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    Clinical Trial Results:
    A Phase I, Open-label, Parallel Group Study to Investigate Olaparib Safety and Tolerability, Efficacy and Pharmacokinetics in Paediatric Patients with Solid Tumours

    Summary
    EudraCT number
    		 2018-003355-38
    Trial protocol
    		 GB   DE   ES   DK   HU   IT   AT   PL  
    Global end of trial date
    04 Feb 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2025
    First version publication date
    20 Aug 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D0816C00025
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04236414
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002269-PIP01-17
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Feb 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Feb 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2025
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To describe the safety and tolerability of olaparib monotherapy and identify the recommended phase II dose (RP2D) of olaparib in the paediatric population.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with ICH/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jan 2020
    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
    Denmark: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    16
    EEA total number of subjects
    8
    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)
    3
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study had 2 phases: dose-finding and signal identification. Dose-finding included those with homologous recombination repair (HRR) deficiency per local test. Signal identification included those with deleterious/suspected HRR gene mutations or by central germline breast cancer susceptibility gene (BRCA) test and needed to receive the RP2D.

    Pre-assignment
    Screening details
    		 Dose-finding phase included 13 participants (Cohort A: 10 participants aged ≥12 to <18; Cohort B: 3 participants aged ≥3 to <12). Signal identification phase included 5 participants, 3 from the dose-finding phase (2 from Cohort A, 1 from Cohort B). 1 additional participant was not evaluable but was counted in the overall total.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cohort A (Dose Finding phase)
    Arm description
    		 Participants with HRR deficiency aged ≥12 to <18 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Up to 300 mg received as a single dose on Day 1, followed by initiation of twice daily continuous dosing from Day 2 onwards taken at the same time each day (morning and evening), approximately 12 hours apart.

    Arm title
    		 Cohort B (Dose-finding phase)
    Arm description
    		 Participants with HRR deficiency aged ≥3 to <12 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Up to 200 mg received as a single dose on Day 1, followed by initiation of twice daily continuous dosing from Day 2 onwards taken at the same time each day (morning and evening), approximately 12 hours apart.

    Arm title
    		 Signal identification phase
    Arm description
    		 Participants with a confirmed HRR gene mutation, including participants from the dose-finding phase, and needed to receive the RP2D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg (for participants aged 6-11) and 300 mg (for participants aged 12-17) received as a single dose on Day 1, followed by initiation of twice daily continuous dosing from Day 2 onwards taken at the same time each day (morning and evening), approximately 12 hours apart.

    Arm title
    		 Overall Total
    Arm description
    		 Participants in the dose-finding and signal identification phases, including any patients who entered the signal identification phase but were not evaluable for analysis (ie, did not have an HRR gene mutation confirmed via central testing)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Refer to dosage and administration details provided for Cohorts A, B, and Signal Identification Phase.

    Number of subjects in period 1
    		Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase Overall Total
    Started
    10
    3
    5
    16
    Completed
    0
    0
    0
    0
    Not completed
    10
    3
    5
    16
         Death [Incl pts who die in surv fwup]
    8
    -
    2
    8
         Consent withdrawn by subject
    -
    2
    2
    4
         Other
    2
    -
    1
    3
         Lost to follow-up
    -
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A (Dose Finding phase)
    Reporting group description
    		 Participants with HRR deficiency aged ≥12 to <18 years

    Reporting group title
    Cohort B (Dose-finding phase)
    Reporting group description
    		 Participants with HRR deficiency aged ≥3 to <12 years

    Reporting group title
    Signal identification phase
    Reporting group description
    		 Participants with a confirmed HRR gene mutation, including participants from the dose-finding phase, and needed to receive the RP2D

    Reporting group title
    Overall Total
    Reporting group description
    		 Participants in the dose-finding and signal identification phases, including any patients who entered the signal identification phase but were not evaluable for analysis (ie, did not have an HRR gene mutation confirmed via central testing)

    Reporting group values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase Overall Total Total
    Number of subjects
    		 10 3 5 16 34
    Age categorical
    The overall total number of participants was 16 instead of 18.
    Units: Subjects
        Participants aged ≥12 to <18 years
    		 10 0 4 13 27
        Participants aged ≥3 to <12 years
    		 0 3 1 3 7
    Age Continuous
    Age at Screening
    Units: Years
        arithmetic mean (standard deviation)
    		 15.1 ( 2.13 ) 8.3 ( 2.52 ) 13.0 ( 4.24 ) 14.0 ( 3.43 ) -
    Sex: Female, Male
    The overall total number of participants was 16 instead of 18. The 2 female participants from the signal identification arm were also in Cohort A.
    Units: Participants
        Female
    		 3 0 2 3 8
        Male
    		 7 3 3 13 26
    Race/Ethnicity, Customized
    The overall total number of participants was 16 instead of 18. The 2 "Other" participants from the signal identification arm were also in Cohort A.
    Units: Subjects
        Asian
    		 4 2 2 8 16
        White
    		 4 1 1 6 12
        Other
    		 2 0 2 2 6
    Race/Ethnicity, Customized
    The overall total number of participants was 16 instead of 18. The 2 participants from the signal identification arm were also in Cohort A and 1 participant was also in Cohort B.
    Units: Subjects
        Not Hispanic or Latino
    		 10 3 5 16 32

    End points

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    End points reporting groups
    Reporting group title
    Cohort A (Dose Finding phase)
    Reporting group description
    		 Participants with HRR deficiency aged ≥12 to <18 years

    Reporting group title
    Cohort B (Dose-finding phase)
    Reporting group description
    		 Participants with HRR deficiency aged ≥3 to <12 years

    Reporting group title
    Signal identification phase
    Reporting group description
    		 Participants with a confirmed HRR gene mutation, including participants from the dose-finding phase, and needed to receive the RP2D

    Reporting group title
    Overall Total
    Reporting group description
    		 Participants in the dose-finding and signal identification phases, including any patients who entered the signal identification phase but were not evaluable for analysis (ie, did not have an HRR gene mutation confirmed via central testing)

    Primary: Dose-limiting toxicity (DLT) events

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    End point title
    		 Dose-limiting toxicity (DLT) events [1] [2]
    End point description
    To describe the safety and tolerability of olaparib monotherapy. The number of participants who experienced DLTs are presented.
    End point type
    Primary
    End point timeframe
    1 cycle of 28 days of therapy
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    [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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase)
    Number of subjects analysed
    10
    3
    Units: Participants
        Number of evaluable participants
    6
    3
        Number of evaluable participants with a DLT
    1
    0
    No statistical analyses for this end point

    Primary: Discontinuation rate of olaparib treatment due to AEs throughout the study

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    End point title
    		 Discontinuation rate of olaparib treatment due to AEs throughout the study [3]
    End point description
    To describe the safety and tolerability of olaparib monotherapy. The number of participants who discontinued olaparib treatment due to AEs is presented.
    End point type
    Primary
    End point timeframe
    Time of signature of ICF throughout the treatment period and including the 30-day follow-up period.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase Overall Total
    Number of subjects analysed
    10
    3
    5
    16
    Units: Participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: Cmax

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    End point title
    		 Pharmacokinetic parameter: Cmax [4]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg twice daily (bd) tablet) dose based upon PK modelling. The median plasma concentration of olaparib on Day 1 is presented. No plasma samples were collected for participants in Cohort A on Day 1. Cmax = maximum concentration
    End point type
    Secondary
    End point timeframe
    Day 1
    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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    3
    5
    Units: ug/mL
        median (full range (min-max))
    8.989 (7.45 to 9.01)
    7.201 (0.825 to 9.01)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: Css,max

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    End point title
    		 Pharmacokinetic parameter: Css,max [5]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. Plasma steady state PK was achieved on Day 8, based on visual comparison of Day 1 and Day 8 trough concentrations. The median plasma concentration of olaparib on Day 8 is presented. Css,max = maximum plasma concentration at steady state
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: ug/mL
        median (full range (min-max))
    7.293 (2.47 to 19.6)
    10.42 (6.99 to 10.9)
    10.42 (0.680 to 13.5)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: CLss/F

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    End point title
    		 Pharmacokinetic parameter: CLss/F [6]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. Plasma steady state PK was achieved on Day 8, based on visual comparison of Day 1 and Day 8 trough concentrations. The median plasma concentration of olaparib on Day 8 is presented. CLss/F = apparent total clearance of the drug from plasma at steady state after oral administration
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [6] - 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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: L/h
        median (full range (min-max))
    6.866 (1.96 to 11.2)
    4.634 (4.34 to 5.78)
    5.784 (3.01 to 105)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: tmax

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    End point title
    		 Pharmacokinetic parameter: tmax [7]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. The median plasma concentration of olaparib on Day 1 is presented. No plasma samples were collected for participants in Cohort A on Day 1. tmax = time to maximum concentration
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [7] - 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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    3
    5
    Units: hours (h)
        median (full range (min-max))
    1.03 (1.00 to 1.95)
    1.95 (1.03 to 2.00)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: Css,min

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    End point title
    		 Pharmacokinetic parameter: Css,min [8]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. Plasma steady state PK was achieved on Day 8, based on visual comparison of Day 1 and Day 8 trough concentrations. The median plasma concentration of olaparib on Day 8 is presented. Css,min = minimum plasma concentration at steady state
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: ug/mL
        median (full range (min-max))
    1.810 (0.828 to 8.22)
    0.6177 (0.381 to 1.37)
    1.710 (0.0277 to 6.35)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: Css,max/D

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    End point title
    		 Pharmacokinetic parameter: Css,max/D [9]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. Plasma steady state PK was achieved on Day 8, based on visual comparison of Day 1 and Day 8 trough concentrations. The median plasma concentration of olaparib on Day 8 is presented. Css,max/D = dose normalised maximum plasma concentration at steady state
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: ug/mL/mg
        median (full range (min-max))
    0.02431 (0.00823 to 0.0654)
    0.05212 (0.0350 to 0.0545)
    0.03599 (0.00227 to 0.0521)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: tss,max

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    End point title
    		 Pharmacokinetic parameter: tss,max [10]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. Plasma steady state PK was achieved on Day 8, based on visual comparison of Day 1 and Day 8 trough concentrations. The median plasma concentration of olaparib on Day 8 is presented. tss,max = time to maximum plasma concentration at steady state
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [10] - 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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: hours (h)
        median (full range (min-max))
    1.52 (1.50 to 6.03)
    1.98 (1.93 to 2.00)
    1.93 (1.50 to 4.02)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: AUCss

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    End point title
    		 Pharmacokinetic parameter: AUCss [11]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. The median AUCss on Day 8 is presented. AUCss = area under the curve at steady state
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: h*ug/mL
        median (full range (min-max))
    45.71 (26.9 to 153)
    43.16 (34.6 to 46.1)
    36.11 (2.86 to 99.6)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: AUC (0-8)

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    End point title
    		 Pharmacokinetic parameter: AUC (0-8) [12]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. The median AUC (0-8) on Day 1 and Day 8 is presented. No plasma samples were collected for participants in Cohort A on Day 1. AUC (0-8) = area under the curve at 0-8 hours
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    Notes
    [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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: h*ug/mL
    median (full range (min-max))
        Day 1
    0 (0 to 0)
    27.61 (27.5 to 30.0)
    27.54 (2.00 to 42.6)
        Day 8
    37.17 (18.3 to 114)
    37.55 (32.1 to 42.6)
    32.08 (2.67 to 71.8)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: AUCss/D

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    End point title
    		 Pharmacokinetic parameter: AUCss/D [13]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. The median AUCss/D on Day 8 is presented. AUCss/D = dose normalised area under the curve at steady state
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [13] - 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: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: h*ug/mL/mg
        median (full range (min-max))
    0.1524 (0.0897 to 0.511)
    0.2158 (0.173 to 0.230)
    0.1729 (0.00954 to 0.332)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter: AUC (0-t)

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    End point title
    		 Pharmacokinetic parameter: AUC (0-t) [14]
    End point description
    To describe the paediatric PK profile and to identify the adult equivalent (300 mg bd tablet) dose based upon PK modelling. The median AUC (0-t) on Day 1 and Day 8 is presented. No plasma samples were collected for participants in Cohort A on Day 1. AUC (0-t) = area under the curve from zero up to time t
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no formal statistical analysis of safety and tolerability data or efficacy data in this study. Demographic and other baseline disease characteristics, concomitant medication, dosing, exposure, safety, tolerability, dose limiting toxicities, efficacy data, and protocol deviations were listed and summarised by cohort and overall in the dose-finding phase, overall in the signal identification phase and in the total study, as appropriate.
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase
    Number of subjects analysed
    8
    3
    5
    Units: h*ug/mL
    median (full range (min-max))
        Day 1
    0 (0 to 0)
    29.53 (28.9 to 32.5)
    29.53 (2.40 to 73.7)
        Day 8
    45.71 (26.9 to 153)
    43.16 (34.6 to 46.1)
    36.11 (2.86 to 99.6)
    No statistical analyses for this end point

    Secondary: DCR as defined by Investigator-assessed RECIST v.1.1, INRC, or RANO

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    End point title
    		 DCR as defined by Investigator-assessed RECIST v.1.1, INRC, or RANO
    End point description
    Disease control rate (DCR) was defined as the percentage of participants who have a best objective response (BOR) of CR, PR, minor response (MR) (if applicable) or who have stable disease (without subsequent cancer therapy) for at least 7 weeks after start of treatment (to allow for an early assessment within the assessment window) in participants with measurable disease.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (±1 week) relative to the date of treatment initiation until week 24, and every 12 weeks (±1 week) thereafter until objective disease progression or withdrawal
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase Overall Total
    Number of subjects analysed
    7
    3
    3
    12
    Units: Percentage
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: ORR as defined by Investigator-assessed RECIST v.1.1, INRC, or RANO

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    End point title
    		 ORR as defined by Investigator-assessed RECIST v.1.1, INRC, or RANO
    End point description
    Objective response rate (ORR) was defined as the percentage of patients with an investigator-assessed response of complete response (CR) or partial response (PR) as per RECIST v1.1, INRC or RANO and was based on a subset of all treated patients with measurable disease at baseline per the site investigator. INRC = International Neuroblastoma Response Criteria RECIST = Response Evaluation Criteria in Solid tumours RANO = Response Assessment in Neuro-oncology
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (±1 week) relative to the date of treatment initiation until week 24, and every 12 weeks (±1 week) thereafter until objective disease progression or withdrawal
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase Overall Total
    Number of subjects analysed
    7
    3
    5
    12
    Units: Percentage
        number (confidence interval 95%)
    0 (0 to 40.96)
    0 (0 to 70.76)
    0 (0 to 70.76)
    0 (0 to 26.46)
    No statistical analyses for this end point

    Secondary: DoR as defined by Investigator-assessed RECIST v.1.1, INRC, or RANO

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    End point title
    		 DoR as defined by Investigator-assessed RECIST v.1.1, INRC, or RANO
    End point description
    Duration of response (DoR) was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. The time of the initial response will be defined as the date of the first visit response that was CR or PR. No participants had an objective response (BOR of CR or PR) and hence the DoR could not be summarised.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (±1 week) relative to the date of treatment initiation until week 24, and every 12 weeks (±1 week) thereafter until objective disease progression or withdrawal
    End point values
    		 Cohort A (Dose Finding phase) Cohort B (Dose-finding phase) Signal identification phase Overall Total
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: weeks
    Notes
    [15] - No participants had a BOR of CR or PR and hence the DoR could not be summarised.
    [16] - No participants had a BOR of CR or PR and hence the DoR could not be summarised.
    [17] - No participants had a BOR of CR or PR and hence the DoR could not be summarised.
    [18] - No participants had a BOR of CR or PR and hence the DoR could not be summarised.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs will be collected from time of signature of ICF throughout the treatment period and including the 30-day follow-up period.
    Adverse event reporting additional description
    Includes AEs with an onset date or that worsen on or after the first dose of study treatment up to (and including) 30 days after the last dose date or until the initiation of the first subsequent anti-cancer therapy, whichever occurs first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Cohort A (Dose-finding phase)
    Reporting group description
    		 Participants with HRR deficiency aged ≥12 years to <18 years

    Reporting group title
    Overall Total
    Reporting group description
    		 Patients in the dose-finding and signal identification phases, including any participant who entered the signal identification phase but was not evaluable for analysis (ie, did not have a confirmed HRR gene mutation)

    Reporting group title
    Signal identification phase
    Reporting group description
    		 Participants with a confirmed HRR gene mutation, including participants from the dose-finding phase

    Reporting group title
    Cohort B (Dose-finding phase)
    Reporting group description
    		 Participants with HRR deficiency aged ≥3 years to <12 years

    Serious adverse events
    		 Cohort A (Dose-finding phase) Overall Total Signal identification phase Cohort B (Dose-finding phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 16 (25.00%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    9
    9
    2
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort A (Dose-finding phase) Overall Total Signal identification phase Cohort B (Dose-finding phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    15 / 16 (93.75%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    1
    Hot flush
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 16 (25.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    5
    2
    0
    Chest discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    4
    0
    0
    Tri-iodothyronine free decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 16 (12.50%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 16 (12.50%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    0
    1
    Injury, poisoning and procedural complications
    Back injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Neuralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 16 (18.75%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Neutropenia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 16 (18.75%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    5
    4
    0
    Anaemia
         subjects affected / exposed
    6 / 10 (60.00%)
    9 / 16 (56.25%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
         occurrences all number
    8
    12
    2
    3
    Lymphopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 16 (18.75%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Eye disorders
    Optic neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 16 (18.75%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    4
    3
    0
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    1
    Ascites
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Vomiting
         subjects affected / exposed
    6 / 10 (60.00%)
    7 / 16 (43.75%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
         occurrences all number
    8
    9
    2
    1
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Nausea
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 16 (31.25%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    6
    2
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Haematuria
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Endocrine disorders
    Central hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Infections and infestations
    Covid-19
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Hypophagia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 16 (25.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    4
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 10 (30.00%)
    5 / 16 (31.25%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
         occurrences all number
    3
    5
    2
    2
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 16 (18.75%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    3
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2019
    Febrile neutropenia of CTCAE ≥3 is considered a standard definition for a DLT in Phase I dose-finding studies where defining safety and tolerability is a primary objective.
    18 May 2020
    The primary reason for this protocol amendment was to permit patients with primary CNS tumours entry into the study. In addition, revisions were made in response to questions from the Health Authorities, to align with current practice and to clarify procedures.
    30 Sep 2021
    The primary reasons for this protocol amendment were to include details for the AAF and to include saliva sampling for PK analysis. In addition, revisions were made to clarify procedures based on Health Authority feedback. Furthermore, additional study mitigation language was added to provide sites with measures that could be implemented during the COVID-19 pandemic.
    21 May 2024
    The primary reasons for this protocol amendment were to prepare for the transition to European Union Clinical Trial Regulation.

    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.
    Study was terminated on 29 January 2025 due to operational futility per CSP criteria (<5 participants/year with HRR mutations). Last patient last visit (LPLV) occurred on 04 February 2025; all data were analyzed using a DCO date of 28 February 2025.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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