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    Clinical Trial Results:
    A TACL Phase 1/2 Study of PO Ixazomib in Combination with Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

    Summary
    EudraCT number
    		 2019-001947-28
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    03 Dec 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Jun 2024
    First version publication date
    03 Dec 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    T2017-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03817320
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, MA, United States, 60015
    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-001410-PIP02-17
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), define and describe toxicities, characterize the pharmacokinetics, and determine the efficacy of orally (PO) administered ixazomib in conjunction with block 1 re-induction chemotherapy in children with relapsed/refractory acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LLy).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    2
    Children (2-11 years)
    11
    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 took part in the study at investigative sites in the United States from 12 February 2019 to 03 December 2023.

    Pre-assignment
    Screening details
    		 Participants with childhood relapsed/refractory acute lymphoblastic leukemia & lymphoblastic lymphoma were enrolled to receive ixazomib 1.6 mg/m^2/day or 2 mg/m^2/day in Phase 1 & those who received 2 mg/m^2/day(RP2D) in Phase 1 continued to Phase 2 to receive ixazomib 2 mg/m^2/day along with the newly enrolled participants in Phase 2 of the study.

    Period 1
    Period 1 title
    Phase 1
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Ixazomib 1.6 mg/m^2
    Arm description
    		 Ixazomib at dose level 1, 1.6 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.05 milligrams per kilograms per day (mg/kg/day), for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    MLN9708
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib capsules.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Oncovin, VCR, LCR
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine IV push

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Adriamycin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin solution for infusion.

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Oncaspar, Pegaspargase, Polyethylene Glycol Conjugated L-asparaginase-H
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    PEG-asparaginase solution for injection/infusion.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Decadron, Hexadrol, Dexone, Dexameth
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone PO or IV.

    Arm title
    		 Ixazomib 2 mg/m^2
    Arm description
    		 Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    MLN9708
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib capsules.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Oncovin, VCR, LCR
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine IV push

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Decadron, Hexadrol, Dexone, Dexameth
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Dexamethasone PO or IV.

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Oncaspar, Pegaspargase, Polyethylene Glycol Conjugated L-asparaginase-H
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    PEG-asparaginase solution for injection/infusion.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Adriamycin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin solution for infusion.

    Number of subjects in period 1
    		Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Started
    4
    6
    Completed
    4
    6
    Period 2
    Period 2 title
    Phase 2
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Ixazomib 2 mg/m^2
    Arm description
    		 Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    MLN9708
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib capsules.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Oncovin, VCR, LCR
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine solution for infusion.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Adriamycin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin solution for infusion.

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Oncaspar, Pegaspargase, Polyethylene Glycol Conjugated L-asparaginase-H
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    PEG-asparaginase solution for injection/infusion.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Decadron, Hexadrol, Dexone, Dexameth
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Dexamethasone PO or IV.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 does not include all subjects enrolled in the study thus, it is not the baseline period.
    Number of subjects in period 2
    		Ixazomib 2 mg/m^2
    Started
    20
    Completed
    18
    Not completed
    2
         Reason Not Specified
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ixazomib 2 mg/m^2
    Reporting group description
    		 Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.

    Reporting group values
    		 Ixazomib 2 mg/m^2 Total
    Number of subjects
    		 20
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 8.2 (1.5 to 20.5) -
    Gender categorical
    Units: Subjects
        Male
    		 11 11
        Female
    		 9 9
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic/Latino
    		 13 13
        Not Hispanic/Latino
    		 7 7
        Unknown
    		 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 2 2
        White
    		 11 11
        More than one race
    		 0 0
        Unknown or Not Reported
    		 6 6
    Region of Enrollment
    Units: Subjects
        United States
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Ixazomib 1.6 mg/m^2
    Reporting group description
    		 Ixazomib at dose level 1, 1.6 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.05 milligrams per kilograms per day (mg/kg/day), for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.

    Reporting group title
    Ixazomib 2 mg/m^2
    Reporting group description
    		 Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.
    Reporting group title
    Ixazomib 2 mg/m^2
    Reporting group description
    		 Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.

    Primary: Number of Participants With Dose Limiting Toxicity (DLT) During Block (Cycle) 1 of Chemotherapy

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    End point title
    		 Number of Participants With Dose Limiting Toxicity (DLT) During Block (Cycle) 1 of Chemotherapy [1]
    End point description
    DLT:defined as per National Cancer Institute Common Toxicity Criteria(NCI CTC)version 5.0 as follows:1)Any Grade 4/3 non-hematologic toxicity that occurs after first dose of ixazomib and results in omission of subsequent block of chemotherapy or delay of beginning of subsequent block of chemotherapy for>7 days,with exception of fever or infection.2)Hematologic toxicities:Failure to recover a peripheral absolute neutrophil count(ANC)≥500/μL and platelet(PLT)>20,000/μL,PLT infusion independent, due to documented bone marrow hypoplasia(cellularity<10-20%)within 49 days of beginning of systemic chemotherapy without evidence of active disease or infection by bone marrow aspiration. Participants from evaluable response set who were evaluable for safety. Evaluable response set: all participants enrolled and received all or part of protocol therapy, are under follow-up for a sufficient period to evaluate disease at end of one treatment cycle or meet definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Up to Cycle 1 (28 days)
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    3
    2
    Units: participants
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Grade 3 or More Treatment Emergent Adverse Events (TEAEs) Graded Using Common Toxicity Criteria for Adverse Event (CTCAE) Criteria Version 5.0 During Block (Cycle) 1 of Chemotherapy

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    End point title
    		 Number of Participants with Grade 3 or More Treatment Emergent Adverse Events (TEAEs) Graded Using Common Toxicity Criteria for Adverse Event (CTCAE) Criteria Version 5.0 During Block (Cycle) 1 of Chemotherapy [2]
    End point description
    TEAEs are defined as any AEs that occurred or worsened during the on-treatment period. TEAEs were graded using National Cancer Institute (NCI) CTCAE Version 5.0. SAEs are generally defined in this Phase 1 study as all Grade 3 and 4 events both unexpected and expected that are possibly, probably, or definitely related to Ixazomib or the chemotherapy backbone, excluding hematologic toxicities unless the event meets the criteria for a DLT. Participants from evaluable response set who were evaluable for safety.
    End point type
    Primary
    End point timeframe
    Up to 104 weeks
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    3
    6
    Units: participants
    3
    6
    No statistical analyses for this end point

    Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib at Day 1

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    End point title
    		 Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib at Day 1 [3]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 1 at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    2
    4
    Units: hours (h)
        median (full range (min-max))
    4.50 (1.00 to 8.00)
    1.50 (1.00 to 4.00)
    No statistical analyses for this end point

    Primary: Cmax: Maximum Observed Plasma Concentration for Ixazomib at Day 1

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration for Ixazomib at Day 1 [4]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 1 at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    2
    4
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    10.0 ( 809.5 )
    28.1 ( 30.5 )
    No statistical analyses for this end point

    Primary: T1/2: Terminal Elimination Half-Life of Ixazomib at Day 1

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    End point title
    		 T1/2: Terminal Elimination Half-Life of Ixazomib at Day 1 [5]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease. 99999 indicates geometric coefficient of variation was not estimable for one participant.
    End point type
    Primary
    End point timeframe
    Day 1 at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    1
    4
    Units: hours (h)
        geometric mean (geometric coefficient of variation)
    67.7 ( 99999 )
    36.4 ( 41.9 )
    No statistical analyses for this end point

    Primary: Adjusted R^2: Coefficient of Determination for the Terminal Disposition Phase Slope Adjusted for the Number of Data Points Used in the Analysis at Day 1

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    End point title
    		 Adjusted R^2: Coefficient of Determination for the Terminal Disposition Phase Slope Adjusted for the Number of Data Points Used in the Analysis at Day 1 [6]
    End point description
    Adjusted Rsq describes the goodness of fit for the terminal phase slope (log concentration vs time, used to then calculate the half-life). Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease. 99999 indicates geometric coefficient of variation was not estimable for one participant.
    End point type
    Primary
    End point timeframe
    Day 1 at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    1
    4
    Units: Unitless
        geometric mean (geometric coefficient of variation)
    0.587 ( 99999 )
    0.495 ( 58.5 )
    No statistical analyses for this end point

    Primary: AUC%extrap,obs: Percent of Area Under the Plasma Concentration-time Curve from Dosing Time Infinity due to Extrapolation From the Last Observed Concentration for lxazomib at Day 1

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    End point title
    		 AUC%extrap,obs: Percent of Area Under the Plasma Concentration-time Curve from Dosing Time Infinity due to Extrapolation From the Last Observed Concentration for lxazomib at Day 1 [7]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease. 99999 indicates geometric coefficient of variation was not estimable for one participant.
    End point type
    Primary
    End point timeframe
    Day 1 at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    1
    4
    Units: percentage of AUC
        geometric mean (geometric coefficient of variation)
    39.7 ( 99999 )
    26.8 ( 45.7 )
    No statistical analyses for this end point

    Primary: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib at Day 1

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    End point title
    		 AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib at Day 1 [8]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 1 at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    2
    4
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    178 ( 125.7 )
    331 ( 61.7 )
    No statistical analyses for this end point

    Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib at Day 11

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    End point title
    		 Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib at Day 11 [9]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 11 pre-dose and at multiple time points post-dose (up to 72 hours for participants weighing <20 kg and up to 264 hours for participants weighing ≥20 kg)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    3
    6
    Units: hours (hr)
        median (full range (min-max))
    4.00 (0.50 to 4.00)
    3.00 (0.50 to 72.00)
    No statistical analyses for this end point

    Primary: Cmax: Maximum Observed Plasma Concentration for Ixazomib at Day 11

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration for Ixazomib at Day 11 [10]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 11 pre-dose and at multiple time points post-dose (up to 72 hours for participants weighing <20 kg and up to 264 hours for participants weighing ≥20 kg)
    Notes
    [10] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    3
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    22.8 ( 169.1 )
    73.6 ( 75.1 )
    No statistical analyses for this end point

    Primary: T1/2: Terminal Elimination Half-Life of Ixazomib at Day 11

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    End point title
    		 T1/2: Terminal Elimination Half-Life of Ixazomib at Day 11 [11]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 11 pre-dose and at multiple time points post-dose (up to 72 hours for participants weighing <20 kg and up to 264 hours for participants weighing ≥20 kg)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    2
    5
    Units: hours (hr)
        geometric mean (geometric coefficient of variation)
    111 ( 59.8 )
    99.4 ( 37.4 )
    No statistical analyses for this end point

    Primary: Adjusted R^2: Coefficient of Determination for the Terminal Disposition Phase Slope Adjusted for the Number of Data Points Used in the Analysis at Day 11

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    End point title
    		 Adjusted R^2: Coefficient of Determination for the Terminal Disposition Phase Slope Adjusted for the Number of Data Points Used in the Analysis at Day 11 [12]
    End point description
    Adjusted Rsq describes the goodness of fit for the terminal phase slope (log concentration vs time, used to then calculate the half-life). Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 11 pre-dose and at multiple time points post-dose (up to 72 hours for participants weighing <20 kg and up to 264 hours for participants weighing ≥20 kg)
    Notes
    [12] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    2
    5
    Units: Unitless
        geometric mean (geometric coefficient of variation)
    0.969 ( 0.5 )
    0.940 ( 3.8 )
    No statistical analyses for this end point

    Primary: AUC%extrap,obs: Percent of Area Under the Plasma Concentration-time Curve from Dosing Time Infinity due to Extrapolation From the Last Observed Concentration for lxazomib at Day 11

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    End point title
    		 AUC%extrap,obs: Percent of Area Under the Plasma Concentration-time Curve from Dosing Time Infinity due to Extrapolation From the Last Observed Concentration for lxazomib at Day 11 [13]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 11 pre-dose and at multiple time points post-dose (up to 72 hours for participants weighing <20 kg and up to 264 hours for participants weighing ≥20 kg)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    2
    5
    Units: percentage of AUC
        geometric mean (geometric coefficient of variation)
    14.6 ( 130.5 )
    12.8 ( 105.6 )
    No statistical analyses for this end point

    Primary: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib at Day 11

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    End point title
    		 AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib at Day 11 [14]
    End point description
    Evaluable response set included all participants enrolled and who received all or part of protocol therapy and are under follow-up for a sufficient period to evaluate the disease at the end of the one treatment cycle or meet the definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose for participants weighing <20 kg and ≥20 kg
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    3
    6
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    586 ( 58.2 )
    1650 ( 35.9 )
    No statistical analyses for this end point

    Primary: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs) [15]
    End point description
    AE:any untoward medical occurrence in a clinical investigation participant administered a investigative drug; it does not necessarily have to have a causal relationship with trial drug administration.SAE:any untoward medical occurrence that:1)results in death,2)is life-threatening, 3)requires inpatient hospitalization or prolongation of existing hospitalization,4)results in persistent or significant disability/incapacity,5)leads to a congenital anomaly/birth defect in offspring of participant or6)is a medically important event that satisfies any of following:a)May require intervention to prevent items 1 to 5 above.b)May expose participant to danger, even though event is not immediately life threatening or fatal or does not result in hospitalization. Participants from evaluable response set who were evaluable for safety.
    End point type
    Primary
    End point timeframe
    Up to 104 weeks
    Notes
    [15] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 1.6 mg/m^2 Ixazomib 2 mg/m^2
    Number of subjects analysed
    3
    6
    Units: percentage of participants
    number (not applicable)
        TEAEs
    100
    100
        SAEs
    100
    100
    No statistical analyses for this end point

    Primary: Phase 2: Number of Participants with Complete Remission (CR), Complete Remission, MRD Negative (CR MRD-) and Complete Response with Incomplete Count Recovery (CRi) After Block 1 Chemotherapy

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    End point title
    		 Phase 2: Number of Participants with Complete Remission (CR), Complete Remission, MRD Negative (CR MRD-) and Complete Response with Incomplete Count Recovery (CRi) After Block 1 Chemotherapy [16]
    End point description
    Best response: measured by bone marrow status as percentage of participants with CR: a bone marrow with<5%blasts by morphology;no evidence of circulating blasts or extramedullary disease;recovery of peripheral counts(ANC≥500/μL, PLT≥20,000/μL,platelet infusion independent) or CR MRD-:a bone marrow with<5% blasts by morphology;MRD<0.1%by flow or molecular testing(e.g.PCR);no evidence of circulating blasts or extramedullary disease;recovery of peripheral counts(ANC≥500/μL,PLT≥20,000/μL,platelet infusion independent) or CRi:all CR criteria except for insufficient recovery of ANC (<500/μL), and/or PLT counts (<20,000/μL) are reported. Evaluable response set: all participants enrolled and received all/part of protocol therapy and are under follow-up for a sufficient period to evaluate disease at end of 1 treatment cycle/meet definition of progressive disease.
    End point type
    Primary
    End point timeframe
    Up to Cycle 1 (28 days)
    Notes
    [16] - 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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Ixazomib 2 mg/m^2
    Number of subjects analysed
    18
    Units: participants
        CR
    2
        CR MRD-
    6
        CRi
    4
    No statistical analyses for this end point

    Secondary: Palatability Assessed as Percentage of Participants who Found the Taste to be at least Tolerable

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    End point title
    		 Palatability Assessed as Percentage of Participants who Found the Taste to be at least Tolerable
    End point description
    After each dose of ixazomib during block 1, a questionnaire was provided to subject and parent/care giver. If the subject was too young to fill the survey, only parent/care giver was surveyed. In each case, a nurse or research staff recorded the verbal responses to the questions. When facial hedonic scales were utilized, the child or parent/care giver was asked to indicate their preference by circling on the pictorial scale of facial expression. Evaluable response set: all participants enrolled and received all/part of protocol therapy and are under follow-up for a sufficient period to evaluate disease at end of 1 treatment cycle/meet definition of progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (28 days)
    End point values
    		 Ixazomib 2 mg/m^2
    Number of subjects analysed
    18
    Units: percentage of participants
        number (not applicable)
    83
    No statistical analyses for this end point

    Secondary: Number of Participants With CTCAE Toxicities During Block 2 Chemotherapy

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    End point title
    		 Number of Participants With CTCAE Toxicities During Block 2 Chemotherapy
    End point description
    TEAEs are defined as any AEs that occurred or worsened during the on-treatment period. TEAEs were graded using NCI CTCAE Version 5.0. Toxicities included the following system organ classes: blood and lymphatic system, cardiac, gastrointestinal, general, metabolism and nutrition, respiratory, thoracic, and mediastinal, skin and subcutaneous tissue disorders, and psychiatric disorders and infections and infestations. Participants from evaluable response set who were evaluable for safety. Subjects analysed is the number of participants enrolled on dose level 2 (DL2) during Phase 2 portion of the study.
    End point type
    Secondary
    End point timeframe
    Cycle 2 (28 days)
    End point values
    		 Ixazomib 2 mg/m^2
    Number of subjects analysed
    14
    Units: participants
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4.8 years
    Adverse event reporting additional description
    At each visit investigator had to document any occurrence of AE and abnormal laboratory findings. Any event reported by participant or by investigator was recorded, irrespective of the relation to study treatment. All-cause mortality: Evaluable response set(n=4,6,20). SAE and non-SAEs: Participants from evaluable response set with data for safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    Unknown
    Reporting groups
    Reporting group title
    Phase 1: Ixazomib 1.6 mg/m^2
    Reporting group description
    		 Phase 1: Ixazomib at dose level 1, 1.6 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.05 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.

    Reporting group title
    Phase 2: Ixazomib 2 mg/m^2
    Reporting group description
    		 Phase 2: Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.

    Reporting group title
    Phase 1: Ixazomib 2 mg/m^2
    Reporting group description
    		 Phase 1: Ixazomib at dose level 2, 2 mg/m^2/day, for participants 1 year of age or older (Strata A), and 0.07 mg/kg/day, for infants less than 1 year of age (Strata B), orally, once on Days 1, 4, 8 and 11 of each 28-day cycle, given in combination with VXLD backbone chemotherapy (vincristine, dexamethasone, asparaginase, and doxorubicin), up to 4 weeks. Participants were followed for safety up to 100 weeks after last dose.

    Serious adverse events
    		 Phase 1: Ixazomib 1.6 mg/m^2 Phase 2: Ixazomib 2 mg/m^2 Phase 1: Ixazomib 2 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    14 / 14 (100.00%)
    6 / 6 (100.00%)
         number of deaths (all causes)
    1
    5
    2
         number of deaths resulting from adverse events
    0
    2
    0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 3 (100.00%)
    0 / 14 (0.00%)
    4 / 6 (66.67%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalized edema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Mucositis oral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 14 (28.57%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Catheter related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypertriglyceridemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AST increased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 14 (21.43%)
    3 / 6 (50.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ALT increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    4 / 6 (66.67%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphatemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GGT increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatremia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1: Ixazomib 1.6 mg/m^2 Phase 2: Ixazomib 2 mg/m^2 Phase 1: Ixazomib 2 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    14 / 14 (100.00%)
    6 / 6 (100.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 14 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    2
    Dehydration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Fever
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 14 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    2
    Oral pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Generalized edema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Mucositis oral
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    2
    Psychiatric disorders
    Anorexia
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 14 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    1
    4
    2
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Irritability
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    4 / 6 (66.67%)
         occurrences all number
    0
    5
    5
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    2
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    3 / 3 (100.00%)
    10 / 14 (71.43%)
    5 / 6 (83.33%)
         occurrences all number
    3
    10
    7
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 14 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 14 (35.71%)
    2 / 6 (33.33%)
         occurrences all number
    3
    5
    6
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    12 / 14 (85.71%)
    5 / 6 (83.33%)
         occurrences all number
    0
    12
    5
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 14 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    1
    Neutrophil count decreased
         subjects affected / exposed
    3 / 3 (100.00%)
    9 / 14 (64.29%)
    5 / 6 (83.33%)
         occurrences all number
    3
    9
    6
    Platelet count decreased
         subjects affected / exposed
    3 / 3 (100.00%)
    9 / 14 (64.29%)
    4 / 6 (66.67%)
         occurrences all number
    3
    9
    6
    White blood cell decreased
         subjects affected / exposed
    3 / 3 (100.00%)
    11 / 14 (78.57%)
    5 / 6 (83.33%)
         occurrences all number
    3
    11
    6
    Edema face
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    2
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Methemoglobinemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Thrombus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Edema limbs
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    3
    Diarrhea
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    10 / 14 (71.43%)
    2 / 6 (33.33%)
         occurrences all number
    2
    10
    4
    Pain in groin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    8 / 14 (57.14%)
    3 / 6 (50.00%)
         occurrences all number
    1
    8
    4
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    3 / 6 (50.00%)
         occurrences all number
    0
    2
    3
    Increased hunger
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Bloating
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    2
    Cool/mottled skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Erythematous facial rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Lesion on left thumb
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Perirectal breakdown
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pressure injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Skin rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Bleeding labial skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Rash acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Hyperuricemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    Proteinuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Rectal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Urinary tract pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Renal colic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Bladder spasm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Cystitis noninfective
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Syndrome of inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    2
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    2
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Muscle cramp
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Edema face
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Sepsis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Parainfluenza 1
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes simplex reactivation
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Decreased respiration, intermittent
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Increased respiration, intermittent
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Parvovirus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Positive MRSA
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    RHINOVIRUS
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Adenovirus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Thrush
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    UTI R/T BK/ADENOVIRUS
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Fever
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 14 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    7
    0
    Metabolism and nutrition disorders
    ALT increased
         subjects affected / exposed
    3 / 3 (100.00%)
    6 / 14 (42.86%)
    2 / 6 (33.33%)
         occurrences all number
    4
    6
    3
    INR increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    AST increased
         subjects affected / exposed
    2 / 3 (66.67%)
    7 / 14 (50.00%)
    3 / 6 (50.00%)
         occurrences all number
    4
    7
    7
    GGT increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    Hypercalcemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Hyperglycemia
         subjects affected / exposed
    3 / 3 (100.00%)
    9 / 14 (64.29%)
    3 / 6 (50.00%)
         occurrences all number
    8
    9
    9
    Hyperkalemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    2
    Hypermagnesemia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    2
    Hypernatremia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    Hyperphosphatemia
         subjects affected / exposed
    1 / 3 (33.33%)
    8 / 14 (57.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    8
    0
    Hypophosphatemia
         subjects affected / exposed
    1 / 3 (33.33%)
    8 / 14 (57.14%)
    3 / 6 (50.00%)
         occurrences all number
    1
    8
    5
    Hyponatremia
         subjects affected / exposed
    2 / 3 (66.67%)
    13 / 14 (92.86%)
    4 / 6 (66.67%)
         occurrences all number
    5
    13
    4
    Hypomagnesemia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    2
    Hypokalemia
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 14 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    7
    1
    Hypoglycemia
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 14 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    2
    4
    2
    Hypocalcemia
         subjects affected / exposed
    1 / 3 (33.33%)
    10 / 14 (71.43%)
    3 / 6 (50.00%)
         occurrences all number
    3
    10
    6
    Hypoalbuminemia
         subjects affected / exposed
    3 / 3 (100.00%)
    9 / 14 (64.29%)
    4 / 6 (66.67%)
         occurrences all number
    4
    9
    4
    Hypertriglyceridemia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Alkaline phosphatase increased
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 14 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    4
    4
    1
    Weight loss
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Weight gain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2019
    The primary purpose of the amendment 1 was to make following changes: • Dose Modification for Intrathecal (IT) Methotrexate (MTX) /Triple Intrathecal Therapy toxicities: Mercaptopurine dose adjustments made to allow for genotype variations in either TPMT or NUDT15. • Dose Modification for Intermediate-Dose Methotrexate toxicities: Added a subsection to provide guidance in the event of excess extravasation of fluids into tissues (third spacing). • Clinical and Laboratory Studies: Added neurological exam to be performed prior to each Ixazomib dosing. • Bone Marrow Response Criteria for participants with leukemia: Amended response definitions to replace CRp category with CRi and divide the CR category to include CR MRD-.
    16 Sep 2020
    The primary purpose of the amendment 2 was to make following changes: • Exclusion criteria: updated the list of excluded CYP3A4 agents. • Treatment program: under Block 1, 2, and Maintenance Block, revised timing of Leucovorin for Down syndrome (DS) participants to be received at hours 24 and 30 after IT MTX or ITT. • Dose Limiting Toxicity: changed platelet criteria for hematological toxicity definition to platelet ≥20,000/μL, platelet infusion independent and length of evaluation time to 49 days.
    11 May 2021
    The primary purpose of the amendment 3 was to make following changes: • Inclusion criteria: clarify the definition of what chemotherapy regimens and drugs and dosages (i.e. maintenance therapy drugs) are allowed prior to enrollment and what length of washout is required for the drugs and biologics. • Treatment program: added clarification to allow for flexibility in the timing of chemotherapy administration, including the timing of Day 29 IT therapy, allowing for up to 72 hours flexibility for scheduling or other issues.
    23 Jan 2022
    The primary purpose of the amendment 4 was to make following changes: • Chemotherapy Backbone: Added clarification that DS and infants (<1 year of age) would enroll to Phase 2 at Dose Level 1. Their data would only be descriptive and not included in DLT and response evaluation. Added clarification regarding leucovorin treatment for DS participants. • Treatment program: Added change crisantapase (Erwinase®) or asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) may be substituted for allergy to Pegaspargase. • Ixazomib: Added clarification that administration of ixazomib capsules should be rounded to the nearest 0.2mg.
    26 Oct 2022
    The primary purpose of the amendment 5 was to make following changes: • Inclusion criteria: Revised eligibility criteria to read “Participants must be <22 years of age at time of enrollment.” Revised eligibility criteria for prior therapeutic attempts for B-cell ALL/LLy participants from failed two or more prior attempts to failed one or more prior attempts. • Exclusion Criteria: Revised exclusion criteria to include allergy or intolerance to Calaspargase. • Treatment program: Added Calaspargase to treatment schedule for Block 1 and Block 2. Added footnote that regarding the administration of either pegaspargase or calaspargase according to current approved labeling based on age and regional availability. Added dosage administration for calaspargase to be only administered once per cycle and on Day 2 for Block 1 and Day 9 or 10 for Block 2. Updated language regarding substituting crisantapase (Erwinase®) asparaginase or Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) for Pegaspargase or Calaspargase. • Correlative Studies: Added clarification regarding leftover samples banked for future therapeutic advances in childhood leukemia and lymphoma (TACL) biology studies.
    20 Jul 2023
    The primary purpose of the amendment 6 was to make following changes: • Statistical Considerations: Revised definition of a participants evaluable for response to include those who die as a result of a DLT and that such participants will be considered a non-responder. Also added that participants who are not considered evaluable for response will be replaced. •Added clarification that the occurrence of a toxic death will be defined as a death occurring anytime during protocol therapy or until 30 days following the last dose of study therapy. • Response Criteria: Added new Non-responder (NR) response criteria.
    07 Sep 2023
    The primary purpose of the amendment 7 was to make following changes: • Ixazomib: Updated Toxicity/Adverse Events to reflect recent updates in the Ixazomib Investigator’s Brochure edition 15.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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