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    Clinical Trial Results:
    Multicenter, Open-label Study to Assess the Pharmacokinetics, Pharmacodynamics, Efficacy, Safety, Tolerability, and Immunogenicity of a Single, Subcutaneous Dose of 100μg/kg XM22 in 21 Children with Ewing Family of Tumors or Rhabdomyosarcoma

    Summary
    EudraCT number
    2011-004742-18
    Trial protocol
    HU   CZ   BG   PL  
    Global end of trial date
    21 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XM22-07
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01585649
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merckle GmbH, Teva ratiopharm
    Sponsor organisation address
    Graf-Arco-Strasse 3, Ulm, Germany, 89079
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, ustevatrials@tevapharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001019-PIP01-10
    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
    Interim
    Date of interim/final analysis
    05 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the pharmacokinetics (PK) of a single subcutaneous (SC) injection of XM22, 100 μg/kg body weight (BW), in children with Ewing family of tumors or rhabdomyosarcoma.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; European Union [EU] Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Information regarding any investigational study centers participating in this study that could not comply with these standards was documented. Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, GCP, and the Declaration of Helsinki, and for collecting, recording, and reporting the data accurately and properly. The principal investigator at each study center was responsible for the conduct and administration of the study at that center and for contacts with study center management, with the IEC/IRB, and with local authorities, where applicable. Written and/or oral information about the study was provided to all patients and their parents/legal guardian in a language understandable by the patients. This included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from the parents/legal guardians of each patient, along with an assent form for adolescent study patients, before any study procedures or assessments were done. It was explained to the patients and parents/legal guardians that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Hungary: 4
    Worldwide total number of subjects
    21
    EEA total number of subjects
    6
    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)
    7
    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
    A total of 23 pediatric patients with Ewing family of tumors or rhabdomyosarcoma scheduled to receive chemotherapy were screened for enrollment into this study. Of the 23 patients screened, 21 patients at 11 study centers in 5 countries (Czech Republic, Hungary, Poland, Russia, and Ukraine) met entry criteria and were eligible for enrollment.

    Pre-assignment
    Screening details
    The 2 patients who were not enrolled were excluded based on inclusion criteria (1 for body weight below 15 kg, prior to Amendment 4; 1 for being under age 2 years).

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    XM22: Age 2 to <6 years
    Arm description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 2-5 years old at the time of study start.
    Arm type
    Experimental

    Investigational medicinal product name
    XM22
    Investigational medicinal product code
    Other name
    lipegfilgrastim, Lonquex®
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    XM22 was to be supplied in glass vials containing a 10 mg/mL solution for subcutaneous injection. Each patient was to receive a single subcutaneous dose of XM22 (100 μg/kg body weight) approximately 24 hours (±3 hours) after the end of the last chemotherapy in week 1 of the first chemotherapy cycle. XM22 administration was generally expected to occur on day 4 with VIDE chemotherapy; day 3 with VDC/IE or IVA chemotherapy; and day 2, 3, 4, or 6 with VAC chemotherapy (depending on the specific actinomycin regimen and the number of days cyclophosphamide was given). The maximum dose was 6 mg, as this is the fixed dose for adults. The abdomen was the preferred location for administration.

    Arm title
    XM22: Age 6 to <12 years
    Arm description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 6-11 years old at the time of study start.
    Arm type
    Experimental

    Investigational medicinal product name
    XM22
    Investigational medicinal product code
    Other name
    lipegfilgrastim, Lonquex®
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    XM22 was to be supplied in glass vials containing a 10 mg/mL solution for subcutaneous injection. Each patient was to receive a single subcutaneous dose of XM22 (100 μg/kg body weight) approximately 24 hours (±3 hours) after the end of the last chemotherapy in week 1 of the first chemotherapy cycle. XM22 administration was generally expected to occur on day 4 with VIDE chemotherapy; day 3 with VDC/IE or IVA chemotherapy; and day 2, 3, 4, or 6 with VAC chemotherapy (depending on the specific actinomycin regimen and the number of days cyclophosphamide was given). The maximum dose was 6 mg, as this is the fixed dose for adults. The abdomen was the preferred location for administration.

    Arm title
    XM22: Age 12 to <18 years
    Arm description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 12-17 years old at the time of study start.
    Arm type
    Experimental

    Investigational medicinal product name
    XM22
    Investigational medicinal product code
    Other name
    lipegfilgrastim, Lonquex®
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    XM22 was to be supplied in glass vials containing a 10 mg/mL solution for subcutaneous injection. Each patient was to receive a single subcutaneous dose of XM22 (100 μg/kg body weight) approximately 24 hours (±3 hours) after the end of the last chemotherapy in week 1 of the first chemotherapy cycle. XM22 administration was generally expected to occur on day 4 with VIDE chemotherapy; day 3 with VDC/IE or IVA chemotherapy; and day 2, 3, 4, or 6 with VAC chemotherapy (depending on the specific actinomycin regimen and the number of days cyclophosphamide was given). The maximum dose was 6 mg, as this is the fixed dose for adults. The abdomen was the preferred location for administration.

    Number of subjects in period 1
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Started
    7
    7
    7
    Completed
    7
    7
    7
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Follow-up: Age 2 to <6 years
    Arm description
    Following the single dose treatment period (lasting approximately 21 days), patients entered the untreated follow-up period which lasted an additional 360 days with patient contact on Days 180 and 360. The purpose of the follow-up period was to gather survival status, use of additional granulocyte colony stimulating factor (G-CSF) therapies, and immunogenicity testing results. Patients in this subpopulation were between 2-5 years old at the time of study start (i.e. start of the treatment period).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Follow-up: Age 6 to < 12 years
    Arm description
    Following the single dose treatment period (lasting approximately 21 days), patients entered the untreated follow-up period which lasted an additional 360 days with patient contact on Days 180 and 360. The purpose of the follow-up period was to gather survival status, use of additional granulocyte colony stimulating factor (G-CSF) therapies, and immunogenicity testing results. Patients in this subpopulation were between 6-11 years old at the time of study start (i.e. start of the treatment period).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Follow-up: Age 12 to <18 years
    Arm description
    Following the single dose treatment period (lasting approximately 21 days), patients entered the untreated follow-up period which lasted an additional 360 days with patient contact on Days 180 and 360. The purpose of the follow-up period was to gather survival status, use of additional granulocyte colony stimulating factor (G-CSF) therapies, and immunogenicity testing results. Patients in this subpopulation were between 12-17 years old at the time of study start (i.e. start of the treatment period). .
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Follow-up: Age 2 to <6 years Follow-up: Age 6 to < 12 years Follow-up: Age 12 to <18 years
    Started
    7
    7
    7
    Completed
    6
    7
    7
    Not completed
    1
    0
    0
         Adverse event, serious fatal
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    XM22: Age 2 to <6 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 2-5 years old at the time of study start.

    Reporting group title
    XM22: Age 6 to <12 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 6-11 years old at the time of study start.

    Reporting group title
    XM22: Age 12 to <18 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 12-17 years old at the time of study start.

    Reporting group values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years Total
    Number of subjects
    7 7 7 21
    Age categorical
    Units: Subjects
        Children (2-11 years)
    7 7 0 14
        Adolescents (12-17 years)
    0 0 7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    3.1 ± 1.2 9.4 ± 1.3 13.7 ± 1.1 -
    Gender categorical
    Units: Subjects
        Female
    2 4 3 9
        Male
    5 3 4 12
    Race
    Units: Subjects
        White
    7 7 7 21
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    7 7 7 21
    Height
    Units: cm
        arithmetic mean (standard deviation)
    104 ± 9.4 141.6 ± 10.2 156.9 ± 14.2 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    17.47 ± 2.83 36.86 ± 8.36 45.61 ± 13.83 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    16.25 ± 2.51 18.14 ± 2.28 18.07 ± 2.93 -

    End points

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    End points reporting groups
    Reporting group title
    XM22: Age 2 to <6 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 2-5 years old at the time of study start.

    Reporting group title
    XM22: Age 6 to <12 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 6-11 years old at the time of study start.

    Reporting group title
    XM22: Age 12 to <18 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 12-17 years old at the time of study start.
    Reporting group title
    Follow-up: Age 2 to <6 years
    Reporting group description
    Following the single dose treatment period (lasting approximately 21 days), patients entered the untreated follow-up period which lasted an additional 360 days with patient contact on Days 180 and 360. The purpose of the follow-up period was to gather survival status, use of additional granulocyte colony stimulating factor (G-CSF) therapies, and immunogenicity testing results. Patients in this subpopulation were between 2-5 years old at the time of study start (i.e. start of the treatment period).

    Reporting group title
    Follow-up: Age 6 to < 12 years
    Reporting group description
    Following the single dose treatment period (lasting approximately 21 days), patients entered the untreated follow-up period which lasted an additional 360 days with patient contact on Days 180 and 360. The purpose of the follow-up period was to gather survival status, use of additional granulocyte colony stimulating factor (G-CSF) therapies, and immunogenicity testing results. Patients in this subpopulation were between 6-11 years old at the time of study start (i.e. start of the treatment period).

    Reporting group title
    Follow-up: Age 12 to <18 years
    Reporting group description
    Following the single dose treatment period (lasting approximately 21 days), patients entered the untreated follow-up period which lasted an additional 360 days with patient contact on Days 180 and 360. The purpose of the follow-up period was to gather survival status, use of additional granulocyte colony stimulating factor (G-CSF) therapies, and immunogenicity testing results. Patients in this subpopulation were between 12-17 years old at the time of study start (i.e. start of the treatment period). .

    Primary: Area Under the Serum Concentration-Time Curve from Time 0 to Infinity (AUC0-inf)

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    End point title
    Area Under the Serum Concentration-Time Curve from Time 0 to Infinity (AUC0-inf) [1]
    End point description
    Pharmacokinetic parameters, including AUC0-inf, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data. PK sampling in the 2 to <6 years group stopped 144 instead of 240 hours after XM22 administration. Therefore, full pharmacokinetic parameters could be derived for only 3 of 7 patients in the 2 to <6 years group.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    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: Datasets for this PK parameter were incomplete compared with other PK exposure parameters, with only n=3, n=7, and n=5 for the youngest to oldest age groups, respectively. Therefore, there was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    3
    7
    5
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    26049.55 ± 55.2
    29985.05 ± 47.2
    38365.19 ± 55.9
    No statistical analyses for this end point

    Primary: Maximum Observed Serum Concentration Over The Time Span Specified (Cmax)

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    End point title
    Maximum Observed Serum Concentration Over The Time Span Specified (Cmax)
    End point description
    Pharmacokinetic parameters, including Cmax, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    7
    7
    7
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    243.066 ± 61
    255.863 ± 47.5
    224.889 ± 111.6
    Statistical analysis title
    Cmax analysis
    Comparison groups
    XM22: Age 6 to <12 years v XM22: Age 2 to <6 years v XM22: Age 12 to <18 years
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.9569 [3]
    Method
    ANOVA
    Confidence interval
    Notes
    [2] - Analysis of variance
    [3] - variance model for age_group

    Primary: The Time To Reach The Maximum Serum Concentration (tmax)

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    End point title
    The Time To Reach The Maximum Serum Concentration (tmax) [4]
    End point description
    Pharmacokinetic parameters, including tmax, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    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: There was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    7
    7
    7
    Units: hours
        arithmetic mean (standard deviation)
    50.26 ± 49.49
    45.43 ± 27.24
    82.23 ± 42.13
    No statistical analyses for this end point

    Primary: The Percentage Of The Extrapolated Area (AUCres) To Time Infinity In Relation To The Total Area Under The Curve (%AUC)

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    End point title
    The Percentage Of The Extrapolated Area (AUCres) To Time Infinity In Relation To The Total Area Under The Curve (%AUC) [5]
    End point description
    Pharmacokinetic parameters, including AUCres, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data. PK sampling in the 2 to <6 years group stopped 144 instead of 240 hours after XM22 administration. Therefore, full pharmacokinetic parameters could be derived for only 3 of 7 patients in the 2 to <6 years group. AUCres is the value of the residual area under the curve from time of last measurable concentration to time infinity.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    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: There was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    3 [6]
    7 [7]
    5 [8]
    Units: percentage
        arithmetic mean (standard deviation)
    5.34 ± 6.41
    0.08 ± 0.12
    3.03 ± 5.79
    Notes
    [6] - Pharmacokinetic analysis set
    [7] - Pharmacokinetic analysis set
    [8] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Primary: The Elimination Half-Life Time (t1/2)

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    End point title
    The Elimination Half-Life Time (t1/2) [9]
    End point description
    Pharmacokinetic parameters, including t1/2, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data. PK sampling in the 2 to <6 years group stopped 144 instead of 240 hours after XM22 administration. Therefore, full pharmacokinetic parameters could be derived for only 3 of 7 patients in the 2 to <6 years group.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    Notes
    [9] - 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: There was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    3 [10]
    7 [11]
    5 [12]
    Units: hours
        arithmetic mean (standard deviation)
    29.07 ± 14.29
    16.74 ± 3.05
    26.42 ± 12.59
    Notes
    [10] - Pharmacokinetic analysis set
    [11] - Pharmacokinetic analysis set
    [12] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Primary: The Apparent Volume Of Distribution During Terminal Phase After Non Intravenous Administration (Vz/F)

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    End point title
    The Apparent Volume Of Distribution During Terminal Phase After Non Intravenous Administration (Vz/F) [13]
    End point description
    Pharmacokinetic parameters, including Vz/F, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data. PK sampling in the 2 to <6 years group stopped 144 instead of 240 hours after XM22 administration. Therefore, full pharmacokinetic parameters could be derived for only 3 of 7 patients in the 2 to <6 years group.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    Notes
    [13] - 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: Datasets for this PK parameter were incomplete compared with other XM22 PK parameters, with only n=3, n=7, and n=5 for the youngest to oldest age groups, respectively. Therefore, there was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    3 [14]
    7 [15]
    5 [16]
    Units: mL
        geometric mean (geometric coefficient of variation)
    2721.33 ± 66.4
    2856.33 ± 154.7
    4076.89 ± 49.9
    Notes
    [14] - Pharmacokinetic analysis set
    [15] - Pharmacokinetic analysis set
    [16] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Primary: Apparent Clearance (CL/F)

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    End point title
    Apparent Clearance (CL/F) [17]
    End point description
    Pharmacokinetic parameters, including CL/F, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data. PK sampling in the 2 to <6 years group stopped 144 instead of 240 hours after XM22 administration. Therefore, full pharmacokinetic parameters could be derived for only 3 of 7 patients in the 2 to <6 years group.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    Notes
    [17] - 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: Datasets for this PK parameter were incomplete compared with other XM22 PK parameters, with only n=3, n=7, and n=5 for the youngest to oldest age groups, respectively. Therefore, there was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    3 [18]
    7 [19]
    5 [20]
    Units: mL/hour
        geometric mean (geometric coefficient of variation)
    70.79 ± 62.2
    119.87 ± 130
    115.97 ± 68.8
    Notes
    [18] - Pharmacokinetic analysis set
    [19] - Pharmacokinetic analysis set
    [20] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Primary: Mean Residence Time (MRT)

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    End point title
    Mean Residence Time (MRT) [21]
    End point description
    Pharmacokinetic parameters, including MRT, were calculated for each patient using noncompartmental analysis of serum XM22 concentration-time data. PK sampling in the 2 to <6 years group stopped 144 instead of 240 hours after XM22 administration. Therefore, full pharmacokinetic parameters could be derived for only 3 of 7 patients in the 2 to <6 years group.
    End point type
    Primary
    End point timeframe
    Within one hour prior to XM22 dose, hours 3, 8, 24, 30, 48, 72, 96, 144, 240 post-dose for 2 highest age groups. Fewer samples were collected for the lower age group.
    Notes
    [21] - 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: Datasets for this PK parameter were incomplete compared with other XM22 PK parameters, with only n=3, n=7, and n=5 for the youngest to oldest age groups, respectively. Therefore, there was no intention to make inference about XM22 dosing based on this PK parameter.
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    3 [22]
    7 [23]
    5 [24]
    Units: hours
        geometric mean (geometric coefficient of variation)
    49.38 ± 42.1
    79.26 ± 16.7
    90.49 ± 14.6
    Notes
    [22] - Pharmacokinetic analysis set
    [23] - Pharmacokinetic analysis set
    [24] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Febrile Neutropenia As Reported by Investigators

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    End point title
    Percentage of Participants with Febrile Neutropenia As Reported by Investigators
    End point description
    The incidence of febrile neutropenia was assessed during the chemotherapy cycle in which XM22 was administered. Results for febrile neutropenia according to investigator definition (based on information provided by the investigator on a CRF) were reported for the Full Analysis Set (21 patients). Febrile neutropenia was defined as an axillary or external ear temperature >38.3°C or 2 consecutive readings >37.8°C for 2 hours (e.g., 2 consecutive readings at least 2 hours apart) and absolute neutrophil count (ANC) <0.5 * 10^9/L. ANC and vital signs including body temperature were obtained at screening and throughout the treatment period.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    7 [25]
    7 [26]
    7 [27]
    Units: percentage of participants
        number (confidence interval 95%)
    14.3 (2.6 to 51.3)
    28.6 (8.2 to 64.1)
    71.4 (35.9 to 91.8)
    Notes
    [25] - Full analysis set
    [26] - Full analysis set
    [27] - Full analysis set
    No statistical analyses for this end point

    Secondary: Participants with Febrile Neutropenia As Reported by Investigators and Total Participants Categorized by Chemotherapy

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    End point title
    Participants with Febrile Neutropenia As Reported by Investigators and Total Participants Categorized by Chemotherapy
    End point description
    XM22 was administered following chemotherapy. Three chemotherapies are reported: 1) chemotherapy combination of ifosfamide plus vincristine plus actinomycin D (IVA) 2) chemotherapy combination of vincristine plus actinomycin D plus cyclophosphamide (VAC) 3) chemotherapy combination of vincristine plus ifosfamide plus doxorubicin plus etoposide (VIDE) This outcome informs which chemotherapy regimen was taken by participants in each arm, and which chemotherapy regimen was taken by participants who had febrile neutropenia as reported by investigators. Febrile neutropenia was defined as an axillary or external ear temperature >38.3°C or 2 consecutive readings >37.8°C for 2 hours (e.g., 2 consecutive readings at least 2 hours apart) and absolute neutrophil count (ANC) <0.5 * 10^9/L. ANC and vital signs including body temperature were obtained at screening and throughout the treatment period.
    End point type
    Secondary
    End point timeframe
    Day 1 to 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    7 [28]
    7 [29]
    7 [30]
    Units: participants
        IVA - febrile neutropenia event
    1
    0
    0
        IVA treatment
    5
    0
    0
        VAC - febrile neutropenia event
    0
    0
    0
        VAC treatment
    1
    2
    1
        VIDE - febrile neutropenia event
    0
    2
    5
        VIDE treatment
    1
    5
    6
    Notes
    [28] - Full analysis set
    [29] - Full analysis set
    [30] - Full analysis set
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Severe Neutropenia

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    End point title
    Percentage of Participants with Severe Neutropenia
    End point description
    Severe neutropenia was defined as absolute neutrophil count (ANC) <0.5 * 10^9/L.
    End point type
    Secondary
    End point timeframe
    Day 1 - 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [31]
    7 [32]
    7 [33]
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (9.7 to 70)
    85.7 (48.7 to 97.4)
    85.7 (48.7 to 97.4)
    Notes
    [31] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [32] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [33] - Per protocol set: patients who received XM22 and had no major protocol violations.
    No statistical analyses for this end point

    Secondary: Participants with Severe Neutropenia Categorized by Chemotherapy

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    End point title
    Participants with Severe Neutropenia Categorized by Chemotherapy
    End point description
    XM22 was administered following chemotherapy. Three chemotherapies are reported: 1) chemotherapy combination of ifosfamide plus vincristine plus actinomycin D (IVA) 2) chemotherapy combination of vincristine plus actinomycin D plus cyclophosphamide (VAC) 3) chemotherapy combination of vincristine plus ifosfamide plus doxorubicin plus etoposide (VIDE) This outcome informs which chemotherapy regimen was taken by participants in each arm, and which chemotherapy regimen was taken by participants who had severe neutropenia. Severe neutropenia was defined as absolute neutrophil count (ANC) <0.5 * 10^9/L.
    End point type
    Secondary
    End point timeframe
    Day 1 to 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [34]
    7 [35]
    7 [36]
    Units: participants
        IVA - severe neutropenia event
    0
    0
    0
        IVA treatment
    4
    0
    0
        VAC - severe neutropenia event
    1
    1
    0
        VAC treatment
    1
    2
    1
        VIDE - severe neutropenia event
    1
    5
    6
        VIDE treatment
    1
    5
    6
    Notes
    [34] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [35] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [36] - Per protocol set: patients who received XM22 and had no major protocol violations.
    No statistical analyses for this end point

    Secondary: Duration of Severe Neutropenia

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    End point title
    Duration of Severe Neutropenia
    End point description
    Duration of severe neutropenia was calculated as the sum of all days after chemotherapy with ANC <0.5 * 10^9/L. If ANC did not drop to <0.5 * 10^9/L, the duration was to be set to zero. Missing ANC values were estimated using linear interpolation. The interpolation was performed only within an interval between the first and last available ANC measurements.
    End point type
    Secondary
    End point timeframe
    Day 1 to 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [37]
    7 [38]
    7 [39]
    Units: days
        median (full range (min-max))
    0 (0 to 3)
    2 (0 to 5)
    3 (0 to 6)
    Notes
    [37] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [38] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [39] - Per protocol set: patients who received XM22 and had no major protocol violations.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Very Severe Neutropenia

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    End point title
    Percentage of Participants with Very Severe Neutropenia
    End point description
    Very severe neutropenia was defined as absolute neutrophil count (ANC) of <0.1 * 10^9/L.
    End point type
    Secondary
    End point timeframe
    Day 1 to 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [40]
    7 [41]
    7 [42]
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 39)
    14.3 (2.6 to 51.3)
    42.9 (15.8 to 75)
    Notes
    [40] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [41] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [42] - Per protocol set: patients who received XM22 and had no major protocol violations.
    No statistical analyses for this end point

    Secondary: Participants with Very Severe Neutropenia Categorized by Chemotherapy

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    End point title
    Participants with Very Severe Neutropenia Categorized by Chemotherapy
    End point description
    XM22 was administered following chemotherapy. Three chemotherapies are reported: 1) chemotherapy combination of ifosfamide plus vincristine plus actinomycin D (IVA) 2) chemotherapy combination of vincristine plus actinomycin D plus cyclophosphamide (VAC) 3) chemotherapy combination of vincristine plus ifosfamide plus doxorubicin plus etoposide (VIDE) This outcome informs which chemotherapy regimen was taken by participants in each arm, and which chemotherapy regimen was taken by participants who had very severe neutropenia.
    End point type
    Secondary
    End point timeframe
    Day 1 to 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [43]
    7 [44]
    7 [45]
    Units: participants
        IVA - very severe neutropenia event
    0
    0
    0
        IVA treatment
    4
    0
    0
        VAC - very severe neutropenia event
    0
    0
    0
        VAC treatment
    1
    2
    1
        VIDE - very severe neutropenia event
    0
    1
    3
        VIDE treatment
    1
    5
    6
    Notes
    [43] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [44] - Per protocol set: patients who received XM22 and had no major protocol violations.
    [45] - Per protocol set: patients who received XM22 and had no major protocol violations.
    No statistical analyses for this end point

    Secondary: Duration of Very Severe Neutropenia

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    End point title
    Duration of Very Severe Neutropenia
    End point description
    Duration of very severe neutropenia was measured in days, and calculated as the sum of all days after chemotherapy with ANC <0.1 * 10^9/L. If ANC did not drop to <0.1 * 10^9/L, the duration was set to zero.
    End point type
    Secondary
    End point timeframe
    Day 1 to 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [46]
    7 [47]
    7 [48]
    Units: days
        median (full range (min-max))
    0 (0 to 0)
    0 (0 to 2)
    0 (0 to 3)
    Notes
    [46] - Per protocol set
    [47] - Per protocol set
    [48] - Per protocol set
    No statistical analyses for this end point

    Secondary: Participants with Adverse Events

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    End point title
    Participants with Adverse Events
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day -10 (screening) to Day 36
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    7 [49]
    7 [50]
    7 [51]
    Units: participants
        Any adverse event (AE)
    7
    7
    7
        Treatment-emergent AE (TEAE)
    7
    6
    7
        XM22-related TEAE
    1
    1
    0
        Severe TEAE
    4
    5
    3
        XM22-related severe TEAE
    0
    0
    0
        Serious TEAE
    0
    1
    2
        XM22-related serious TEAE
    0
    0
    0
        Withdrawn from study due to TEAE
    0
    0
    0
        Deaths
    0
    0
    0
    Notes
    [49] - Safety analysis set
    [50] - Safety analysis set
    [51] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Absolute Neutrophil Count (ANC) Nadir

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    End point title
    Absolute Neutrophil Count (ANC) Nadir
    End point description
    Lowest measured value of the absolute neutrophil count, recorded as observed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [52]
    7 [53]
    7 [54]
    Units: 10^9/L
        arithmetic mean (standard deviation)
    0.88 ± 0.76
    0.21 ± 0.35
    0.37 ± 0.77
    Notes
    [52] - Full analysis set. One patient's nadir was a value deemed not plausible so is omitted.
    [53] - Full analysis set
    [54] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Nadir From Start of Chemotherapy

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    End point title
    Time to Absolute Neutrophil Count (ANC) Nadir From Start of Chemotherapy
    End point description
    Time (days) to the lowest observed value of the absolute neutrophil count, recorded as observed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [55]
    7 [56]
    7 [57]
    Units: days
        arithmetic mean (standard deviation)
    10.2 ± 3.6
    8.3 ± 1.9
    8.6 ± 0.8
    Notes
    [55] - Full analysis set
    [56] - Full analysis set
    [57] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=1.0*10^9/L) From ANC Nadir

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    End point title
    Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=1.0*10^9/L) From ANC Nadir
    End point description
    If ANC values did not drop below specified threshold, time to ANC recovery was set to 0.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    5 [58]
    7 [59]
    7 [60]
    Units: days
        arithmetic mean (standard deviation)
    1.2 ± 0.4
    3 ± 1.7
    3.1 ± 1.3
    Notes
    [58] - Full analysis set.
    [59] - Full analysis set
    [60] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=2.0*10^9/L) From ANC Nadir

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    End point title
    Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=2.0*10^9/L) From ANC Nadir
    End point description
    If ANC values did not drop below specified threshold, time to ANC recovery was set to 0.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    4 [61]
    7 [62]
    7 [63]
    Units: days
        arithmetic mean (standard deviation)
    3 ± 1.8
    3.7 ± 1.7
    3.6 ± 1.4
    Notes
    [61] - Full analysis set
    [62] - Full analysis set
    [63] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=1.0*10^9/L) From Start of Chemotherapy

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    End point title
    Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=1.0*10^9/L) From Start of Chemotherapy
    End point description
    If ANC values did not drop below specified threshold, time to ANC recovery was set to 0.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    5 [64]
    7 [65]
    7 [66]
    Units: days
        arithmetic mean (standard deviation)
    6.2 ± 5.8
    9.4 ± 4.3
    10.3 ± 4.8
    Notes
    [64] - Full analysis set
    [65] - Full analysis set
    [66] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=2.0*10^9/L) From Start of Chemotherapy

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    End point title
    Time to Absolute Neutrophil Count (ANC) Recovery (ANC>=2.0*10^9/L) From Start of Chemotherapy
    End point description
    If ANC values did not drop below specified threshold, time to ANC recovery was set to 0.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    4 [67]
    7 [68]
    7 [69]
    Units: days
        arithmetic mean (standard deviation)
    8.8 ± 5.9
    12 ± 0.8
    10.7 ± 4.9
    Notes
    [67] - Full analysis set
    [68] - Full analysis set
    [69] - Full analysis set
    No statistical analyses for this end point

    Secondary: CD34+ Area Over the Baseline Effect Curve

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    End point title
    CD34+ Area Over the Baseline Effect Curve
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [70]
    7 [71]
    7 [72]
    Units: days*cells/µL
        arithmetic mean (standard deviation)
    356.09 ± 304.73
    466.32 ± 610.14
    688.25 ± 618.28
    Notes
    [70] - Full analysis set
    [71] - Full analysis set
    [72] - Full analysis set
    No statistical analyses for this end point

    Secondary: CD34+ Area Under the Curve (AUC)

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    End point title
    CD34+ Area Under the Curve (AUC)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [73]
    7 [74]
    7 [75]
    Units: days*cells/µL
        arithmetic mean (standard deviation)
    402.2 ± 330.54
    518.42 ± 628.69
    705.13 ± 645.91
    Notes
    [73] - Full analysis set
    [74] - Full analysis set
    [75] - Full analysis set
    No statistical analyses for this end point

    Secondary: CD34+ Maximum

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    End point title
    CD34+ Maximum
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [76]
    7 [77]
    7 [78]
    Units: cells/µL
        arithmetic mean (standard deviation)
    96.33 ± 66.07
    130.35 ± 123.19
    151.75 ± 122.87
    Notes
    [76] - Full analysis set
    [77] - Full analysis set
    [78] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to CD34+ Maximum from Start of Chemotherapy

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    End point title
    Time to CD34+ Maximum from Start of Chemotherapy
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [79]
    7 [80]
    7 [81]
    Units: days
        arithmetic mean (standard deviation)
    9.7 ± 2.3
    11.7 ± 2.8
    14.9 ± 3.5
    Notes
    [79] - Full analysis set
    [80] - Full analysis set
    [81] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to CD34+ Maximum from XM22 Dose

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    End point title
    Time to CD34+ Maximum from XM22 Dose
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to day 21
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    6 [82]
    7 [83]
    7 [84]
    Units: days
        arithmetic mean (standard deviation)
    7.7 ± 2.6
    8.7 ± 2.1
    11.3 ± 3.1
    Notes
    [82] - Full analysis set
    [83] - Full analysis set
    [84] - Full analysis set
    No statistical analyses for this end point

    Secondary: Survival Status on Day 180 and Day 360 of the Follow-up Period

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    End point title
    Survival Status on Day 180 and Day 360 of the Follow-up Period
    End point description
    Data reports the number of patients who were still alive at the timepoints.
    End point type
    Secondary
    End point timeframe
    Day 180 and Day 360 of the Follow-up Period
    End point values
    Follow-up: Age 2 to <6 years Follow-up: Age 6 to < 12 years Follow-up: Age 12 to <18 years
    Number of subjects analysed
    7 [85]
    7 [86]
    7 [87]
    Units: participants
        Day 180
    7
    7
    7
        Day 360
    6
    7
    7
    Notes
    [85] - All Patients Who Entered the Follow-up Period
    [86] - All Patients Who Entered the Follow-up Period
    [87] - All Patients Who Entered the Follow-up Period
    No statistical analyses for this end point

    Secondary: Use of Granulocyte Colony Stimulating Factor Therapy By Day 180 of the Follow-up Period

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    End point title
    Use of Granulocyte Colony Stimulating Factor Therapy By Day 180 of the Follow-up Period
    End point description
    During the follow-up period additional G-CSF therapy was administered at the discretion of the investigator during subsequent chemotherapy. Additional G-CSF therapy consisted of filgrastim, lenograstim, and pegfilgrastim.
    End point type
    Secondary
    End point timeframe
    Day 180 during the Follow-up Period
    End point values
    Follow-up: Age 2 to <6 years Follow-up: Age 6 to < 12 years Follow-up: Age 12 to <18 years
    Number of subjects analysed
    7 [88]
    7 [89]
    7 [90]
    Units: participants
        No additional G-CSF since end of Treatment Period
    1
    0
    0
        Additional G-CSF therapy
    6
    7
    7
        Filgrastim
    5
    6
    4
        Lenograstim
    2
    1
    2
        Pegfilgrastim
    1
    0
    2
    Notes
    [88] - All Patients Who Entered the Follow-up Period
    [89] - All Patients Who Entered the Follow-up Period
    [90] - All Patients Who Entered the Follow-up Period
    No statistical analyses for this end point

    Secondary: Use of Granulocyte Colony Stimulating Factor Therapy from Day 181 to Day 360 of the Follow-up Period

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    End point title
    Use of Granulocyte Colony Stimulating Factor Therapy from Day 181 to Day 360 of the Follow-up Period
    End point description
    During the follow-up period additional G-CSF therapy was administered at the discretion of the investigator during subsequent chemotherapy. Additional G-CSF therapy consisted of filgrastim, lenograstim, and pegfilgrastim.
    End point type
    Secondary
    End point timeframe
    Day 181 up to Day 360 during the Follow-up Period
    End point values
    Follow-up: Age 2 to <6 years Follow-up: Age 6 to < 12 years Follow-up: Age 12 to <18 years
    Number of subjects analysed
    7 [91]
    7 [92]
    7 [93]
    Units: participants
        No additional G-CSF
    5
    1
    2
        Additional G-CSF therapy
    2
    6
    5
        Filgrastim
    2
    5
    3
        Lenograstim
    0
    1
    1
        Pegfilgrastim
    0
    0
    1
    Notes
    [91] - All Patients Who Entered the Follow-up Period
    [92] - All Patients Who Entered the Follow-up Period
    [93] - All Patients Who Entered the Follow-up Period
    No statistical analyses for this end point

    Secondary: Patients with Positive Anti-Drug Antibody (ADA) at Screening, Treatment Period Day 21, Follow-up Period Days 180 and 360

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    End point title
    Patients with Positive Anti-Drug Antibody (ADA) at Screening, Treatment Period Day 21, Follow-up Period Days 180 and 360
    End point description
    Samples for immunogenicity testing, specifically anti-drug antibody (ADA), were collected during the screening phase before administration of XM22, at the end of XM22 treatment period (day 21), and during the follow-up period at approximately 180 days ±2 weeks (day 180) and 360 days ±2 weeks (day 360) after XM22 administration. Sampling timeframes are listed below, as are the number of patients who had a positive ADA value at any of the timepoints ('Total with positive ADA'). The last row represents the number of patients with a positive treatment-related ADA response., which is defined as an observation of ADA-positive sample(s) after XM22 treatment or an observation of ADA-positive samples at both pre- and post-dose timepoints with titer value increased by 2.2 fold from baseline to post-XM22 treatment. Values represent patients with positive ADA assays.
    End point type
    Secondary
    End point timeframe
    Day -10 (screening), Day 21 (Treatment Period), Days 180 and 360 (Follow-up Period)
    End point values
    XM22: Age 2 to <6 years XM22: Age 6 to <12 years XM22: Age 12 to <18 years
    Number of subjects analysed
    7
    7
    7
    Units: participants
        Screening
    2
    1
    1
        Day 21 Treatment
    0
    1
    0
        Day 180 Follow-up
    2
    0
    0
        Day 360 Follow-up
    0
    0
    0
        Total with positive ADA
    3
    1
    1
        Total with treatment-related positive ADA
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Day 15
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    2 to 6 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 2-5 years old at the time of study start.

    Reporting group title
    6 to 12 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 6-11 years old at the time of study start.

    Reporting group title
    12 to 18 years
    Reporting group description
    A single, subcutaneous injection of XM22 was administered approximately 24 hours (±3 hours) after the end of the last chemotherapy treatment in week 1 of the regimen. Dose level was 100 μg/kg body weight with a maximum of 6 mg. Participants in this subpopulation were between 12-17 years old at the time of study start.

    Serious adverse events
    2 to 6 years 6 to 12 years 12 to 18 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    2 to 6 years 6 to 12 years 12 to 18 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    6 / 7 (85.71%)
    7 / 7 (100.00%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Asthma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    4 / 7 (57.14%)
         occurrences all number
    2
    2
    5
    Neutropenia
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 7 (28.57%)
    3 / 7 (42.86%)
         occurrences all number
    5
    2
    4
    Thrombocytopenia
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 7 (14.29%)
    4 / 7 (57.14%)
         occurrences all number
    3
    1
    4
    Anaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 7 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    3
    0
    6
    Febrile neutropenia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
         occurrences all number
    1
    1
    3
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    5
    1
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    1
    Stomatitis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    2
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    1
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Enteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2011
    Amendment 1 (dated 16 December 2011) to the protocol was issued before any patients were enrolled into the study. The following procedural changes (not all-inclusive) were made to the protocol: • In preparing the dose of XM22 for injection, after the syringe was filled, the needle was to be changed. • The manufacturer of XM22 shifted from Merckle Biotec in Germany to Teva Pharmaceuticals Europe in The Netherlands.
    13 Dec 2012
    Amendment 2 (dated 13 December 2012) to the protocol became effective after 14 total patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following procedural changes (not all-inclusive) were made to the protocol: • Allow screening procedures to be completed on the first day of the first chemotherapy cycle (day 1), prior to the start of chemotherapy • Emphasize that parental informed consent and patient assent, if appropriate, had to be obtained before screening procedures were initiated • Clarify that XM22 could be administered on day 2, 3, 4, or 6 with VAC chemotherapy (depending on the specific actinomycin regimen and the number of days cyclophosphamide was given)
    19 Mar 2013
    Amendment 3 (dated 19 March 2013) to the protocol became effective after 15 total patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural change (not all-inclusive) was made to the protocol: • Allow enrollment of patients with rhabdomyosarcoma who receive chemotherapy with IVA. This multidrug regimen has been shown to be efficacious in treating rhabdomyosarcoma. The preference in Europe for ifosfamide-based chemotherapy over regimens containing cyclophosphamide reflects emerging evidence for less impact on male fertility and generally acceptable levels of renal toxicity.
    19 Aug 2013
    Amendment 4 (dated 19 August 2013) to the protocol became effective after 18 total patients were enrolled into the study. The change to the protocol was considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • Allow enrollment of patients with previous chemotherapy treatment. The purpose was to facilitate recruitment of children into the 2 to <6 years group. The enrollment of patients with previous chemotherapy treatments did not affect the safety of the children. The safety of XM22 was not dependent on the number of previous chemotherapy treatments received; patients were to be given only chemotherapy for which a G-CSF was recommended. This change should not have affected efficacy since enrolled patients should not have received a G-CSF within the last 6 months (Exclusion criteria #1: "Previous exposure to filgrastim, pegfilgrastim or lenograstim or other G-CSFs in clinical development within 6 months prior to the XM22 administration”). • Allow enrollment of patients with body weight ≥12.5 kg. It was shown that several children between 2 and 3 years of age had a body weight below 15 kg and, therefore, failed inclusion criterion #7, although otherwise eligible. To enable the enrollment of those children weighing between 12.5 kg and 15 kg, a reduced sampling schedule for pharmacokinetics and pharmacodynamics (comprising 6 pharmacokinetic and 8 pharmacodynamic samples apart from the clinical safety and antibody samples) was defined in order to comply with the requirements of total blood loss in children during the study.
    18 Nov 2013
    Amendment 5 (dated 18 November 2013) to the protocol became effective after 20 total patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following change (not all-inclusive) was made to the protocol: • Clarify that new safety information relative to Neulasta® regarding capillary leak syndrome was reported, but similar adverse events for XM22 were not expected.

    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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