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    Clinical Trial Results:
    A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation

    Summary
    EudraCT number
    		 2019-002549-39
    Trial protocol
    		 GB   FR   CZ   NL   IT   PL   PT   ES  
    Global end of trial date
    19 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2025
    First version publication date
    04 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Ponatinib-1501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04501614
    WHO universal trial number (UTN)
    		 U1111-1225-0394
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, Massachusetts, United States, 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001186-PIP01-11
    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
    19 Jul 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to determine the recommended phase 2 dose (RP2D) and rate of complete remission (CR) at the end of the reinduction block of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy.
    Protection of trial subjects
    Each participant or their guardians were required to sign an informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2021
    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
    China: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Brazil: 1
    Worldwide total number of subjects
    11
    EEA total number of subjects
    3
    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)
    6
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with a diagnosis of Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) took part in the study at various investigative sites globally from 24 February 2021 to 19 July 2024.

    Pre-assignment
    Screening details
    		 Participants were enrolled in Phase 1 & received ponatinib per protocol. Due to multiple dose-limiting toxicities(DLTs) in Phase 1,enrollment was terminated & no recommended phase 2 dose(RP2D) was determined. Sponsor terminated study after 6-month follow-up & no participants were enrolled in Phase 2 of study. Thus, no Phase 2 results are presented.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ponatinib 30 mg Adult Equivalent
    Arm description
    		 Participants received weight-based dose of ponatinib tablets 30 milligrams (mg) adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ponatinib
    Investigational medicinal product code
    Other name
    Ponatinib AAF, Chemotherapy Agents
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received weight-based doses of ponatinib tablets equivalent to 30 mg in adults, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment followed by rest period from chemotherapy for a minimum of 6 days consisting of daily ponatinib only) up to Week 8 in Phase 1.

    Arm title
    		 Ponatinib 15 mg Adult Equivalent
    Arm description
    		 Participants received weight-based dose of ponatinib tablets 15 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ponatinib
    Investigational medicinal product code
    Other name
    Ponatinib AAF, Chemotherapy agents
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received weight-based doses of ponatinib tablets equivalent to 15 mg in adults, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment followed by rest period from chemotherapy for a minimum of 6 days consisting of daily ponatinib only) up to Week 8 in Phase 1.

    Number of subjects in period 1
    		Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Started
    7
    4
    Completed
    0
    0
    Not completed
    7
    4
         Withdrawal by Participant (Parent/Legal Guardian)
    1
    1
         Study Terminated by Sponsor
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ponatinib 30 mg Adult Equivalent
    Reporting group description
    		 Participants received weight-based dose of ponatinib tablets 30 milligrams (mg) adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.

    Reporting group title
    Ponatinib 15 mg Adult Equivalent
    Reporting group description
    		 Participants received weight-based dose of ponatinib tablets 15 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.

    Reporting group values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent Total
    Number of subjects
    		 7 4
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.1 ( 2.41 ) 13.5 ( 3.70 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 2 6
        Male
    		 3 2 5
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 4 2 6
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 3 2 5
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 6 3 9
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Ponatinib 30 mg Adult Equivalent
    Reporting group description
    		 Participants received weight-based dose of ponatinib tablets 30 milligrams (mg) adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.

    Reporting group title
    Ponatinib 15 mg Adult Equivalent
    Reporting group description
    		 Participants received weight-based dose of ponatinib tablets 15 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.

    Subject analysis set title
    Ponatinib RP2D
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants were planned to receive weight-based dose of ponatinib tablets at the RP2D adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) followed by optional ponatinib continuation with or without chemotherapy in Phase 2.

    Primary: Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy

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    End point title
    		 Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy [1]
    End point description
    The RP2D is the maximum tolerated dose (MTD) or less. '99999' indicates that due to DLTs observed in both dose cohorts, study enrollment was terminated per protocol and participants were discontinued from study treatment per independent data monitoring committee (IDMC) advice followed by study termination by Sponsor. Thus, the RP2D could not be determined. The Safety Population included all participants who received at least 1 dose of ponatinib.
    End point type
    Primary
    End point timeframe
    Up to Day 35 in Phase 1
    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: Due to DLTs observed in both dose cohorts, study enrollment was terminated per protocol and participants were discontinued from study treatment per independent data monitoring committee (IDMC) advice followed by study termination by Sponsor. Thus, the RP2D could not be determined.
    End point values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Number of subjects analysed
    7
    4
    Units: milligrams per square meter (mg/m^2)
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Primary: Phase 2: Percentage of Participants with Complete Remission (CR) at the End of the Reinduction Block

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    End point title
    		 Phase 2: Percentage of Participants with Complete Remission (CR) at the End of the Reinduction Block [2]
    End point description
    CR was defined as no circulating blasts and less than (<)5 percent (%) blasts in the bone marrow (BM); normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) greater than (>)1000 cells/microliter (μL) (or >1.0 × 10^9 cells/liter [L]); Platelets >100,000/μL (or >100 × 10^9 platelets/L). The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Primary
    End point timeframe
    Up to Day 35 in Phase 2
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No data was collected as no participants were enrolled in Phase 2.
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [3]
    Units: percentage of participants
        number (not applicable)
    Notes
    [3] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 1: Number of Participants with CR at the end of Reinduction Block

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    End point title
    		 Phase 1: Number of Participants with CR at the end of Reinduction Block
    End point description
    CR was defined as no circulating blasts and <5% blasts in the BM; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μL (or >1.0 × 10^9 cells/L); Platelets >100,000/μL (or >100 × 10^9 platelets/L). The Safety Population included all participants who received at least 1 dose of ponatinib. Overall number of participants analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Day 35 in Phase 1
    End point values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Number of subjects analysed
    6
    3
    Units: participants
    1
    2
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Ph+ ALL Participants who Achieved CR at the End of Consolidation Block

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    End point title
    		 Phase 2: Percentage of Ph+ ALL Participants who Achieved CR at the End of Consolidation Block
    End point description
    CR was defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μL (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μL (or >100 × 10^9 platelets/L). The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Day 70 in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [4]
    Units: percentage of participants
        number (not applicable)
    Notes
    [4] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Ph+ ALL Participants with Negative Minimal Residual Disease (MRD) Among Those who Achieved CR

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    End point title
    		 Phase 2: Percentage of Ph+ ALL Participants with Negative Minimal Residual Disease (MRD) Among Those who Achieved CR
    End point description
    MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate at <0.01% threshold. The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to Day 70 (end of consolidation block) in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [5]
    Units: participants
    Notes
    [5] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation

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    End point title
    		 Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation
    End point description
    The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 3 years of follow-up in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [6]
    Units: participants
    Notes
    [6] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Event-free Survival (EFS)

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    End point title
    		 Phase 2: Event-free Survival (EFS)
    End point description
    EFS was defined as time from date of enrollment until death due to any cause; refractory to treatment (defined as failure to achieve CR by end of the consolidation block) or relapse from CR. CR was defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μL (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μL (or >100 × 10^9 platelets/L). The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 3 years of follow-up in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [7]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [7] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-free Survival (PFS)

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    End point title
    		 Phase 2: Progression-free Survival (PFS)
    End point description
    PFS was defined as time from date of enrolment until death related to disease under study; disease progression (clinical deterioration associated with disease process, including evidence of increasing blasts in the bone marrow from baseline and/or evidence of new organ involvement) or relapse from CR. CR was defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μL (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μL (or >100 × 10^9 platelets/L). The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 3 years of follow-up in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [8]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [8] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplantation (HSCT)

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    End point title
    		 Phase 2: Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplantation (HSCT)
    End point description
    The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 3 years of follow-up in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [9]
    Units: participants
    Notes
    [9] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

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    End point title
    		 Phase 2: Duration of Response (DOR)
    End point description
    DOR was defined as the interval between the first assessment at which the criteria for CR are met until the time at which relapse from CR occurs. CR was defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μL (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μL (or >100 × 10^9 platelets /L). The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 3 years of follow-up in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [10]
    Units: participants
    Notes
    [10] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS)
    End point description
    OS was defined as time from first dose of ponatinib until death due to any cause. The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 3 years of follow-up in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [11]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [11] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Secondary: Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib

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    End point title
    		 Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib
    End point description
    '99999' indicates geometric coefficient of variation (CV) was not estimable for a single participant. The Pharmacokinetic (PK) Analysis Population included all participants in the Phase 1 portion of the study who had sufficient ponatinib dosing data and concentration-time data to permit the calculation of ponatinib PK parameters. Number analyzed is the number of participants with data available for analysis for the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
    End point values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Number of subjects analysed
    7
    4
    Units: nanograms/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1
    65.8 ( 29.5 )
    24.9 ( 71.1 )
        Day 22
    183 ( 99999 )
    47.7 ( 92.8 )
    No statistical analyses for this end point

    Secondary: Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib

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    End point title
    		 Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib
    End point description
    '99999' indicates geometric CV was not estimable for a single participant. The PK Analysis Population included all participants in the Phase 1 portion of the study who had sufficient ponatinib dosing data and concentration-time data to permit the calculation of ponatinib PK parameters. Number analyzed is the number of participants with data available for analysis for the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
    End point values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Number of subjects analysed
    7
    4
    Units: h*ng/ml
    geometric mean (geometric coefficient of variation)
        Day 1
    883 ( 22.8 )
    264 ( 62.1 )
        Day 22
    2800 ( 99999 )
    815 ( 83.2 )
    No statistical analyses for this end point

    Secondary: Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib

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    End point title
    		 Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib
    End point description
    '99999' indicates full range was not estimable for a single participant. The PK Analysis Population included all participants in the Phase 1 portion of the study who had sufficient ponatinib dosing data and concentration-time data to permit the calculation of ponatinib PK parameters. Number analyzed is the number of participants with data available for analysis for the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
    End point values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Number of subjects analysed
    7
    4
    Units: hours
    median (full range (min-max))
        Day 1
    6.00 (2.0 to 7.5)
    3.99 (3.8 to 4.1)
        Day 22
    4.08 (-99999 to 99999)
    3.92 (2.0 to 5.8)
    No statistical analyses for this end point

    Secondary: Phase 1: Number of Participants with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs)

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    End point title
    		 Phase 1: Number of Participants with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs)
    End point description
    AE: any untoward medical occurrence in clinical study participant,temporally associated with use of study intervention,whether/not occurrence was considered related to study intervention including any unfavorable & unintended sign (eg,clinically significant abnormal laboratory finding),symptom/disease.TEAE: any AE that occurs after administration of first dose of any study drug & through 30 days after last dose of any study drug.Serious TEAE:AE that at any dose resulted in death,was life-threatening,required inpatient hospitalisation/prolongation of existing hospitalisation,resulted in persistent/significant incapacity,was congenital anomaly/birth defect,was medically important event. AESI: Protocol-defined AEs resulting in compromise of organ function/other significant consequences. VTEs were identified as AESIs for ponatinib & included arterial, VTEs that meet criteria for serious TEAEs. The Safety Population included all participants who received at least 1 dose of ponatinib.
    End point type
    Secondary
    End point timeframe
    Up to 34.8 months in Phase 1
    End point values
    		 Ponatinib 30 mg Adult Equivalent Ponatinib 15 mg Adult Equivalent
    Number of subjects analysed
    7
    4
    Units: participants
        TEAEs
    7
    4
        Serious TEAEs
    5
    2
        VTEs
    0
    0
        AESIs
    0
    0
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Participants With TEAEs, Serious TEAEs, VTEs, and AESIs

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    End point title
    		 Phase 2: Number of Participants With TEAEs, Serious TEAEs, VTEs, and AESIs
    End point description
    AE:untoward medical occurrence in study participant,temporally associated with use of intervention,whether/not occurrence was considered related to intervention including any unfavorable&unintended sign(eg,clinically significant abnormal laboratory finding),symptom/disease.TEAE:AE that occurs after administration of first dose of any study drug & through 30 days after last dose of any study drug.Serious TEAE:AE that at any dose resulted in death,was life-threatening,required inpatient hospitalisation/prolongation of existing hospitalisation,resulted in persistent/significant incapacity,was congenital anomaly/birth defect,was medically important event.AESI:Protocol-defined AEs resulting in compromise of organ function/other significant consequences.VTEs were identified as AESIs for ponatinib & included arterial,VTEs that meet criteria for serious TEAEs.Study enrollment was terminated per protocol due to DLTs in Phase 1. No data was collected as no participants were enrolled in Phase 2.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after last dose of ponatinib in Phase 2
    End point values
    		 Ponatinib RP2D
    Number of subjects analysed
    0 [12]
    Units: participants
    Notes
    [12] - No data was collected as no participants were enrolled in Phase 2 due to study termination.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 34.8 months in Phase 1
    Adverse event reporting additional description
    The Safety Population included all participants who received at least 1 dose of ponatinib. The study was terminated following the Sponsor's decision attributed to DLTs observed in Phase 1. Hence, no participants were enrolled in Phase 2 of the study and no data for the same could be presented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Ponatinib 15 mg Adult Equivalent
    Reporting group description
    		 Participants received weight-based dose of ponatinib tablets 15 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.

    Reporting group title
    Ponatinib 30 mg Adult Equivalent
    Reporting group description
    		 Participants received weight-based dose of ponatinib tablets 30 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator’s discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1.

    Serious adverse events
    		 Ponatinib 15 mg Adult Equivalent Ponatinib 30 mg Adult Equivalent
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    5 / 7 (71.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ventricle dilatation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Disseminated mucormycosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ponatinib 15 mg Adult Equivalent Ponatinib 30 mg Adult Equivalent
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    5
    Deep vein thrombosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Facial pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    3
    Malaise
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    4
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    7
    Swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Anxiety
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 7 (57.14%)
         occurrences all number
    5
    15
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    4
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 4 (100.00%)
    7 / 7 (100.00%)
         occurrences all number
    20
    56
    Amylase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Antithrombin III decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 4 (75.00%)
    7 / 7 (100.00%)
         occurrences all number
    16
    33
    Bilirubin conjugated increased
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 7 (14.29%)
         occurrences all number
    10
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    6
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    7
    Blood calcium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 7 (57.14%)
         occurrences all number
    2
    12
    Blood glucose increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    6
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    4
    Blood magnesium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    Blood triglycerides increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    6
    C-reactive protein increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Eosinophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 4 (75.00%)
    6 / 7 (85.71%)
         occurrences all number
    14
    20
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 7 (57.14%)
         occurrences all number
    8
    62
    Monocyte count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    3 / 4 (75.00%)
    5 / 7 (71.43%)
         occurrences all number
    11
    40
    Neutrophil count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Platelet count decreased
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 7 (57.14%)
         occurrences all number
    10
    38
    Platelet count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Protein total decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Protein urine present
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 7 (57.14%)
         occurrences all number
    23
    48
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    5
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Lip injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Mouth injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Vascular injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial thrombosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Ventricular hypertrophy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Mental impairment
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hemiplegia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hemiparesis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 7 (71.43%)
         occurrences all number
    1
    8
    Neuropathy peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 4 (100.00%)
    7 / 7 (100.00%)
         occurrences all number
    30
    51
    Coagulopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Leukopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    6
    13
    Hypofibrinogenaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    8
    0
    Hypercoagulation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Lymphopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    14
    Thrombocytopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 7 (42.86%)
         occurrences all number
    23
    16
    Neutropenia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    17
    Gastrointestinal disorders
    Mouth ulceration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 7 (28.57%)
         occurrences all number
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Anal erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Anal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Anal ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 7 (57.14%)
         occurrences all number
    2
    4
    Faeces hard
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Flatulence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gingival erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Glossitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    5
    Pancreatitis acute
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Stomatitis
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 7 (42.86%)
         occurrences all number
    2
    3
    Tongue ulceration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 7 (57.14%)
         occurrences all number
    1
    10
    Oral disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Gallbladder oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Papule
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Pain of skin
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Eczema asteatotic
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Dermatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Rash erythematous
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Skin toxicity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    Skin exfoliation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Rash papular
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Rash macular
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    2
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    5
    Muscle spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    3
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Bacteraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Disseminated mucormycosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Myringitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Oral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Parotitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Pneumonia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    2
    8
    Respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    5
    Hyperlipidaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Hypermagnesaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    3
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 4 (100.00%)
    2 / 7 (28.57%)
         occurrences all number
    9
    6
    Hyperuricaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    7
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 7 (57.14%)
         occurrences all number
    12
    8
    Hypocalcaemia
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 7 (42.86%)
         occurrences all number
    7
    9
    Hypochloraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Hypokalaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 7 (42.86%)
         occurrences all number
    5
    5
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 7 (28.57%)
         occurrences all number
    7
    6
    Hypophosphataemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2020
    The following changes were made as per Amendment 1: 1. Updated the timing of EFS, PFS, and OS assessments, and end of treatment 1 (EOT1). 2. Removed peripheral blood samples for MRD. 3. Updated the exclusion criterion for current systemic use of any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 3A4 (CYP3A). 4. Updated procedures for recording and reporting adverse events and serious adverse events. 5. Added definition of relapse from CR.
    23 Feb 2021
    The following changes were made as per Amendment 2: 1. Removed a dose of asparaginase therapy given in combination with ponatinib. 2. Updated the projected duration of study. 3. Updated the number of study sites and countries. 4. Updated inclusion/exclusion criteria.
    23 May 2023
    The following changes were made as per Amendment 3: 1. Modified inclusion and exclusion criteria. 2. Defined the second cohort (cohort 2) of the phase 1 portion of the study. 3. Revised the disease assessment at end of reinduction and consolidation blocks. 4. Modified the medical management of elevated alanine aminotransferase. 5. Changed a secondary objective to an exploratory objective. 6. Corrected the schedule of events (SOEs) on which days the study treatment was administered. 7. Updated the definition of progression-free survival event for death.
    02 Nov 2023
    The following changes were made as per Amendment 4: 1. Modified Phase 1 cohort 2 to enroll a single cohort for determination of RP2D rather than 2 weight groups with separate evaluations. 2. Modified the definition of related adverse events for DLT. 3. Modified dose modifications for ponatinib with the occurrence of lipase elevations and pancreatitis. 4. Modified the criteria for beginning a consolidation block or optional continuation therapy. 5. Updated the number of participants in Phase 1 portion of the study. 6. Updated the minimum percentage and number of days of ponatinib dosing required for a participant to be evaluable for DLTs.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jul 2024
    The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated.
    -

    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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    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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