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    Clinical Trial Results:
    INTELLANCE-2: ABT-414 Alone or ABT-414 plus Temozolomide Versus Lomustine or Temozolomide for Recurrent Glioblastoma: A Randomized Phase 2 Study of the EORTC Brain Tumor Group

    Summary
    EudraCT number
    		 2014-004438-24
    Trial protocol
    		 NL   DE   HU   AT   FI   GB   IE   ES   BE   CZ   FR   PL   IT  
    Global end of trial date
    24 Jun 2019

    Results information
    Results version number
    		 v1
    This version publication date
    05 Jan 2020
    First version publication date
    05 Jan 2020
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M14-483
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02343406
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 1410-BTG: EORTC Protocol Number
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    1 North Waukegan Road, North Chicago, IL, United States, 60064
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110,
    Scientific contact
    Jim Looman, AbbVie, jim.looman@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study objectives were to assess whether depatuxizumab mafodotin (ABT-414) alone or in combination with temozolomide (TMZ) improved overall survival (OS), progression-free survival (PFS), tumor response, quality of life, neurological deterioration-free survival (NDFS), and steroid use compared to standard treatment with lomustine single agent or TMZ re-challenge in adult subjects ≥ 18 years of age with centrally-confirmed recurrent epidermal growth factor receptor (EGFR)-amplified glioblastoma. The safety, pharmacokinetics, and efficacy of depatuxizumab mafodotin in children <18 years of age was evaluated in a pediatric substudy. The EMEA-001732-PIP02-15 pediatric investigation plan was withdrawn on 07 July 2019 due to the discontinuation of the depatuxizumab mafodotin research program.
    Protection of trial subjects
    Participant and/or legal guardian read and understood information provided about the study and gave written permission.
    Background therapy
    		 Due to the risk of eye toxicity, each administration of depatuxizumab mafodotin was to be given with a steroid ophthalmic solution. The recommended type, dose, and schedule of eye drops was as follows: dexamethasone 0.1% solution, 2 drops (gtts) in each eye (OU) every 8 (q8) hours to start 48 hours prior to depatuxizumab mafodotin dosing and continue for a total of 7 days (or 21 doses total). The type of ophthalmic solution used may have varied depending on the availability of the solution at each location. A modification to the eye drop dosing or schedule based on ongoing clinical experience may have been suggested.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2014
    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
    Australia: 20
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Netherlands: 32
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    275
    EEA total number of subjects
    202
    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)
    4
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    204
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study included a 30-day screening period.

    Pre-assignment
    Screening details
    		 Randomized adult subjects: histologically confirmed glioblastoma with unequivocal first progression after radiation therapy, concurrent/adjuvant TMZ chemotherapy, and presence of EGFR amplification. Pediatric subjects: histologically proven high grade glioma, grade IV glioma, or DIPG and presence of EGFR amplification.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    In the subject disposition table, "Completed" and "Not completed" refer to study drug treatment, and the reasons not completed listings refer to study drug treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ABT-414/temozolomide
    Arm description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult subjects
    Arm type
    		 Experimental

    Investigational medicinal product name
    Depatuxizumab mafodotin
    Investigational medicinal product code
    Other name
    ABT-414
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous administration (1.25 mg/kg or 1.0 mg/kg body weight) over 30 to 40 minutes once every 2 weeks until one of the treatment withdrawal criteria was met. The dose was 1.25 mg/kg in the original protocol (Version 1) and Version 2, Amendment 1, and was lowered to 1.0 mg/kg in protocol Version 3, Amendment 2.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    TMZ
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg/m^2 on Days 1-5 for the first 28-day cycle, with dose escalation to 200 mg/m^2 in subsequent cycles in case of adequate tolerance until one of the treatment withdrawal criteria was met.

    Arm title
    		 ABT-414_adult
    Arm description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult subjects
    Arm type
    		 Experimental

    Investigational medicinal product name
    Depatuxizumab mafodotin
    Investigational medicinal product code
    Other name
    ABT-414
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous administration (1.25 mg/kg or 1.0 mg/kg body weight) over 30 to 40 minutes once every 2 weeks until one of the treatment withdrawal criteria was met. The dose was 1.25 mg/kg in the original protocol (Version 1) and Version 2, Amendment 1, and was lowered to 1.0 mg/kg in protocol Version 3, Amendment 2.

    Arm title
    		 Control_lomustine
    Arm description
    		 Adult subjects relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lomustine
    Investigational medicinal product code
    Other name
    Gleostine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    110 mg/m^2 on Day 1 of every 42-day treatment period. Treatment continued until one of the treatment withdrawal criteria was met, for a maximum of one year.

    Arm title
    		 Control_ temozolomide
    Arm description
    		 Adult subjects relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    TMZ
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg/m^2 on Day 1 to Day 5 for the first 28-day cycle, with dose escalation to 200 mg/m^2 in subsequent cycles in case of adequate tolerance. Treatment continued until one of the treatment withdrawal criteria was met.

    Arm title
    		 ABT-414_ pediatric
    Arm description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to pediatric subjects. Temozolomide (TMZ) was only allowed for pediatric subjects if its use was in accordance with local clinical practice, and was not considered an investigational product for the study (unless this was a local requirement).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Depatuxizumab mafodotin
    Investigational medicinal product code
    Other name
    ABT-414
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous administration (1.0 mg/kg body weight for subjects who are 6 to 17 years old at the date of first depatuxizumab mafodotin dose, or 1.3 mg/kg for subjects who are 0 to 5 years old) over 30 to 40 minutes or as directed by the administration guidelines once every 2 weeks until one of the treatment withdrawal criteria was met, for a maximum of one year. If depatuxizumab mafodotin was used in combination with temozolomide (TMZ), depatuxizumab mafodotin was dosed on Day 1 and Day 15 of the TMZ cycle (assuming a standard regimen of 200 mg/m^2/day for 5 days of each 28-day cycle; for other TMZ schedules, timing of the depatuxizumab mafodotin dosing schedule were to be discussed with the medical monitor).

    Number of subjects in period 1 [1]
    		ABT-414/temozolomide ABT-414_adult Control_lomustine Control_ temozolomide ABT-414_ pediatric
    Started
    88
    86
    60
    26
    6
    Completed
    0
    0
    2
    0
    1
    Not completed
    88
    86
    58
    26
    5
         Other primary malignancy
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    15
    8
    6
    3
    -
         Death
    2
    1
    -
    -
    -
         Other, not specified
    8
    1
    1
    4
    -
         Start of a new anti-cancer treatment
    -
    1
    -
    1
    -
         Progressive disease
    56
    70
    43
    15
    5
         Withdrawal by subject
    7
    4
    8
    3
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Nine of the 275 enrolled adult subjects did not have a screen failure form reported and were not randomized. A total of 260 adult and 6 pediatric subjects were randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ABT-414/temozolomide
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult subjects

    Reporting group title
    ABT-414_adult
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult subjects

    Reporting group title
    Control_lomustine
    Reporting group description
    		 Adult subjects relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year.

    Reporting group title
    Control_ temozolomide
    Reporting group description
    		 Adult subjects relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met.

    Reporting group title
    ABT-414_ pediatric
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to pediatric subjects. Temozolomide (TMZ) was only allowed for pediatric subjects if its use was in accordance with local clinical practice, and was not considered an investigational product for the study (unless this was a local requirement).

    Reporting group values
    		 ABT-414/temozolomide ABT-414_adult Control_lomustine Control_ temozolomide ABT-414_ pediatric Total
    Number of subjects
    		 88 86 60 26 6 266
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ( 8.15 ) 58.1 ( 9.18 ) 57.8 ( 10.62 ) 55.9 ( 11.04 ) 10.5 ( 5.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 29 36 19 9 5 98
        Male
    		 59 50 41 17 1 168

    End points

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    End points reporting groups
    Reporting group title
    ABT-414/temozolomide
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult subjects

    Reporting group title
    ABT-414_adult
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult subjects

    Reporting group title
    Control_lomustine
    Reporting group description
    		 Adult subjects relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year.

    Reporting group title
    Control_ temozolomide
    Reporting group description
    		 Adult subjects relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met.

    Reporting group title
    ABT-414_ pediatric
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to pediatric subjects. Temozolomide (TMZ) was only allowed for pediatric subjects if its use was in accordance with local clinical practice, and was not considered an investigational product for the study (unless this was a local requirement).

    Subject analysis set title
    Control (Temozolomide/Lomustine)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Adult subjects relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle who received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year OR adult subjects relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle who received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met.

    Primary: Pediatric study: Maximum observed serum concentration (Cmax) of ABT-414

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    End point title
    		 Pediatric study: Maximum observed serum concentration (Cmax) of ABT-414 [1] [2]
    End point description
    Cmax is the peak concentration that a drug achieves in a specified compartment after the drug has been administrated and before administration of a second dose.
    End point type
    Primary
    End point timeframe
    Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose
    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: Statistical analysis was not applicable for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    5 [3]
    Units: µg/mL
        arithmetic mean (standard deviation)
    31.4 ( 15.0 )
    Notes
    [3] - Pediatric subjects with available data
    No statistical analyses for this end point

    Primary: Adult study: Progression-Free Survival (PFS)

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    End point title
    		 Adult study: Progression-Free Survival (PFS) [4]
    End point description
    Progression-free survival was assessed per response assessment in neuro-oncology criteria (RANO) criteria and assessed by an independent review committee and was defined as the length of time during and after the treatment of a disease, that the participant lived with the disease but did not get worse.
    End point type
    Primary
    End point timeframe
    Measured every 8 weeks from date of randomization until the date of first objective progression or subject's death, whichever occurred first, up to 2 years
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression-Free Survival was analyzed using the data sets reported in this end point.
    End point values
    		 ABT-414/temozolomide ABT-414_adult Control (Temozolomide/Lomustine)
    Number of subjects analysed
    88 [5]
    86 [6]
    86 [7]
    Units: months
    number (confidence interval 95%)
        25th quartile
    1.8 (1.7 to 2.0)
    1.5 (1.1 to 1.7)
    1.6 (1.3 to 1.7)
        50th quartile
    2.7 (2.0 to 3.8)
    1.9 (1.8 to 2.0)
    1.9 (1.9 to 2.2)
        75th quartile
    4.9 (3.9 to 9.3)
    3.5 (2.1 to 3.9)
    4.2 (3.4 to 5.8)
    Notes
    [5] - All randomized adult participants
    [6] - All randomized adult participants
    [7] - All randomized adult participants
    Statistical analysis title
    		 ABT-414/temozolomide vs Control (TMZ/Lomustine)
    Comparison groups
    ABT-414/temozolomide v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.123
    Method
    		 Log rank test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.07
    Statistical analysis title
    		 ABT-414_adult vs Control (TMZ/Lomustine)
    Comparison groups
    ABT-414_adult v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.117
    Method
    		 Log rank test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.84

    Primary: Pediatric study: Area Under the Concentration-time-curve (AUC) observed for unconjugated Cys-mcMMAF

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    End point title
    		 Pediatric study: Area Under the Concentration-time-curve (AUC) observed for unconjugated Cys-mcMMAF [8] [9]
    End point description
    AUC is a measure of how long and how much drug or drug metabolite is present in the body after dosing. The AUC of Cys-mcMMAF, a toxic metabolite of depatuxizumab mafodotin, in the pediatric population was measured following treatment to confirm that this was comparable to adults, and that the dosing levels are appropriate for a pediatric population.
    End point type
    Primary
    End point timeframe
    Samples collected Cycle 1 Days 1, 2, 3, 5, 8
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable for this endpoint.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    5 [10]
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    14.1 ( 6.22 )
    Notes
    [10] - Pediatric subjects with available data
    No statistical analyses for this end point

    Primary: Pediatric study: Maximum observed plasma concentration (Cmax) of Cys-mcMMAF

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    End point title
    		 Pediatric study: Maximum observed plasma concentration (Cmax) of Cys-mcMMAF [11] [12]
    End point description
    Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose. Cys-mcMMAF is a toxic metabolite of depatuxizumab mafodotin.
    End point type
    Primary
    End point timeframe
    Samples collected Cycle 1 Days 1, 2, 3, 5, 8
    Notes
    [11] - 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: Statistical analysis was not applicable for this endpoint.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    5 [13]
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.272 ( 0.0983 )
    Notes
    [13] - Pediatric subjects with available data
    No statistical analyses for this end point

    Primary: Pediatric study: Half-life (t1/2) observed for ABT-414

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    End point title
    		 Pediatric study: Half-life (t1/2) observed for ABT-414 [14] [15]
    End point description
    Half-life is the calculated time it takes for half of the drug to leave the body.
    End point type
    Primary
    End point timeframe
    Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose
    Notes
    [14] - 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: Statistical analysis was not applicable for this endpoint.
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    4 [16]
    Units: days
        arithmetic mean (standard deviation)
    9.0 ( 1.5 )
    Notes
    [16] - Pediatric subjects with available data
    No statistical analyses for this end point

    Primary: Pediatric study: Area Under the Concentration-time Curve (AUC) observed for ABT-414

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    End point title
    		 Pediatric study: Area Under the Concentration-time Curve (AUC) observed for ABT-414 [17] [18]
    End point description
    AUC is a measure of how long and how much drug is present in the body after dosing. The AUC of depatuxizumab mafodotin (ABT-414) in the pediatric population was measured following treatment to confirm that this was comparable to adults, and that the dosing levels are appropriate for a pediatric population.
    End point type
    Primary
    End point timeframe
    Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose
    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: Statistical analysis was not applicable for this endpoint.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    5 [19]
    Units: µg*h/mL
        arithmetic mean (standard deviation)
    3170 ( 1320 )
    Notes
    [19] - Pediatric subjects with available data
    No statistical analyses for this end point

    Primary: Pediatric study: Percentage of participants with adverse events from the first visit until 49 days after the last dose of study drug

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    End point title
    		 Pediatric study: Percentage of participants with adverse events from the first visit until 49 days after the last dose of study drug [20] [21]
    End point description
    The severity of each adverse event was rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0)
    End point type
    Primary
    End point timeframe
    From participant's first visit until 49 days after the participant's last dose of study drug
    Notes
    [20] - 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: Statistical analysis was not applicable for this endpoint.
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    6 [22]
    Units: Percentage of participants
        number (not applicable)
    100
    Notes
    [22] - Pediatric subjects (safety population)
    No statistical analyses for this end point

    Primary: Adult study: Overall Survival (OS)

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    End point title
    		 Adult study: Overall Survival (OS) [23]
    End point description
    Overall Survival (OS) was defined as time from randomization to death due to any cause, regardless of whether the event occurred on or off study drug (depatuxizumab mafodotin/temozolomide/lomustine).
    End point type
    Primary
    End point timeframe
    From the date of randomization up to the date of participant's death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Overall survival was analyzed using the data sets reported in this end point.
    End point values
    		 ABT-414/temozolomide ABT-414_adult Control (Temozolomide/Lomustine)
    Number of subjects analysed
    88 [24]
    86 [25]
    86 [26]
    Units: months
    number (confidence interval 95%)
        25th quartile
    5.7 (4.0 to 6.8)
    4.6 (3.5 to 5.5)
    4.9 (4.1 to 5.4)
        50th quartile
    9.6 (7.4 to 11.8)
    7.9 (6.1 to 8.7)
    8.2 (5.9 to 9.5)
        75th quartile
    16.9 (14.4 to 999)
    15.5 (10.2 to 19.0)
    12.6 (10.2 to 14.9)
    Notes
    [24] - All randomized adult participants; 999= not calculable
    [25] - All randomized adult participants
    [26] - All randomized adult participants
    Statistical analysis title
    		 ABT-414/temozolomide vs Control (TMZ/Lomustine)
    Statistical analysis description
    Stratified at randomization by regions of the world (North America, Europe and Australia, Asia/Other Regions), WHO performance status (0, > 0), timing of relapse (< 16 weeks, ≥ 16 weeks after first day of last TMZ cycle).
    Comparison groups
    ABT-414/temozolomide v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.062
    Method
    		 Log rank test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.02
    Statistical analysis title
    		 ABT-414_adult vs Control (TMZ/Lomustine)
    Statistical analysis description
    Stratified at randomization by regions of the world (North America, Europe and Australia, Asia/Other Regions), WHO performance status (0, > 0), timing of relapse (< 16 weeks, ≥ 16 weeks after first day of last TMZ cycle).
    Comparison groups
    ABT-414_adult v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.835
    Method
    		 Log rank test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.48

    Primary: Pediatric study: Half-life (t1/2) observed for Cys-mcMMAF

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    End point title
    		 Pediatric study: Half-life (t1/2) observed for Cys-mcMMAF [27] [28]
    End point description
    Half-life is the calculated time it takes for half of the drug or drug metabolite to leave the body. Cys-mcMMAF is a toxic metabolite of depatuxizumab mafodotin.
    End point type
    Primary
    End point timeframe
    Samples collected Cycle 1 Days 1, 2, 3, 5, 8
    Notes
    [27] - 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: Statistical analysis was not applicable for this endpoint.
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    2 [29]
    Units: days
        arithmetic mean (standard deviation)
    11.2 ( 22.9 )
    Notes
    [29] - Pediatric subjects with available data
    No statistical analyses for this end point

    Secondary: Adult study: Objective Response Rate (ORR)

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    End point title
    		 Adult study: Objective Response Rate (ORR) [30]
    End point description
    The objective response rate (ORR) included best overall responses – complete response (CR) and partial response (PR) – assessed by the independent review committee per response assessment in neuro-oncology criteria (RANO) criteria from the date of randomization until disease progression or death, whichever came first. All objective responses (CR and PR) must be have been confirmed by repeat MRI 4 weeks after the first time when CR or PR is identified. Any subject who did not meet CR or PR including those who did not have post-baseline radiological assessments was considered a nonresponder.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks at each assessment of disease, up to 28 months
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Objective Response Rate was analyzed using the data sets reported in this end point.
    End point values
    		 ABT-414/temozolomide ABT-414_adult Control (Temozolomide/Lomustine)
    Number of subjects analysed
    49 [31]
    39 [32]
    45 [33]
    Units: Percentage of participants
        number (confidence interval 95%)
    14.3 (5.9 to 27.2)
    7.7 (1.6 to 20.9)
    4.4 (0.5 to 15.1)
    Notes
    [31] - Subjects with measurable disease at baseline
    [32] - Subjects with measurable disease at baseline
    [33] - Subjects with measurable disease at baseline
    Statistical analysis title
    		 ABT-414/temozolomide vs Control (TMZ/Lomustine)
    Comparison groups
    ABT-414/temozolomide v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.06
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 16.16
    Notes
    [34] - Comparison is based on Cochran-Mantel-Haenszel method with stratification factors. Stratified at randomization by regions of the world (North America, Europe and Australia, Asia/Other Regions), WHO performance status (0, > 0), timing of relapse (< 16 weeks, ≥ 16 weeks after first day of last TMZ cycle).
    Statistical analysis title
    		 ABT-414_adult vs Control (TMZ/Lomustine)
    Comparison groups
    ABT-414_adult v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.767
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 12.49
    Notes
    [35] - Comparison is based on Cochran-Mantel-Haenszel method with stratification factors. Stratified at randomization by regions of the world (North America, Europe and Australia, Asia/Other Regions), WHO performance status (0, > 0), timing of relapse (< 16 weeks, ≥ 16 weeks after first day of last TMZ cycle).

    Secondary: Pediatric study: Objective Response Rate (ORR)

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    End point title
    		 Pediatric study: Objective Response Rate (ORR) [36]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [37]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    Notes
    [37] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Pediatric study: Overall Survival

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    End point title
    		 Pediatric study: Overall Survival [38]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy OS analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment to the date of death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months.
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [39]
    Units: months
        number (confidence interval 95%)
    ( to )
    Notes
    [39] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Pediatric study: Percentage of Participants With Changes in Neurological Status and Function

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    End point title
    		 Pediatric study: Percentage of Participants With Changes in Neurological Status and Function [40]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric neurological status and function data analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 and 15 of each cycle, every 6 months for 5 years thereafter, and then annually
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [41]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [41] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Adult study: Overall Survival in the Subgroup with Epidermal Growth Factor Receptor (EGFRvIII) Mutation

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    End point title
    		 Adult study: Overall Survival in the Subgroup with Epidermal Growth Factor Receptor (EGFRvIII) Mutation [42]
    End point description
    Overall Survival (OS) was defined as time from randomization to death due to any cause, regardless of whether the event occurred on or off study drug (depatuxizumab mafodotin/temozolomide/lomustine) for all randomized participants that had the Epidermal Growth Factor Receptor (EGFRvIII) mutation.
    End point type
    Secondary
    End point timeframe
    From the date of randomization up to the date of participant's death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months.
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Overall survival was analyzed using the data sets reported in this end point.
    End point values
    		 ABT-414/temozolomide ABT-414_adult Control (Temozolomide/Lomustine)
    Number of subjects analysed
    39 [43]
    36 [44]
    47 [45]
    Units: months
    number (confidence interval 95%)
        25th quartile
    6.3 (3.1 to 7.4)
    5.0 (3.1 to 5.9)
    4.7 (3.0 to 5.8)
        50th quartile
    9.4 (7.1 to 11.0)
    8.4 (5.5 to 9.0)
    7.5 (5.1 to 9.6)
        75th quartile
    14.4 (10.3 to 999)
    13.9 (8.7 to 999)
    12.4 (9.5 to 16.2)
    Notes
    [43] - Randomized subjects with EGFRvIII-mutated tumors; 999=not calculable
    [44] - Randomized subjects with EGFRvIII-mutated tumors; 999=not calculable
    [45] - EGFRvIII-mutated population: randomized subjects with EGFRvIII-mutated tumors
    Statistical analysis title
    		 ABT-414/temozolomide vs Control (TMZ/Lomustine)
    Comparison groups
    ABT-414/temozolomide v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.127
    Method
    		 Log rank test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.13
    Statistical analysis title
    		 ABT-414_adult vs Control (TMZ/Lomustine)
    Comparison groups
    ABT-414_adult v Control (Temozolomide/Lomustine)
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.64
    Method
    		 Log rank test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.49

    Secondary: Pediatric study: Best Tumor Response Rate

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    End point title
    		 Pediatric study: Best Tumor Response Rate [46]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric best tumor response rate data analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [47]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    Notes
    [47] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Pediatric study: Duration of Response

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    End point title
    		 Pediatric study: Duration of Response [48]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, pediatric duration of response data analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [49]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [49] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Pediatric study: Time to Progression

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    End point title
    		 Pediatric study: Time to Progression [50]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, pediatric time to progression data analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks (+/- 7 days) from the date of enrollment until the date of first objective progression or participant’s death, whichever occurs first, up to approximately 52 weeks
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [51]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [51] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Pediatric study: Progression-Free Survival (PFS)

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    End point title
    		 Pediatric study: Progression-Free Survival (PFS) [52]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, pediatric progression-free survival data analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks (+/- 7 days) from the date of enrollment until the date of first objective progression or participant’s death, whichever occurs first, up to approximately 52 weeks
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [53]
    Units: months
        number (confidence interval 95%)
    ( to )
    Notes
    [53] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Secondary: Pediatric study: Mean Change in Pediatric Quality of Life Inventory (PedsQL) Scores

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    End point title
    		 Pediatric study: Mean Change in Pediatric Quality of Life Inventory (PedsQL) Scores [54]
    End point description
    The pediatric data collection for this study was still ongoing when INTELLANCE-1 (EudraCT number 2015-001166-26; NCT02573324) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma multiforme patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric patients into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, mean change in pediatric quality of life inventory scores data analysis was not summarized due to the small number of pediatric subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 on treatment, and 6 months
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pediatric substudy-specific endpoint.
    End point values
    		 ABT-414_ pediatric
    Number of subjects analysed
    0 [55]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    Notes
    [55] - Pediatric data except safety were not summarized when INTELLANCE-1 deemed futile
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from the time of study drug administration until 35 days (adults) or 49 days (pediatric subjects) after the last dose of study drug, up to 125 weeks.
    Adverse event reporting additional description
    Serious and non-serious adverse events occurring after the subject signed the study-specific informed consent and prior to the initial dose of study drug were to be collected only if they were considered by the Investigator to be causally related to required study procedures.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    ABT-414/temozolomide
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult subjects

    Reporting group title
    ABT-414_adult
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult subjects

    Reporting group title
    Control_lomustine
    Reporting group description
    		 Adult subjects relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year.

    Reporting group title
    Control_ temozolomide
    Reporting group description
    		 Adult subjects relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met.

    Reporting group title
    ABT-414_ pediatric
    Reporting group description
    		 Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to pediatric subjects. Temozolomide (TMZ) was only allowed for pediatric subjects if its use was in accordance with local clinical practice, and was not considered an investigational product for the study (unless this was a local requirement).

    Serious adverse events
    		 ABT-414/temozolomide ABT-414_adult Control_lomustine Control_ temozolomide ABT-414_ pediatric
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 88 (44.32%)
    30 / 84 (35.71%)
    19 / 56 (33.93%)
    5 / 21 (23.81%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    80
    80
    52
    21
    5
         number of deaths resulting from adverse events
    12
    9
    3
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MALIGNANT NEOPLASM PROGRESSION
         subjects affected / exposed
    11 / 88 (12.50%)
    7 / 84 (8.33%)
    2 / 56 (3.57%)
    2 / 21 (9.52%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 7
    0 / 6
    0 / 2
    0 / 0
    0 / 1
    METASTASES TO PERITONEUM
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    NEOPLASM PROGRESSION
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    SUBGALEAL HAEMATOMA
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DISEASE PROGRESSION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    FATIGUE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    PYREXIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    HYPOXIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    PNEUMONITIS
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    PULMONARY EMBOLISM
         subjects affected / exposed
    3 / 88 (3.41%)
    0 / 84 (0.00%)
    2 / 56 (3.57%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    Psychiatric disorders
    COMPLETED SUICIDE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    BODY TEMPERATURE INCREASED
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    Injury, poisoning and procedural complications
    CLAVICLE FRACTURE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    FALL
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    HIP FRACTURE
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    APRAXIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    BRAIN OEDEMA
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    EPILEPSY
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERALISED TONIC-CLONIC SEIZURE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEMIPLEGIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    HYDROCEPHALUS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    MUSCLE SPASTICITY
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    NERVOUS SYSTEM DISORDER
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 84 (2.38%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROLOGICAL DECOMPENSATION
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 84 (3.57%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARTIAL SEIZURES
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 84 (2.38%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    9 / 88 (10.23%)
    3 / 84 (3.57%)
    4 / 56 (7.14%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 3
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STATUS EPILEPTICUS
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HYGROMA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    SYNCOPE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    Eye disorders
    CORNEAL EPITHELIAL MICROCYSTS
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 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
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    DIVERTICULAR PERFORATION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         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
    VOMITING
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC STEATOSIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    BACK PAIN
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    MUSCULAR WEAKNESS
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    DIVERTICULITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    MENINGITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         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
    PNEUMONIA
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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 TRACT INFECTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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 / 1
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    SEPSIS
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    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
    DECREASED APPETITE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         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
    DEHYDRATION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    0 / 6 (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
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (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
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ABT-414/temozolomide ABT-414_adult Control_lomustine Control_ temozolomide ABT-414_ pediatric
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    84 / 88 (95.45%)
    76 / 84 (90.48%)
    46 / 56 (82.14%)
    20 / 21 (95.24%)
    6 / 6 (100.00%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    9 / 88 (10.23%)
    6 / 84 (7.14%)
    4 / 56 (7.14%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences all number
    18
    9
    5
    1
    0
    HYPOTENSION
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 84 (3.57%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    0
    0
    1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    6 / 88 (6.82%)
    3 / 84 (3.57%)
    4 / 56 (7.14%)
    2 / 21 (9.52%)
    1 / 6 (16.67%)
         occurrences all number
    9
    4
    7
    2
    1
    FATIGUE
         subjects affected / exposed
    33 / 88 (37.50%)
    27 / 84 (32.14%)
    13 / 56 (23.21%)
    5 / 21 (23.81%)
    2 / 6 (33.33%)
         occurrences all number
    60
    39
    16
    6
    6
    GAIT DISTURBANCE
         subjects affected / exposed
    4 / 88 (4.55%)
    3 / 84 (3.57%)
    2 / 56 (3.57%)
    2 / 21 (9.52%)
    1 / 6 (16.67%)
         occurrences all number
    5
    5
    2
    2
    1
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    4 / 88 (4.55%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    4
    0
    1
    1
    1
    OEDEMA PERIPHERAL
         subjects affected / exposed
    7 / 88 (7.95%)
    2 / 84 (2.38%)
    4 / 56 (7.14%)
    4 / 21 (19.05%)
    0 / 6 (0.00%)
         occurrences all number
    9
    2
    5
    4
    0
    PYREXIA
         subjects affected / exposed
    5 / 88 (5.68%)
    4 / 84 (4.76%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    5
    4
    1
    1
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    5 / 88 (5.68%)
    2 / 84 (2.38%)
    3 / 56 (5.36%)
    3 / 21 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    7
    2
    3
    3
    2
    DYSPHONIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    1
    DYSPNOEA
         subjects affected / exposed
    8 / 88 (9.09%)
    1 / 84 (1.19%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences all number
    8
    1
    1
    1
    0
    EPISTAXIS
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    0
    0
    1
    NASAL CONGESTION
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    0
    0
    2
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    5 / 88 (5.68%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    6
    2
    1
    1
    1
    DEPRESSION
         subjects affected / exposed
    4 / 88 (4.55%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    0
    1
    1
    DISINHIBITION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    INSOMNIA
         subjects affected / exposed
    8 / 88 (9.09%)
    6 / 84 (7.14%)
    2 / 56 (3.57%)
    2 / 21 (9.52%)
    0 / 6 (0.00%)
         occurrences all number
    10
    7
    2
    2
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    11 / 88 (12.50%)
    12 / 84 (14.29%)
    3 / 56 (5.36%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    24
    17
    4
    1
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    9 / 88 (10.23%)
    13 / 84 (15.48%)
    2 / 56 (3.57%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    12
    15
    2
    0
    4
    BLOOD CULTURE POSITIVE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    4 / 88 (4.55%)
    8 / 84 (9.52%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    15
    0
    0
    0
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    7 / 88 (7.95%)
    4 / 84 (4.76%)
    6 / 56 (10.71%)
    2 / 21 (9.52%)
    0 / 6 (0.00%)
         occurrences all number
    11
    4
    13
    2
    0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    8 / 56 (14.29%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    11
    1
    10
    PLATELET COUNT DECREASED
         subjects affected / exposed
    21 / 88 (23.86%)
    9 / 84 (10.71%)
    15 / 56 (26.79%)
    2 / 21 (9.52%)
    1 / 6 (16.67%)
         occurrences all number
    46
    17
    31
    6
    29
    WEIGHT DECREASED
         subjects affected / exposed
    4 / 88 (4.55%)
    7 / 84 (8.33%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    4
    9
    4
    0
    8
    WEIGHT INCREASED
         subjects affected / exposed
    6 / 88 (6.82%)
    6 / 84 (7.14%)
    3 / 56 (5.36%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    8
    9
    3
    1
    1
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    3 / 88 (3.41%)
    2 / 84 (2.38%)
    5 / 56 (8.93%)
    1 / 21 (4.76%)
    2 / 6 (33.33%)
         occurrences all number
    7
    2
    15
    1
    8
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    4 / 88 (4.55%)
    4 / 84 (4.76%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    5
    5
    3
    0
    2
    Cardiac disorders
    BRADYCARDIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    SINUS BRADYCARDIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    2
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    9 / 88 (10.23%)
    9 / 84 (10.71%)
    3 / 56 (5.36%)
    3 / 21 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    10
    10
    3
    3
    0
    ATAXIA
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    2 / 56 (3.57%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    2
    0
    3
    BALANCE DISORDER
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 84 (1.19%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    3
    0
    0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    1
    DIZZINESS
         subjects affected / exposed
    7 / 88 (7.95%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    3 / 21 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    9
    2
    1
    3
    1
    DYSARTHRIA
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 84 (3.57%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    4
    0
    0
    ENCEPHALOPATHY
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    HEADACHE
         subjects affected / exposed
    21 / 88 (23.86%)
    20 / 84 (23.81%)
    8 / 56 (14.29%)
    2 / 21 (9.52%)
    2 / 6 (33.33%)
         occurrences all number
    31
    21
    8
    2
    3
    HEMIPARESIS
         subjects affected / exposed
    2 / 88 (2.27%)
    7 / 84 (8.33%)
    7 / 56 (12.50%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    7
    9
    0
    2
    HYDROCEPHALUS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    SEIZURE
         subjects affected / exposed
    6 / 88 (6.82%)
    7 / 84 (8.33%)
    5 / 56 (8.93%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    13
    11
    9
    1
    1
    SOMNOLENCE
         subjects affected / exposed
    3 / 88 (3.41%)
    3 / 84 (3.57%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    3
    6
    0
    1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    7 / 88 (7.95%)
    4 / 84 (4.76%)
    5 / 56 (8.93%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    13
    7
    0
    1
    LEUKOPENIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    5 / 56 (8.93%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    11
    4
    0
    LYMPHOPENIA
         subjects affected / exposed
    9 / 88 (10.23%)
    8 / 84 (9.52%)
    9 / 56 (16.07%)
    4 / 21 (19.05%)
    0 / 6 (0.00%)
         occurrences all number
    17
    16
    13
    8
    0
    NEUTROPENIA
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 84 (1.19%)
    10 / 56 (17.86%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    12
    0
    0
    THROMBOCYTOPENIA
         subjects affected / exposed
    19 / 88 (21.59%)
    7 / 84 (8.33%)
    19 / 56 (33.93%)
    8 / 21 (38.10%)
    0 / 6 (0.00%)
         occurrences all number
    55
    11
    34
    11
    0
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    0
    0
    2
    Eye disorders
    CATARACT
         subjects affected / exposed
    4 / 88 (4.55%)
    5 / 84 (5.95%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    0
    0
    CORNEAL EPITHELIAL MICROCYSTS
         subjects affected / exposed
    25 / 88 (28.41%)
    12 / 84 (14.29%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    64
    22
    0
    0
    1
    CORNEAL OPACITY
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    0
    0
    1
    DRY EYE
         subjects affected / exposed
    20 / 88 (22.73%)
    22 / 84 (26.19%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    36
    33
    1
    0
    2
    EYE IRRITATION
         subjects affected / exposed
    6 / 88 (6.82%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    8
    1
    0
    0
    2
    EYE PAIN
         subjects affected / exposed
    7 / 88 (7.95%)
    11 / 84 (13.10%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    10
    20
    0
    0
    2
    EYELID PTOSIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    KERATITIS
         subjects affected / exposed
    16 / 88 (18.18%)
    27 / 84 (32.14%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    24
    45
    0
    0
    1
    KERATOPATHY
         subjects affected / exposed
    15 / 88 (17.05%)
    7 / 84 (8.33%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    24
    8
    0
    0
    3
    LACRIMATION INCREASED
         subjects affected / exposed
    9 / 88 (10.23%)
    3 / 84 (3.57%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    10
    5
    0
    0
    1
    OCULAR DISCOMFORT
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    PHOTOPHOBIA
         subjects affected / exposed
    12 / 88 (13.64%)
    8 / 84 (9.52%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    14
    11
    0
    0
    4
    PUNCTATE KERATITIS
         subjects affected / exposed
    3 / 88 (3.41%)
    6 / 84 (7.14%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    6
    0
    0
    0
    PUPILLARY REFLEX IMPAIRED
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 84 (2.38%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    0
    0
    1
    VISION BLURRED
         subjects affected / exposed
    30 / 88 (34.09%)
    17 / 84 (20.24%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    52
    27
    1
    0
    5
    VISUAL IMPAIRMENT
         subjects affected / exposed
    3 / 88 (3.41%)
    5 / 84 (5.95%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    6
    0
    0
    1
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    0
    1
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 84 (2.38%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    0
    0
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    CONSTIPATION
         subjects affected / exposed
    23 / 88 (26.14%)
    8 / 84 (9.52%)
    2 / 56 (3.57%)
    6 / 21 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    28
    9
    2
    6
    0
    DIARRHOEA
         subjects affected / exposed
    8 / 88 (9.09%)
    6 / 84 (7.14%)
    3 / 56 (5.36%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    9
    6
    3
    1
    2
    NAUSEA
         subjects affected / exposed
    21 / 88 (23.86%)
    8 / 84 (9.52%)
    6 / 56 (10.71%)
    6 / 21 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    33
    8
    6
    7
    3
    PROCTALGIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    VOMITING
         subjects affected / exposed
    19 / 88 (21.59%)
    5 / 84 (5.95%)
    3 / 56 (5.36%)
    6 / 21 (28.57%)
    3 / 6 (50.00%)
         occurrences all number
    23
    5
    4
    6
    5
    Skin and subcutaneous tissue disorders
    DERMATITIS DIAPER
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    DRY SKIN
         subjects affected / exposed
    1 / 88 (1.14%)
    5 / 84 (5.95%)
    0 / 56 (0.00%)
    2 / 21 (9.52%)
    1 / 6 (16.67%)
         occurrences all number
    1
    5
    0
    2
    1
    ERYTHEMA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    HYPERKERATOSIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    PRURITUS
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 84 (1.19%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    0
    0
    1
    RASH
         subjects affected / exposed
    7 / 88 (7.95%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    2 / 21 (9.52%)
    0 / 6 (0.00%)
         occurrences all number
    7
    3
    1
    2
    0
    Renal and urinary disorders
    URINARY INCONTINENCE
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 84 (3.57%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    3
    3
    0
    2
    Endocrine disorders
    CUSHINGOID
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    6 / 88 (6.82%)
    3 / 84 (3.57%)
    3 / 56 (5.36%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences all number
    7
    3
    3
    1
    0
    BACK PAIN
         subjects affected / exposed
    7 / 88 (7.95%)
    7 / 84 (8.33%)
    4 / 56 (7.14%)
    2 / 21 (9.52%)
    1 / 6 (16.67%)
         occurrences all number
    8
    7
    4
    2
    1
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    0
    1
    MUSCULAR WEAKNESS
         subjects affected / exposed
    4 / 88 (4.55%)
    3 / 84 (3.57%)
    2 / 56 (3.57%)
    2 / 21 (9.52%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    2
    2
    0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    5 / 88 (5.68%)
    2 / 84 (2.38%)
    0 / 56 (0.00%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences all number
    6
    2
    0
    1
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    6 / 88 (6.82%)
    1 / 84 (1.19%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    7
    1
    1
    1
    2
    PAIN IN JAW
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Infections and infestations
    CONJUNCTIVITIS
         subjects affected / exposed
    7 / 88 (7.95%)
    6 / 84 (7.14%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    8
    6
    1
    0
    1
    EYE INFECTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    INFLUENZA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    NASOPHARYNGITIS
         subjects affected / exposed
    5 / 88 (5.68%)
    1 / 84 (1.19%)
    3 / 56 (5.36%)
    0 / 21 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    3
    0
    0
    ORAL CANDIDIASIS
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    0
    1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    1
    VAGINAL INFECTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    2
    VULVOVAGINAL CANDIDIASIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    10 / 88 (11.36%)
    5 / 84 (5.95%)
    2 / 56 (3.57%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    11
    7
    2
    0
    2
    HYPERGLYCAEMIA
         subjects affected / exposed
    5 / 88 (5.68%)
    3 / 84 (3.57%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    0 / 6 (0.00%)
         occurrences all number
    8
    3
    1
    1
    0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    6
    HYPERMAGNESAEMIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
    0 / 56 (0.00%)
    0 / 21 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    HYPOKALAEMIA
         subjects affected / exposed
    7 / 88 (7.95%)
    2 / 84 (2.38%)
    1 / 56 (1.79%)
    1 / 21 (4.76%)
    1 / 6 (16.67%)
         occurrences all number
    12
    2
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2015
    ● Updates to selection criteria to exclude subjects with coeliac diseases and wheat allergy, plus subjects with planned live vaccinations ● Requirement that national prescribing information should be followed for all concomitant medications
    13 Jul 2015
    ● Depatuxizumab mafodotin starting dose reduced from 1.25 mg/kg to 1.0 mg/kg ● Clarification of timings of electrocardiograms (ECGs) for subjects receiving depatuxizumab mafodotin and types of samples required for translational research
    25 Nov 2015
    ● Requirement for dose adjustment (depatuxizumab mafodotin, TMZ, lomustine) if ≥ 10% change in body weight, addition of depatuxizumab mafodotin 20 mg vial strength ● Clarification that subjects who discontinued lomustine treatment for non hematologic toxicity should not discontinue the entire study ● Requirement for reporting of clinically significant laboratory values outside the reference range as adverse events (AEs) ● Clarification that AEs deemed related to glioblastoma or the progression of glioblastoma will be considered expected for this study and not have expedited reporting
    01 Jul 2016
    ● Update to allow subjects with radiological pseudoprogression to resume study treatment ● Addition of ± 2-day dosing window for depatuxizumab mafodotin on Day 1 and Day 15 ● End of study definition updated to include 35 days after all subjects have completed treatment ● Addition of pediatric sub-study
    18 Jan 2017
    ● Updates to withdrawal criteria in the event that a subject withdraws consent from all further data collection ● Addition of process for optional collection of images of ocular AEs, window (± 7 days) for magnetic resonance imaging (MRI) scan after end of treatment, and clarifications to align with Statistical Analysis Plan version 1.0. ● Multiple updates to Appendix I (pediatric sub-study) including addition of background and introduction information; exclusion of subjects < 3 years of age until favorable results of a juvenile repeated mouse toxicity study are available; restriction of treatment duration to 12 months; addition of Quality of Life measurements, WHO performance evaluation replaced by Karnofsky/Lansky; updates to (serious) adverse event/progression/survival collection during long term follow-up; added language for data safety monitoring; and updates to the statistical analysis plan
    24 May 2018
    ● Addition of precautionary safety measures regarding hepatotoxicity including updates to safety information, guidelines for dose modifications due to hepatic laboratory abnormalities, and guidelines for management and evaluation of severe hepatic laboratory abnormalities ● Addition of eligibility criteria regarding liver function for pediatric sub-study
    04 Jan 2019
    ● Updated safety profile of depatuxizumab mafodotin (additional safety information; updated information on monitoring and management of intraocular pressure; addition of a follow up visit at 49 days after last treatment administration (End of Study) with extension of the safety monitoring period) ● In the pediatric sub-study, safety primary endpoint updated to include subjects with adverse events up until 49 days post last dose and requirement for a follow-up ophthalmology assessment at Day 49 day visit; addition of live attenuated vaccines prohibited during the study and for a period of 49 days after the end of depatuxizumab mafodotin administration; amended enrollment criteria for pediatric sub-study with regards to liver function; amended enrollment criteria for pediatric sub-study with regards to pregnancy and contraception language

    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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