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    Clinical Trial Results:
    A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children with Solid Tumors

    Summary
    EudraCT number
    2014-005190-36
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    25 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2016
    First version publication date
    29 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20050252
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00658658
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and pharmacokinetics of up to 3 different dose schedules of panitumumab in pediatric patients with solid tumors.
    Protection of trial subjects
    This study was conducted in accordance with ICH GCP regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Mar 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
    United States: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    14
    Adolescents (12-17 years)
    17
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 7 centers in the United States. Participants were enrolled from 14 March 2008 to 4 March 2015.

    Pre-assignment
    Screening details
    Three dose regimens were to be tested in pediatric patients stratified by age group (1 to 11 versus 12 to 17 years). Participants were enrolled sequentially into each dose group, beginning with the 2.5 mg/kg, 12 to 17 year old cohort, based upon demonstration of sufficient safety.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Age 12–17: 2.5 mg/kg QW
    Arm description
    Participants aged 12 to 17 years received panitumumab 2.5 mg/kg administered by intravenous (IV) infusion weekly (QW) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

    Arm title
    Age 12–17: 6 mg/kg Q2W
    Arm description
    Participants aged 12 to 17 years received panitumumab 6 mg/kg administered by IV infusion every 2 weeks (Q2W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

    Arm title
    Age 12–17: 9 mg/kg Q3W
    Arm description
    Participants aged 12 to 17 years received panitumumab 9 mg/kg administered by IV infusion every 3 weeks (Q3W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

    Arm title
    Age 1–11: 2.5 mg/kg QW
    Arm description
    Participants aged 1 to 11 years received panitumumab 2.5 mg/kg administered by IV infusion QW until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

    Arm title
    Age 1–11: 6 mg/kg Q2W
    Arm description
    Participants aged 1 to 11 years received panitumumab 6 mg/kg administered by IV infusion Q2W until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

    Number of subjects in period 1
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Started
    6
    7
    4
    6
    8
    Completed
    1
    5
    4
    4
    3
    Not completed
    5
    2
    0
    2
    5
         Disease Progression
    -
    1
    -
    1
    3
         Death
    4
    -
    -
    1
    1
         Protocol-specified Criteria
    1
    -
    -
    -
    -
         Other
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age 12–17: 2.5 mg/kg QW
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 2.5 mg/kg administered by intravenous (IV) infusion weekly (QW) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 12–17: 6 mg/kg Q2W
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 6 mg/kg administered by IV infusion every 2 weeks (Q2W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 12–17: 9 mg/kg Q3W
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 9 mg/kg administered by IV infusion every 3 weeks (Q3W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 1–11: 2.5 mg/kg QW
    Reporting group description
    Participants aged 1 to 11 years received panitumumab 2.5 mg/kg administered by IV infusion QW until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 1–11: 6 mg/kg Q2W
    Reporting group description
    Participants aged 1 to 11 years received panitumumab 6 mg/kg administered by IV infusion Q2W until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W Total
    Number of subjects
    6 7 4 6 8 31
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 6 8 14
        Adolescents (12-17 years)
    6 7 4 0 0 17
        Adults (18-64 years)
    0 0 0 0 0 0
        From 65-84 years
    0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    13.2 ± 0.8 15.6 ± 1.5 15.8 ± 1.9 7.8 ± 3.1 8.4 ± 2.8 -
    Gender, Male/Female
    Units: participants
        Female
    3 1 3 3 4 14
        Male
    3 6 1 3 4 17
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    0 2 0 0 0 2
        Black (or African American)
    1 1 0 1 0 3
        Hispanic or Latino
    0 0 1 0 1 2
        Other
    0 0 0 1 0 1
        White or Caucasian
    5 4 3 4 7 23

    End points

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    End points reporting groups
    Reporting group title
    Age 12–17: 2.5 mg/kg QW
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 2.5 mg/kg administered by intravenous (IV) infusion weekly (QW) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 12–17: 6 mg/kg Q2W
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 6 mg/kg administered by IV infusion every 2 weeks (Q2W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 12–17: 9 mg/kg Q3W
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 9 mg/kg administered by IV infusion every 3 weeks (Q3W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 1–11: 2.5 mg/kg QW
    Reporting group description
    Participants aged 1 to 11 years received panitumumab 2.5 mg/kg administered by IV infusion QW until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 1–11: 6 mg/kg Q2W
    Reporting group description
    Participants aged 1 to 11 years received panitumumab 6 mg/kg administered by IV infusion Q2W until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

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    End point title
    Number of Participants with Dose-limiting Toxicities (DLTs) [1]
    End point description
    Any panitumumab related grade 3 or 4 hematologic or non-hematologic toxicity (graded according to the modified Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria) was considered a DLT with the exception of alopecia and fatigue. Hypomagnesemia, nausea, diarrhea, vomiting, and skin or nail toxicities constituted a DLT only of the following occured: • Grade 3 or 4 hypomagnesemia that persisted for at least 5 days despite maximal magnesium replacement; • Grade 3 or 4 diarrhea, nausea, or vomiting that persisted for at least 5 days despite maximum supportive therapy; • Grade 4 skin or nail toxicity. This analysis was perfored in the DLT Analysis Set which included all participants who received at least 1 dose of panitumumab and were evaluated for DLTs and completed at least 28 days (for the 2.5 and 6 mg/kg cohorts) or 21 days (for 9 mg/kg cohort) of therapy unless due to a DLT.
    End point type
    Primary
    End point timeframe
    28 days from initial administration of panitumumab for the 2.5 and 6 mg/kg cohorts and 21 days from first administration for the 9 mg/kg cohort.
    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: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    4
    5
    4
    4
    5
    Units: participants
        number (not applicable)
    1
    0
    0
    1
    3
    No statistical analyses for this end point

    Primary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs) [2]
    End point description
    A serious adverse event is defined as an AE that: • is fatal; • is life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • is a congenital anomaly/birth defect; • other significant medical hazard. The investigator assessed whether adverse events were related to panitumumab. The severity of adverse events was based on CTCAE version 3 (with the exception of skin- or nail-related toxicities which were graded using the CTCAE version 3.0 with modifications), according to the following: Grade 1 = Mild (aware of sign or symptom, but easily tolerated); Grade 2 = Moderate (discomfort enough to cause interference with usual activity); Grade 3 = Severe (incapacitating with inability to work or do usual activity); Grade 4 = Life-threatening or disabling; Grade 5 = Fatal. Adverse event analyses include all participants who received at least one dose of panitumumab.
    End point type
    Primary
    End point timeframe
    From first dose date to end of study date. The median duration of study was 47 days.
    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: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    6
    7
    4
    6
    8
    Units: participants
    number (not applicable)
        Any adverse event
    6
    7
    3
    6
    8
        Serious adverse events
    5
    3
    2
    3
    5
        Treatment-related adverse event
    5
    5
    3
    5
    6
        Treatment-related serious adverse event
    1
    0
    0
    1
    2
        Withdrawals due to adverse event
    0
    0
    0
    0
    0
        Grade 1
    5
    7
    3
    6
    6
        Grade 2
    5
    6
    3
    4
    7
        Grade 3
    4
    5
    2
    4
    6
        Grade 4
    4
    0
    0
    1
    2
        Fatal
    4
    0
    0
    1
    1
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration (Cmax) of Panitumumab

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    End point title
    Maximum Observed Concentration (Cmax) of Panitumumab [3]
    End point description
    Panitumumab serum concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the assay was 400 pg/mL. Concentrations below the LLOQ were set to zero. The Pharmacokinetic (PK) Analysis Set included all participants who received the correct dose of panitumumab and from whom the PK parameters could be assessed; "n" indicates the number of participants with available data for each time point. Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.
    End point type
    Primary
    End point timeframe
    First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    6
    7
    3
    4
    7
    Units: μg/mL
    arithmetic mean (standard deviation)
        First Dose (n=6, 7, 3, 4, 7)
    52.8 ± 11.4
    161 ± 41.2
    205 ± 45.9
    42.9 ± 8.51
    120 ± 29.4
        Third Dose (n=3, 5, 1, 3, 2)
    76.6 ± 21.1
    187 ± 45.2
    327 ± 99999
    60.8 ± 15.7
    126 ± 99999
    No statistical analyses for this end point

    Primary: Minimum Observed Concentration (Cmin) of Panitumumab

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    End point title
    Minimum Observed Concentration (Cmin) of Panitumumab [4]
    End point description
    Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.
    End point type
    Primary
    End point timeframe
    First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively).
    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: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    4
    7
    2
    4
    5
    Units: μg/mL
    arithmetic mean (standard deviation)
        First Dose (n=4, 7, 2, 4, 5)
    6.62 ± 6.83
    24.7 ± 18.6
    35.3 ± 99999
    4.87 ± 3.64
    19.7 ± 15.5
        Third Dose (n=3, 5, 0, 3, 2)
    24.2 ± 22.9
    48.1 ± 25.1
    99999 ± 99999
    17.3 ± 8.83
    26.1 ± 99999
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab

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    End point title
    Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab [5]
    End point description
    The area under the serum concentration-time curve from time zero to the end of the dosing interval (AUCtau), estimated using the linear trapezoidal method. Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.
    End point type
    Primary
    End point timeframe
    First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively).
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    4
    7
    2
    4
    5
    Units: day*μg/mL
    arithmetic mean (standard deviation)
        First Dose (n=4, 7, 2, 4, 5)
    167 ± 86.1
    1040 ± 357
    1580 ± 99999
    127 ± 37.9
    708 ± 247
        Third Dose (n=3, 5, 0, 3, 2)
    306 ± 178
    1330 ± 357
    99999 ± 99999
    255 ± 70.7
    754 ± 99999
    No statistical analyses for this end point

    Primary: Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab

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    End point title
    Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab [6]
    End point description
    Standard deviation was not calculated when n < 3; "99999" is entered as placeholder.
    End point type
    Primary
    End point timeframe
    First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively).
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    2
    5
    1
    3
    3
    Units: days
    arithmetic mean (standard deviation)
        First Dose (n=2, 5, 1, 3, 3)
    1.33 ± 99999
    4.49 ± 1.09
    4.27 ± 99999
    2.11 ± 0.913
    4.23 ± 1.64
        Third Dose (n=2, 2, 0, 1, 1)
    2.94 ± 99999
    4.98 ± 99999
    99999 ± 99999
    3.07 ± 99999
    4.91 ± 99999
    No statistical analyses for this end point

    Primary: Serum Clearance (CL) of Panitumumab

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    End point title
    Serum Clearance (CL) of Panitumumab [7]
    End point description
    Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.
    End point type
    Primary
    End point timeframe
    First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively).
    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: A formal hypothesis was not tested in this study. All results are descriptive in nature.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    3
    5
    1
    4
    3
    Units: mL/day/kg
    arithmetic mean (standard deviation)
        First Dose (n=3, 5, 1, 4, 3)
    19.8 ± 8.57
    6.38 ± 0.466
    7.15 ± 99999
    18.7 ± 6.35
    8.06 ± 1.4
        Third Dose (n=3, 5, 0, 3, 2)
    9.92 ± 4.4
    4.69 ± 1
    99999 ± 99999
    10.1 ± 2.44
    8.05 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Participants who Developed Antibodies to Panitumumab

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    End point title
    Number of Participants who Developed Antibodies to Panitumumab
    End point description
    Three validated assays were used to detect the presence of anti-panitumumab antibodies. Two screening immunoassays, an acid-dissociation enzyme-linked immunosorbent assay (ELISA) and a Biacore-based biosensor assay, were used to detect antibodies capable of binding to panitumumab. All samples confirmed to be positive by drug specificity in either screening immunoassay were further tested for neutralizing antibodies in a cell-based epidermal growth factor receptor (EGFR) phosphorylation bioassay. The number of participants who developed antibodies to panitumumab is the number of participants with a non-positive (including missing) antibody result at baseline and a positive antibody result at any post-baseline time point. This analysis includes all participants who received at least 1 dose of panitumumab and who had at least one post-baseline immunoassay result.
    End point type
    Secondary
    End point timeframe
    Before panitumumab administration on Day 1, Day 43, Day 169 and 30 days after last dose for all cohorts.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    4
    5
    4
    3
    4
    Units: participants
    number (not applicable)
        Binding antibodies
    1
    0
    0
    2
    0
        Neutralizing antibodies
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an Objective Response

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    End point title
    Percentage of Participants with an Objective Response
    End point description
    Disease assessments were based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria. Objective ersponse is defined as a best response of either complete response (CR) or partial response (PR). Participants with no post-baseline assessments were considered non-responders. CR or PR was confirmed no less than 4-weeks after the criteria for response were first met. CR: Disappearance of all target and non-target lesions, normalization of tumor markers and no new lesions. PR: At least 30% decrease in the size of target lesions, no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of 1 or more non-target lesion(s) not qualifying for either CR or progressive disease (PD) or/and maintenance of tumor marker level above normal limits and no new lesions. Analysis includes all participants with baseline measurable disease who received at least 1 dose of panitumumab.
    End point type
    Secondary
    End point timeframe
    Tumor response was assessed every 8 weeks through week 48 and every 3 months thereafter until disease progression or end of study. The data cut-off for the analysis was 17 June 2015; median duration of study was 47 days.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    4
    3
    4
    2
    3
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 60.24)
    0 (0 to 70.76)
    0 (0 to 60.24)
    0 (0 to 84.19)
    0 (0 to 70.76)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Disease Control

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    End point title
    Percentage of Participants with Disease Control
    End point description
    Disease assessments were based on investigator review of scans using modified RECIST version 1.0 criteria. A participant was considered to have disease control if their best response is either a complete or partial response, or stable disease (SD). Participants without a post-baseline assessment were considered to not have disease control. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. A best overall response of SD requires a visit response of SD or better, no earlier than 49 days after the date of enrollment. Stable disease: Neither sufficient shrinkage of target lesions to qualify for a PR nor sufficient increase to qualify for PD and no progression of existing non-target lesions and no new lesions. Analysis includes all participants with baseline measurable disease who received at least 1 dose of panitumumab.
    End point type
    Secondary
    End point timeframe
    Tumor response was assessed every 8 weeks through week 48 and every 3 months thereafter until disease progression or end of study. The data cut-off for the analysis was 17 June 2015; median duration of study was 47 days.
    End point values
    Age 12–17: 2.5 mg/kg QW Age 12–17: 6 mg/kg Q2W Age 12–17: 9 mg/kg Q3W Age 1–11: 2.5 mg/kg QW Age 1–11: 6 mg/kg Q2W
    Number of subjects analysed
    4
    3
    4
    2
    3
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 60.24)
    33.33 (0.84 to 90.57)
    0 (0 to 60.24)
    50 (1.26 to 98.74)
    66.67 (9.43 to 99.16)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose date to end of study date. The median duration of study is 47 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Age 12–17: 2.5 mg/kg QW
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 2.5 mg/kg administered by intravenous (IV) infusion weekly (QW) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 12-17: 6 mg/kg Q2W
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 6 mg/kg administered by IV infusion every 2 weeks (Q2W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 12-17: 9 mg/kg Q3W
    Reporting group description
    Participants aged 12 to 17 years received panitumumab 9 mg/kg administered by IV infusion every 3 weeks (Q3W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 1-11: 2.5 mg/kg QW
    Reporting group description
    Participants aged 1 to 11 years received panitumumab 2.5 mg/kg administered by IV infusion QW until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Reporting group title
    Age 1-11: 6 mg/kg Q2W
    Reporting group description
    Participants aged 1 to 11 years received panitumumab 6 mg/kg administered by IV infusion Q2W until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

    Serious adverse events
    Age 12–17: 2.5 mg/kg QW Age 12-17: 6 mg/kg Q2W Age 12-17: 9 mg/kg Q3W Age 1-11: 2.5 mg/kg QW Age 1-11: 6 mg/kg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    3 / 7 (42.86%)
    2 / 4 (50.00%)
    3 / 6 (50.00%)
    5 / 8 (62.50%)
         number of deaths (all causes)
    4
    0
    0
    1
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood urea increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Haemoglobin decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Osteosarcoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyosarcoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Bronchostenosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory acidosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Respiratory failure
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    Substance-induced psychotic disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Ascites
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Pancreatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Hydronephrosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Oliguria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Hyperuricaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypocalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Hyponatraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Age 12–17: 2.5 mg/kg QW Age 12-17: 6 mg/kg Q2W Age 12-17: 9 mg/kg Q3W Age 1-11: 2.5 mg/kg QW Age 1-11: 6 mg/kg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    7 / 7 (100.00%)
    3 / 4 (75.00%)
    6 / 6 (100.00%)
    7 / 8 (87.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Pallor
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    7
    2
    0
    2
    Hypothermia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Agitation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    0
    0
    2
    Confusional state
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    1
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Wound secretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood creatinine
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood lactate dehydrogenase decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Haemoglobin
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    2
    Heart rate increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    0
    1
    Temperature difference of extremities
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    4
    2
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    1
    Pleural effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory distress
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Cerebellar syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cranial nerve disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    4
    1
    0
    3
    Hemiplegia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Motor dysfunction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Nystagmus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    0
    2
    Phantom pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Exophthalmos
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Change of bowel habit
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    4
    3
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    0
    0
    0
    3
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gingival erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    0
    2
    0
    4
    Oral pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    4 / 6 (66.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    4
    5
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Urogenital haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    1
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 7 (71.43%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    18
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 7 (57.14%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
         occurrences all number
    0
    7
    3
    1
    3
    Erythema
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    3
    2
    0
    4
    0
    Exfoliative rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    3
    0
    1
    Petechiae
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    1
    0
    1
    Purpura
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
         occurrences all number
    2
    1
    0
    2
    4
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin fissures
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin hypopigmentation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Bone atrophy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Fracture pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Scoliosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Torticollis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Alkalosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    0
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    5
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    3
    0
    3
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    4
    0
    2
    Hyponatraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Peritonitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Purulent discharge
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Streptococcal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2011
    - Removed the requirement for epidermal growth factor receptor (EGFR) immunohistochemical staining of tumor tissue prior to enrollment, but rather allow the central EGFR testing to be performed within 4 weeks after enrollment. - Updated the eligibility criteria to state that male subjects of reproductive potential were no longer required to use contraception precautions during the study and female subjects of childbearing potential were required to use adequate contraception precautions during treatment and for 2 months after the end of treatment. - Updated the interruption of panitumumab infusion to be consistent with the most recent guidelines regarding the management of panitumumab-related infusion reactions. - Deleted the instructions to allow treatment of subjects with central nervous system (CNS) disease only with stable glucocorticoid dosing. The dose of glucocorticoid to manage CNS disease may change while subjects are on the study. - Updated study procedures to specify that any blood and/or tumor tissue sample collected according to the Schedule of Assessments may be analyzed for any of the tests outlined in the protocol and for any tests necessary to minimize risks to study subjects. In addition, if informed consent is provided by the subject, Amgen may do additional testing on remaining samples. - Updated the Screening section to clarify that tumor tissue samples for EGFR testing should be submitted to the designated central laboratory within 4 weeks after enrollment. - Updated the End of Study Visit section to clarify that in case a subject tests positive for human antipanitumumab antibodies (HAPA) at the end of study visit, additional serum samples will be drawn and tested every 3 months from the date that the site is informed by Amgen of the positive result until the HAPA result is negative, withdrawal of consent, death, or up to 1 year after the positive result has been reported, whichever occurs first.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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