investigations
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 34 (2.94%)
    3 / 115 (2.61%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    3
    2
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    8 / 115 (6.96%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    11
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    9 / 115 (7.83%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    11
    1
    Haemoglobin Decreased
         subjects affected / exposed
    5 / 34 (14.71%)
    1 / 34 (2.94%)
    3 / 115 (2.61%)
    6 / 33 (18.18%)
         occurrences all number
    6
    1
    4
    12
    Platelet Count Decreased
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    1 / 33 (3.03%)
         occurrences all number
    4
    0
    6
    1
    Weight Decreased
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
    11 / 115 (9.57%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    13
    1
    Cardiac disorders
    Sinus Tachycardia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
    4 / 115 (3.48%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 34 (29.41%)
    6 / 34 (17.65%)
    16 / 115 (13.91%)
    7 / 33 (21.21%)
         occurrences all number
    10
    6
    19
    9
    Dyspnoea
         subjects affected / exposed
    6 / 34 (17.65%)
    4 / 34 (11.76%)
    7 / 115 (6.09%)
    4 / 33 (12.12%)
         occurrences all number
    7
    4
    7
    4
    Dyspnoea Exertional
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 34 (5.88%)
    11 / 115 (9.57%)
    2 / 33 (6.06%)
         occurrences all number
    5
    2
    11
    2
    Epistaxis
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
    9 / 115 (7.83%)
    2 / 33 (6.06%)
         occurrences all number
    6
    0
    11
    5
    Haemoptysis
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 34 (5.88%)
    2 / 115 (1.74%)
    2 / 33 (6.06%)
         occurrences all number
    3
    3
    3
    2
    Pleural Effusion
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
    6 / 115 (5.22%)
    1 / 33 (3.03%)
         occurrences all number
    4
    2
    6
    1
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 34 (5.88%)
    11 / 115 (9.57%)
    1 / 33 (3.03%)
         occurrences all number
    4
    2
    15
    1
    Pneumothorax
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 34 (2.94%)
    2 / 115 (1.74%)
    2 / 33 (6.06%)
         occurrences all number
    5
    1
    2
    3
    Wheezing
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 34 (2.94%)
    1 / 115 (0.87%)
    5 / 33 (15.15%)
         occurrences all number
    1
    1
    1
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 34 (17.65%)
    3 / 34 (8.82%)
    22 / 115 (19.13%)
    2 / 33 (6.06%)
         occurrences all number
    8
    4
    44
    3
    Thrombocytopenia
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 34 (2.94%)
    17 / 115 (14.78%)
    0 / 33 (0.00%)
         occurrences all number
    2
    1
    35
    0
    Leukopenia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    3 / 115 (2.61%)
    2 / 33 (6.06%)
         occurrences all number
    1
    0
    4
    2
    Neutropenia
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 34 (0.00%)
    6 / 115 (5.22%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    6
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    7 / 115 (6.09%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    10
    1
    Headache
         subjects affected / exposed
    9 / 34 (26.47%)
    7 / 34 (20.59%)
    24 / 115 (20.87%)
    7 / 33 (21.21%)
         occurrences all number
    16
    10
    57
    8
    Somnolence
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    7 / 115 (6.09%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    9
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    3 / 33 (9.09%)
         occurrences all number
    2
    0
    1
    3
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    9 / 115 (7.83%)
    3 / 33 (9.09%)
         occurrences all number
    1
    0
    13
    3
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
    9 / 115 (7.83%)
    0 / 33 (0.00%)
         occurrences all number
    2
    1
    10
    0
    Constipation
         subjects affected / exposed
    9 / 34 (26.47%)
    3 / 34 (8.82%)
    34 / 115 (29.57%)
    9 / 33 (27.27%)
         occurrences all number
    9
    3
    43
    10
    Diarrhoea
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 34 (5.88%)
    29 / 115 (25.22%)
    6 / 33 (18.18%)
         occurrences all number
    6
    2
    42
    11
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    6 / 115 (5.22%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Dyspepsia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
    4 / 115 (3.48%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    5
    2
    Nausea
         subjects affected / exposed
    13 / 34 (38.24%)
    5 / 34 (14.71%)
    35 / 115 (30.43%)
    12 / 33 (36.36%)
         occurrences all number
    20
    6
    48
    18
    Vomiting
         subjects affected / exposed
    9 / 34 (26.47%)
    3 / 34 (8.82%)
    25 / 115 (21.74%)
    8 / 33 (24.24%)
         occurrences all number
    12
    4
    40
    9
    Stomatitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    6 / 115 (5.22%)
    1 / 33 (3.03%)
         occurrences all number
    2
    0
    6
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 34 (8.82%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    2 / 33 (6.06%)
         occurrences all number
    1
    0
    1
    2
    Pruritus
         subjects affected / exposed
    6 / 34 (17.65%)
    2 / 34 (5.88%)
    5 / 115 (4.35%)
    4 / 33 (12.12%)
         occurrences all number
    8
    2
    6
    6
    Rash
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
    11 / 115 (9.57%)
    2 / 33 (6.06%)
         occurrences all number
    6
    1
    12
    2
    Urticaria
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Subcutaneous Emphysema
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    1 / 115 (0.87%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 34 (8.82%)
    10 / 115 (8.70%)
    2 / 33 (6.06%)
         occurrences all number
    4
    3
    12
    4
    Bone Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 34 (11.76%)
    6 / 115 (5.22%)
    1 / 33 (3.03%)
         occurrences all number
    0
    4
    6
    1
    Back Pain
         subjects affected / exposed
    5 / 34 (14.71%)
    6 / 34 (17.65%)
    15 / 115 (13.04%)
    4 / 33 (12.12%)
         occurrences all number
    5
    7
    19
    4
    Flank Pain
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    5
    0
    Muscle Spasms
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 34 (5.88%)
    11 / 115 (9.57%)
    3 / 33 (9.09%)
         occurrences all number
    3
    2
    13
    6
    Muscular Weakness
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
    3 / 115 (2.61%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Myalgia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
    6 / 115 (5.22%)
    0 / 33 (0.00%)
         occurrences all number
    1
    2
    7
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 34 (11.76%)
    7 / 115 (6.09%)
    2 / 33 (6.06%)
         occurrences all number
    0
    4
    8
    2
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
    13 / 115 (11.30%)
    2 / 33 (6.06%)
         occurrences all number
    3
    1
    16
    2
    Pain In Extremity
         subjects affected / exposed
    7 / 34 (20.59%)
    6 / 34 (17.65%)
    12 / 115 (10.43%)
    4 / 33 (12.12%)
         occurrences all number
    9
    8
    25
    8
    Neck Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
    6 / 115 (5.22%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Pain In Jaw
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 34 (11.76%)
    27 / 115 (23.48%)
    4 / 33 (12.12%)
         occurrences all number
    6
    4
    37
    5
    Hyperglycaemia
         subjects affected / exposed
    6 / 34 (17.65%)
    1 / 34 (2.94%)
    12 / 115 (10.43%)
    3 / 33 (9.09%)
         occurrences all number
    11
    1
    18
    6
    Dehydration
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
    6 / 115 (5.22%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    6
    0
    Hypocalcaemia
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 34 (5.88%)
    4 / 115 (3.48%)
    0 / 33 (0.00%)
         occurrences all number
    6
    2
    8
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    5 / 115 (4.35%)
    3 / 33 (9.09%)
         occurrences all number
    2
    0
    5
    3
    Hypokalaemia
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
    6 / 115 (5.22%)
    2 / 33 (6.06%)
         occurrences all number
    4
    0
    8
    3
    Hypophosphataemia
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 34 (2.94%)
    2 / 115 (1.74%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    2
    2
    Hyponatraemia
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 34 (2.94%)
    2 / 115 (1.74%)
    2 / 33 (6.06%)
         occurrences all number
    5
    1
    2
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
    0 / 115 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
    1 / 115 (0.87%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    2
    2
    Sinusitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    5 / 115 (4.35%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    6
    0
    Rhinitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
    2 / 115 (1.74%)
    1 / 33 (3.03%)
         occurrences all number
    2
    0
    2
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 34 (2.94%)
    4 / 34 (11.76%)
    8 / 115 (6.96%)
    0 / 33 (0.00%)
         occurrences all number
    1
    4
    12
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 34 (2.94%)
    7 / 115 (6.09%)
    3 / 33 (9.09%)
         occurrences all number
    7
    1
    13
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2008
    AM1: Inclusion criteria were modified to permit a wider selection of previous chemotherapy regimens for Groups 1 and 2. Study objectives were modified and overall survival for all groups added. For subjects relapsing after treatment with SCH 717454 at 0.3 mg/kg IV not eligible for surgical resection, consideration for treatment with 10 mg/kg IV was to be discussed with the Sponsor.
    01 Aug 2008
    AM2: Response criteria were modified because of characteristics of osteosarcoma tumors (significant matrix); participants with disease after resection could remain on study treatment; observation of participants post-treatment could be adjusted for state and local regulations.
    01 May 2009
    AM3: Allowed younger participants to be enrolled.
    08 Dec 2010
    AM4: Changes to vial fill and drug supply.
    14 Sep 2011
    AM5:The primary reason for amendment is to discontinue protocol-specific procedures that fall outside of the standard-of-care and to stop data collection except for SAE reports.

    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 stopped prematurely for administrative reasons; not all planned endpoints were analyzed.
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