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    Clinical Trial Results:
    A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

    Summary
    EudraCT number
    2014-002217-31
    Trial protocol
    DE   IT   FR  
    Global end of trial date
    07 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Mar 2019
    First version publication date
    22 Mar 2019
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    2215-CL-0101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02014558
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., 1 8008887704, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., 1 8008887704, astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were to assess the safety and tolerability, including determination of the maximum tolerated dose (MTD) of oral gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML) and determine the pharmacokinetic parameters of gilteritinib.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 245
    Worldwide total number of subjects
    265
    EEA total number of subjects
    20
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    151
    From 65 to 84 years
    111
    85 years and over
    3

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    This dose-escalation/dose-expansion study was conducted in sites in the United States, Germany and Italy. The study had 7 dose-escalation cohorts with ≥3 participants enrolled at each dose level. Following escalation to the next dose cohort, additional participants were enrolled to the dose-expansion cohorts per protocol-specified criteria.

    Pre-assignment
    Screening details
    Participants with AML who relapsed after or were refractory to induction or salvage treatment were selected for this study. Re-enrollment into the dose-expansion cohorts was permissible for participants who discontinued treatment for reasons other than toxicity or disease progression, as long as they met the eligibility criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Gilteritinib 20 mg in Escalation Phase
    Arm description
    Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 40 mg in Escalation Phase
    Arm description
    Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 80 mg in Escalation Phase
    Arm description
    Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 120 mg in Escalation Phase
    Arm description
    Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 200 mg in Escalation Phase
    Arm description
    Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 300 mg in Escalation Phase
    Arm description
    Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 450 mg in Escalation Phase
    Arm description
    Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 20 mg in Expansion Phase
    Arm description
    Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Voriconazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 200 mg voriconazole tablets daily every 12 hours starting from day 16 of cycle 1 through day 1 of cycle 2.

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 40 mg in Expansion Phase
    Arm description
    Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 80 mg in Expansion Phase
    Arm description
    Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 120 mg in Expansion Phase
    Arm description
    Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Arm title
    Gilteritinib 200 mg in Expansion Phase
    Arm description
    Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 500 mg cephalexin as a single oral dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Investigational medicinal product name
    Cephalexin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single oral dose of 500 mg cephalexin tablet or capsule on day -1 and day 15 of cycle 1.

    Arm title
    Gilteritinib 300 mg in Expansion Phase
    Arm description
    Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single oral dose of 2 mg midazolam syrup on day -1 and day 15 of cycle 1.

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    ASP2215
    Other name
    Xospata
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

    Number of subjects in period 1
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase Gilteritinib 20 mg in Expansion Phase Gilteritinib 40 mg in Expansion Phase Gilteritinib 80 mg in Expansion Phase Gilteritinib 120 mg in Expansion Phase Gilteritinib 200 mg in Expansion Phase Gilteritinib 300 mg in Expansion Phase
    Started
    5
    3
    3
    3
    4
    3
    4
    11
    15
    21
    70
    106
    17
    Treated
    5
    3
    3
    3
    3
    3
    3
    11
    13
    21
    66
    100
    17
    Incorrect dose taken (should be 120 mg)
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Re-enrolled
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    4
    0
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    5
    3
    3
    3
    4
    3
    4
    11
    15
    21
    70
    106
    17
         Death
    1
    -
    -
    -
    -
    -
    1
    1
    2
    5
    5
    20
    2
         Withdrawal by Patient
    -
    -
    -
    -
    1
    -
    -
    -
    -
    2
    6
    10
    -
         Miscellaneous
    2
    1
    1
    1
    -
    1
    -
    1
    1
    3
    12
    11
    1
         Never Received Drug
    -
    -
    -
    -
    1
    -
    1
    -
    2
    -
    2
    2
    -
         Lack of Efficacy
    1
    2
    1
    1
    -
    -
    1
    3
    3
    3
    16
    8
    5
         Progressive Disease
    1
    -
    1
    1
    1
    2
    1
    6
    5
    6
    23
    32
    6
         Adverse Event
    -
    -
    -
    -
    1
    -
    -
    -
    2
    2
    5
    22
    3
         Lost to Follow-up
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gilteritinib 20 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 40 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 80 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 120 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 200 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 300 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 450 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 20 mg in Expansion Phase
    Reporting group description
    Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.

    Reporting group title
    Gilteritinib 40 mg in Expansion Phase
    Reporting group description
    Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilteritinib 80 mg in Expansion Phase
    Reporting group description
    Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilteritinib 120 mg in Expansion Phase
    Reporting group description
    Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilteritinib 200 mg in Expansion Phase
    Reporting group description
    Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 500 mg cephalexin as a single oral dose.

    Reporting group title
    Gilteritinib 300 mg in Expansion Phase
    Reporting group description
    Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.

    Reporting group values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase Gilteritinib 20 mg in Expansion Phase Gilteritinib 40 mg in Expansion Phase Gilteritinib 80 mg in Expansion Phase Gilteritinib 120 mg in Expansion Phase Gilteritinib 200 mg in Expansion Phase Gilteritinib 300 mg in Expansion Phase Total
    Number of subjects
    5 3 3 3 4 3 4 11 15 21 70 106 17
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.8 ± 6.8 56.7 ± 6.7 61.0 ± 8.7 61.7 ± 6.0 55.3 ± 17.5 55.3 ± 25.0 59.3 ± 10.0 62.5 ± 11.4 54.6 ± 18.5 56.3 ± 18.1 58.2 ± 16.9 59.7 ± 14.3 57.6 ± 15.9 -
    Gender categorical
    Units: Subjects
        Male
    3 2 2 2 2 2 3 3 11 9 32 53 12 136
        Femaile
    2 1 1 1 2 1 1 8 4 12 38 53 5 129
    Race
    Units: Subjects
        White
    5 2 3 2 1 3 4 9 11 14 61 96 13 224
        Black or African American
    0 0 0 1 1 0 0 1 0 4 2 5 3 17
        Asian
    0 1 0 0 1 0 0 0 0 0 1 4 0 7
        Other
    0 0 0 0 1 0 0 1 4 3 6 1 1 17
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    5 3 2 3 4 3 4 10 13 20 65 103 17 252
        Hispanic or latino
    0 0 1 0 0 0 0 1 2 1 5 3 0 13
    Local FLT3 Mutation Status
    Units: Subjects
        Negative
    1 0 0 1 2 1 1 1 8 12 13 11 9 60
        Positive
    4 3 3 2 2 2 3 10 7 9 57 95 8 205
    Duration of Disease (AML)
    The number of participants with available data for each arm are 4, 3, 2, 3, 2, 1, 3, 9, 11,17, 48, 80, 15. SD could not be calculated for the 300 mg due to sample size of 1.
    Units: months
        arithmetic mean (standard deviation)
    19.7 ± 24.62 10.81 ± 8.58 62.46 ± 6.97 49.53 ± 72.17 9.46 ± 2.23 19.75 ± 99999 7.21 ± 4.27 11.79 ± 6.82 10.53 ± 11.22 16.3 ± 9.85 12.43 ± 11.13 11.04 ± 9.86 12.09 ± 17.76 -

    End points

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    End points reporting groups
    Reporting group title
    Gilteritinib 20 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 40 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 80 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 120 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 200 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 300 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 450 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilteritinib 20 mg in Expansion Phase
    Reporting group description
    Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.

    Reporting group title
    Gilteritinib 40 mg in Expansion Phase
    Reporting group description
    Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilteritinib 80 mg in Expansion Phase
    Reporting group description
    Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilteritinib 120 mg in Expansion Phase
    Reporting group description
    Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilteritinib 200 mg in Expansion Phase
    Reporting group description
    Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 500 mg cephalexin as a single oral dose.

    Reporting group title
    Gilteritinib 300 mg in Expansion Phase
    Reporting group description
    Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.

    Subject analysis set title
    Gilteritinib 20 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Subject analysis set title
    Gilteritinib 40 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Subject analysis set title
    Gilteritinib 80 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Subject analysis set title
    Gilteritinib 120 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Subject analysis set title
    Gilteritinib 200 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Subject analysis set title
    Gilteritinib 300 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Subject analysis set title
    Gilteritinib 450 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

    Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

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    End point title
    Number of Participants with Dose Limiting Toxicities (DLTs) [1]
    End point description
    To determine the maximum tolerated dose, safety was assessed by DLTs, defined as any grade ≥3 non-hematologic or extramedullary toxicity that occurred within 30 days starting with the first dose taken on day -2, and included the first treatment cycle in the dose escalation phase and in the first treatment cycle (28 days) in the dose expansion phase, that was considered to be possibly or probably related to study drug. Exceptions to this were the following: (1) Alopecia, anorexia or fatigue, (2) Grade 3 nausea and/or vomiting if not required tube feeding or total parenteral nutrition, or diarrhea if not required or prolonged hospitalization that was managed to grade ≤2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset, (3) Grade 3 fever with neutropenia, with or without infection, (4) Grade 3 infection. Only evaluable participants (received at least 80% of intended dose or had DLT in cycle 1) in SAF were included in the analysis.
    End point type
    Primary
    End point timeframe
    From first dose up to end of cycle 1 (30 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: There is no statistical analysis applicable for this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase Gilteritinib 20 mg in Expansion Phase Gilteritinib 40 mg in Expansion Phase Gilteritinib 80 mg in Expansion Phase Gilteritinib 120 mg in Expansion Phase Gilteritinib 200 mg in Expansion Phase Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    3
    3
    3
    3
    3
    3
    3
    9
    11
    18
    62
    87
    13
    Units: Participants
        Any DLT
    0
    0
    0
    0
    0
    0
    2
    1
    1
    2
    7
    15
    3
        Blood and lymphatic system disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
        Cardiac disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
        Eye disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
        Gastrointestinal disorders
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    4
    1
        General disorders & administration site conditions
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Hepatobiliary disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
        Infections and infestations
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
        Investigations
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    2
    6
    2
        Metabolism and nutrition disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
        Musculoskeletal and connective tissue disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
        Nervous system disorders
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    3
    0
        Renal and urinary disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
        Reproductive system and breast disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Respiratory, thoracic and mediastinal disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    1
        Vascular disorders
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs) [2]
    End point description
    Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug (for participants who underwent hematopoietic stem cell transplantation [HSCT]: defined as AEs observed after starting study drug until the last dose before on study HSCT plus 30 days, and AEs that began after resumption of gilteritinib and w/in 30 days after the last dose of gilteritinib). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (1-Mild, 2-Moderate, 3-Severe, 4-LifeThreatening, 5-Death). The analysis population was the SAF (reflected actual treatment).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    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: There is no statistical analysis applicable for this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase Gilteritinib 20 mg in Expansion Phase Gilteritinib 40 mg in Expansion Phase Gilteritinib 80 mg in Expansion Phase Gilteritinib 120 mg in Expansion Phase Gilteritinib 200 mg in Expansion Phase Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    3
    11 [3]
    13
    21
    66
    100
    17
    Units: Participants
        AEs
    5
    3
    3
    3
    3
    3
    3
    11
    13
    20
    64
    100
    17
        Drug-Related AEs
    3
    2
    1
    3
    3
    2
    3
    7
    6
    17
    52
    77
    13
        Deaths
    2
    2
    0
    1
    1
    1
    1
    3
    4
    11
    23
    49
    7
        Serious AEs
    2
    2
    2
    1
    2
    2
    2
    8
    12
    19
    52
    92
    14
        Drug-Related Serious AEs
    0
    0
    0
    1
    1
    0
    2
    2
    1
    10
    19
    36
    4
        AEs Leading to Discontinuation of Study Drug
    2
    0
    1
    0
    1
    0
    1
    2
    5
    11
    12
    46
    6
        Drug-Related AEs Leading to Discont. of Study Drug
    0
    0
    0
    0
    0
    0
    0
    1
    1
    4
    5
    10
    3
        Grade 3 or Higher TEAEs
    3
    2
    2
    1
    2
    2
    3
    9
    13
    20
    59
    99
    14
        AEs During On-Study HSCT Period
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    7
    0
        Serious AEs During On-Study HSCT
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Notes
    [3] - Actual number of participants treated & analyzed is 12. Need to reflect 11 due to validation error.
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) after Single and Multiple Doses of Gilteritinib

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    End point title
    Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) after Single and Multiple Doses of Gilteritinib [4]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the pharmacokinetics analysis set (PKAS), which consisted of the subset of the SAF for which sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known. N is the number of participants with available data (applies to all endpoints). Data that could not be calculated due to low number of participants with evaluable samples is denoted as "+/-99999."
    End point type
    Primary
    End point timeframe
    Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only gilteritinib escalation groups are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    3
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Day -2 [N=5, 3, 3, 3, 3, 3, 2]
    302.1 ± 207.0
    360.0 ± 223.5
    1216 ± 472.6
    2480 ± 1972
    3022 ± 843.6
    4163 ± 3178
    3324 ± 221.1
        Cycle 1 day 15 [N=3, 2, 3, 3, 2, 3, 1]
    1299 ± 1006
    2482 ± 33.28
    6958 ± 3273
    6943 ± 3221
    31428 ± 21412
    31005 ± 10068
    34768 ± 99999
    Statistical analysis title
    Statistial Analysis 1
    Statistical analysis description
    Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.
    Comparison groups
    Gilteritinib 450 mg in Escalation Phase v Gilteritinib 20 mg in Escalation Phase v Gilteritinib 300 mg in Escalation Phase v Gilteritinib 200 mg in Escalation Phase v Gilteritinib 120 mg in Escalation Phase v Gilteritinib 80 mg in Escalation Phase v Gilteritinib 40 mg in Escalation Phase
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Slope
    Point estimate
    0.99
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.788
         upper limit
    1.19
    Statistical analysis title
    Statistial Analysis 2
    Statistical analysis description
    Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.
    Comparison groups
    Gilteritinib 450 mg in Escalation Phase v Gilteritinib 20 mg in Escalation Phase v Gilteritinib 300 mg in Escalation Phase v Gilteritinib 200 mg in Escalation Phase v Gilteritinib 120 mg in Escalation Phase v Gilteritinib 80 mg in Escalation Phase v Gilteritinib 40 mg in Escalation Phase
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Slope
    Point estimate
    1.22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1
         upper limit
    1.43

    Primary: Maximum Concentration (Cmax) after Single and Multiple Doses of Gilteritinib

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    End point title
    Maximum Concentration (Cmax) after Single and Multiple Doses of Gilteritinib [5]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS. Data that could not be calculated due to low number of participants with evaluable samples is denoted as "+/-99999."
    End point type
    Primary
    End point timeframe
    Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only gilteritinib escalation groups are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day -2 [N=5, 3, 3, 3, 3, 3, 3]
    28.13 ± 21.49
    24.98 ± 14.58
    75.29 ± 25.22
    136.7 ± 94.37
    168.2 ± 45.34
    204.3 ± 136.4
    207.6 ± 51.81
        Cycle 1 day 15 [N=4, 3, 3, 3, 2, 3, 1]
    64.64 ± 48.77
    107.6 ± 31.92
    376.4 ± 150.5
    374.2 ± 190.1
    1462 ± 815.1
    1525 ± 664.6
    1528 ± 99999
    Statistical analysis title
    Statistial Analysis 1
    Statistical analysis description
    Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.
    Comparison groups
    Gilteritinib 20 mg in Escalation Phase v Gilteritinib 450 mg in Escalation Phase v Gilteritinib 200 mg in Escalation Phase v Gilteritinib 300 mg in Escalation Phase v Gilteritinib 120 mg in Escalation Phase v Gilteritinib 80 mg in Escalation Phase v Gilteritinib 40 mg in Escalation Phase
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Slope
    Point estimate
    0.808
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.629
         upper limit
    0.988
    Statistical analysis title
    Statistial Analysis 2
    Statistical analysis description
    Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.
    Comparison groups
    Gilteritinib 20 mg in Escalation Phase v Gilteritinib 450 mg in Escalation Phase v Gilteritinib 200 mg in Escalation Phase v Gilteritinib 300 mg in Escalation Phase v Gilteritinib 120 mg in Escalation Phase v Gilteritinib 80 mg in Escalation Phase v Gilteritinib 40 mg in Escalation Phase
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Slope
    Point estimate
    1.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    1.41

    Primary: Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) after Single and Multiple Doses of Gilteritinib

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    End point title
    Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) after Single and Multiple Doses of Gilteritinib [6] [7]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS. Data that could not be calculated due to low number of participants with evaluable samples is denoted as "+/-99999."
    End point type
    Primary
    End point timeframe
    Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
    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: There is no statistical analysis applicable for this endpoint.
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only gilteritinib escalation groups are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    3
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Day -2 [N=5, 3, 3, 3, 3, 3, 3]
    303.0 ± 207.1
    360.4 ± 224.1
    1216 ± 472.6
    2480 ± 1972
    3024 ± 846.2
    4181 ± 3189
    2544 ± 1427
        Cycle 1 day 15 [N=4, 3, 3, 3, 2, 3, 1]
    1030 ± 984.2
    1990 ± 1422
    7111 ± 3525
    6943 ± 3221
    32248 ± 22571
    31749 ± 10090
    35506 ± 99999
    No statistical analyses for this end point

    Primary: Time to Observed Cmax (tmax) after Single and Multiple Doses of Gilteritinib

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    End point title
    Time to Observed Cmax (tmax) after Single and Multiple Doses of Gilteritinib [8] [9]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS. Data that could not be calculated due to low number of participants with evaluable samples is denoted as "+/-99999."
    End point type
    Primary
    End point timeframe
    Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
    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: There is no statistical analysis applicable for this endpoint.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only gilteritinib escalation groups are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    3
    Units: hours
    median (full range (min-max))
        Day -2 [N=5, 3, 3, 3, 3, 3, 3]
    2.00 (0.500 to 4.03)
    5.983 (3.97 to 24.0)
    4.000 (4.00 to 4.08)
    2.083 (2.00 to 3.83)
    5.233 (4.00 to 5.97)
    6.067 (4.08 to 24.1)
    5.783 (4.08 to 5.92)
        Cycle 1 day 15 [N=4, 3, 3, 3, 2, 3, 1]
    4.008 (4.00 to 6.00)
    3.867 (0.50 to 6.00)
    4.333 (4.00 to 4.42)
    2.167 (1.95 to 5.75)
    6.033 (6.00 to 6.07)
    6.050 (4.08 to 6.07)
    5.933 (-99999 to 99999)
    No statistical analyses for this end point

    Primary: Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib

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    End point title
    Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib [10] [11]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
    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: There is no statistical analysis applicable for this endpoint.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only gilteritinib escalation groups are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase
    Number of subjects analysed
    3
    2
    3
    3
    2
    3
    0 [12]
    Units: hours
        arithmetic mean (standard deviation)
    62.14 ± 17.88
    151.8 ± 129.2
    86.11 ± 24.08
    45.85 ± 18.83
    141.9 ± 61.51
    142.2 ± 55.04
    ±
    Notes
    [12] - Data could not be calculated due to no evaluable samples.
    No statistical analyses for this end point

    Primary: Accumulation Ratio After Multiple Doses of Gilteritinib

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    End point title
    Accumulation Ratio After Multiple Doses of Gilteritinib [13] [14]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS.
    End point type
    Primary
    End point timeframe
    Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
    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: There is no statistical analysis applicable for this endpoint.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only gilteritinib escalation groups are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Escalation Phase Gilteritinib 40 mg in Escalation Phase Gilteritinib 80 mg in Escalation Phase Gilteritinib 120 mg in Escalation Phase Gilteritinib 200 mg in Escalation Phase Gilteritinib 300 mg in Escalation Phase Gilteritinib 450 mg in Escalation Phase
    Number of subjects analysed
    3
    2
    3
    3
    2
    3
    0 [15]
    Units: ratio
        arithmetic mean (standard deviation)
    4.259 ± 1.069
    9.640 ± 7.754
    5.693 ± 1.442
    3.290 ± 1.118
    9.041 ± 3.693
    9.057 ± 3.303
    ±
    Notes
    [15] - Data could not be calculated due to no evaluable samples.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Complete Remission (CR) During the First 2 Cycles

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    End point title
    Percentage of Participants with Complete Remission (CR) During the First 2 Cycles
    End point description
    CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    During the first 2 cycles (56 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14, 8, 12,56, 89, 10, 2]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    8.3 (0.2 to 38.5)
    3.6 (0.4 to 12.3)
    3.4 (0.7 to 9.5)
    10 (0.3 to 44.5)
    0 (-99999 to 99999)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    50.0 (1.3 to 98.7)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    6.3 (0.2 to 30.2)
    0 (-99999 to 99999)
    4.2 (0.1 to 21.1)
    2.9 (0.3 to 9.9)
    3.0 (0.6 to 8.5)
    5.0 (0.1 to 24.9)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CR During Treatment

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    End point title
    Percentage of Participants with CR During Treatment
    End point description
    CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14, 8,12, 56, 89, 10, 2]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    16.7 (2.1 to 48.4)
    12.5 (5.2 to 24.1)
    11.2 (5.5 to 19.7)
    10.0 (0.3 to 44.5)
    0 (-99999 to 99999)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    50.0 (1.3 to 98.7)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    6.3 (0.2 to 30.2)
    0 (-99999 to 99999)
    8.3 (1.0 to 27.0)
    10.0 (4.1 to 19.5)
    10.0 (4.9 to 17.6)
    5.0 (0.1 to 24.9)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CR with Incomplete Platelet Recovery (CRp)

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    End point title
    Percentage of Participants with CR with Incomplete Platelet Recovery (CRp)
    End point description
    CRp was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRp when they achieved CR except for incomplete platelet recovery (< 100 x 10^9/L). The analysis population was the full analysis set (FAS), which consisted of all participants who were enrolled, took at least 1 dose of study drug and who had at least 1 posttreatment data point. Re-enrolled participants and participants from one site due to concerns with this site’s GCP compliance were excluded. Participants were summarized under planned reporting groups in the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14, 8, 12,56, 89, 10, 2]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    3.6 (0.4 to 12.3)
    9.0 (4.0 to 16.9)
    10.0 (0.3 to 44.5)
    0 (-99999 to 99999)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    2.9 (0.3 to 9.9)
    8.0 (3.5 to 15.2)
    5.0 (0.1 to 24.9)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CR with Incomplete Hematological Recovery (CRi)

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    End point title
    Percentage of Participants with CR with Incomplete Hematological Recovery (CRi)
    End point description
    CRi was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRi when they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence were not required. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14, 8, 12,56, 89, 10, 2]
    7.1 (0.2 to 33.9)
    0 (-99999 to 99999)
    25.0 (5.5 to 57.2)
    30.4 (18.8 to 44.1)
    20.2 (12.4 to 30.1)
    10.0 (0.3 to 44.5)
    0 (-99999 to 99999)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    16.7 (2.1 to 48.4)
    7.1 (0.2 to 33.9)
    9.1 (0.2 to 41.3)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    6.3 (0.2 to 30.2)
    0 (-99999 to 99999)
    20.8 (7.1 to 42.2)
    25.7 (16.0 to 37.6)
    19.0 (11.8 to 28.1)
    5.0 (0.1 to 24.9)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Complete Remission with Partial Hematologic Recovery (CRh)

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    End point title
    Percentage of Participants with Complete Remission with Partial Hematologic Recovery (CRh)
    End point description
    CRh was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRh when they could not be classified as being in CR and had bone marrow blasts < 5% and partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L. There should not be evidence of extramedullary leukemia. The analysis population was the FAS. CRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    14
    8
    12
    56
    89
    10
    2
    Units: percentage of participants
        number (confidence interval 95%)
    7.1 (0.2 to 33.9)
    0 (-99999 to 99999)
    8.3 (0.2 to 38.5)
    10.7 (4.0 to 21.9)
    7.9 (3.2 to 15.5)
    20.0 (2.5 to 55.6)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Composite CR (CRc)

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    End point title
    Percentage of Participants with Composite CR (CRc)
    End point description
    CRc was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRc when they had achieved either CR, complete remission with incomplete platelet recovery (CRp, defined as had achieved CR except for incomplete platelet recovery (< 100 x 10^9/L) or complete remission with incomplete hematologic recovery (CRi, defined as had fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery; RBC platelet transfusion independence not required). The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14,8, 12, 56, 89, 10, 2]
    7.1 (0.2 to 33.9)
    0 (-99999 to 99999)
    41.7 (15.2 to 72.3)
    46.4 (33.0 to 60.3)
    40.4 (30.2 to 51.4)
    30.0 (6.7 to 65.2)
    0 (-99999 to 99999)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    50.0 (1.3 to 98.7)
    0 (-99999 to 99999)
    16.7 (2.1 to 48.4)
    7.1 (0.2 to 33.9)
    9.1 (0.2 to 41.3)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    12.5 (1.6 to 38.3)
    0 (-99999 to 99999)
    29.2 (12.6 to 51.1)
    38.6 (27.2 to 51.0)
    37.0 (27.6 to 47.2)
    15.0 (3.2 to 37.9)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Partial Remission (PR)

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    End point title
    Percentage of Participants with Partial Remission (PR)
    End point description
    PR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in PR when they had bone marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. A value of less or equal than 5% blasts was also considered a PR if Auer rods were present. There should be no evidence of extramedullary leukemia. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14,8, 12, 56, 89, 10, 2]
    7.1 (0.2 to 33.9)
    37.5 (8.5 to 75.5)
    25.0 (5.5 to 57.2)
    7.1 (2.0 to 17.3)
    7.9 (3.2 to 15.5)
    30.0 (6.7 to 65.2)
    50.0 (1.3 to 98.7)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    7.1 (0.2 to 33.9)
    9.1 (0.2 to 41.3)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    6.3 (0.2 to 30.2)
    18.8 (4.0 to 45.6)
    12.5 (2.7 to 32.4)
    7.1 (2.4 to 15.9)
    8.0 (3.5 to 15.2)
    15.0 (3.2 to 37.9)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Best Response

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    End point title
    Percentage of Participants with Best Response
    End point description
    Best response was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). BR was defined as the best measured response for all visits (in the order of CR, CRp, CRi, and PR) post-treatment. Participants who achieved the best response of CR, CRp, CRi or PR were classified as responders. Participants who did not achieve at least PR were considered as non-responders. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=14,8, 12, 56, 89, 10, 2]
    14.3 (1.8 to 42.8)
    37.5 (8.5 to 75.5)
    66.7 (34.9 to 90.1)
    53.6 (39.7 to 67.0)
    48.3 (37.6 to 59.2)
    60.0 (26.2 to 87.8)
    50.0 (1.3 to 98.7)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    50.0 (1.3 to 98.7)
    0 (-99999 to 99999)
    16.7 (2.1 to 48.4)
    14.3 (1.8 to 42.8)
    18.2 (2.3 to 51.8)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    18.8 (4.0 to 45.6)
    18.8 (4.0 to 45.6)
    41.7 (22.1 to 63.4)
    45.7 (33.7 to 58.1)
    45.0 (35.0 to 55.3)
    30.0 (11.9 to 54.3)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh)

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    End point title
    Percentage of Participants with Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh)
    End point description
    Participants with CR/CRh were defined as participants who achieved either CR or CRh. Participants with CR had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an ANC > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, and normal marrow differential with < 5% blasts, had been RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). Also, there had been no presence of Auer rods, no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Participants with CRh could not be in CR and had bone marrow blasts < 5%, partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L and should not have evidence of extramedullary leukemia. The analysis population was the FAS. CR/CRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    14
    8
    12
    56
    89
    10
    2
    Units: percentage of participants
        number (confidence interval 95%)
    7.1 (0.2 to 33.9)
    0 (-99999 to 99999)
    25.0 (5.5 to 57.2)
    23.2 (13.0 to 36.4)
    19.1 (11.5 to 28.8)
    30.0 (6.7 to 65.2)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of CR (DCR)

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    End point title
    Duration of CR (DCR)
    End point description
    DCR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCR was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [16]
    2
    7
    10
    1
    0 [17]
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=0, 0, 2, 7, 10, 1, 0]
    99999 (99999 to 99999)
    ( to )
    99999 (99999 to 99999)
    99999 (86.0 to 99999)
    419.0 (64.0 to 99999)
    99999 (99999 to 99999)
    ( to )
        FLT3 Mutation Negative [N=1, 0, 0, 0, 0, 0, 0]
    99999 (99999 to 99999)
    ( to )
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=1, 0, 2, 7, 10, 1, 0]
    99999 (99999 to 99999)
    ( to )
    99999 (99999 to 99999)
    99999 (86.0 to 99999)
    419.0 (64.0 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [16] - Data could not be calculated due to low number of events.
    [17] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Duration of CRp (DCRp)

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    End point title
    Duration of CRp (DCRp)
    End point description
    DCRp was defined as the time from the date of first CRp until the date of documented relapse for participants who achieved CRp. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRp were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRp was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    0 [18]
    0 [19]
    1
    6
    12
    2
    0 [20]
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=0, 0, 1, 6, 12, 2, 0]
    ( to )
    ( to )
    99999 (99999 to 99999)
    99999 (57.0 to 99999)
    450.0 (43.0 to 99999)
    99999 (99999 to 99999)
    ( to )
        FLT3 Mutation Negative [N=0, 0, 0, 0, 0, 0, 0]
    ( to )
    ( to )
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=0, 0, 1, 6, 12, 2, 0]
    ( to )
    ( to )
    99999 (99999 to 99999)
    99999 (57.0 to 99999)
    450.0 (43.0 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [18] - Data could not be calculated due to low number of events.
    [19] - Data could not be calculated due to low number of events.
    [20] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Duration of CRi (DCRi)

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    End point title
    Duration of CRi (DCRi)
    End point description
    DCRi was defined as the time from the date of first CRi until the date of documented relapse for participants who achieved CRi. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRi were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRi was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [21]
    7
    24
    31
    1
    0 [22]
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=1, 0, 5, 23, 30, 1, 0]
    99999 (99999 to 99999)
    ( to )
    99999 (79.0 to 99999)
    120.0 (56.0 to 383.0)
    191.0 (57.0 to 420.0)
    99999 (99999 to 99999)
    ( to )
        FLT3 Mutation Negative [N=0, 0, 2, 1, 0, 0, 0]
    99999 (99999 to 99999)
    ( to )
    41.0 (22.0 to 60.0)
    99.0 (-99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=1, 0, 7, 24, 31, 1, 0]
    99999 (99999 to 99999)
    ( to )
    79.0 (22.0 to 99999)
    120.0 (58.0 to 383.0)
    191.0 (57.0 to 420.0)
    99999 (99999 to 99999)
    ( to )
    Notes
    [21] - Data could not be calculated due to low number of events.
    [22] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Duration of CRh (DCRh)

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    End point title
    Duration of CRh (DCRh)
    End point description
    DCRh was defined as the time from the date of first CRh until the date of documented relapse for participants who achieved CRh but did not have a best response of CR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date.The analysis population was the FAS. Only participants who achieved CRh were included in the analysis. DCRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRh was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [23]
    1
    6
    7
    2
    0 [24]
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    ( to )
    99999 (99999 to 99999)
    64.0 (18.0 to 85.0)
    101.0 (29.0 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [23] - Data could not be calculated due to low number of events.
    [24] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Duration of CRc (DCRc)

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    End point title
    Duration of CRc (DCRc)
    End point description
    DCRc was defined as the time from the date of first CRc until the date of documented relapse for participants who achieved CRc. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRc were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRc was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    2
    0 [25]
    7
    27
    37
    3
    0 [26]
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=1, 0, 5, 26, 36, 3, 0]
    99999 (99999 to 99999)
    ( to )
    99999 (79.0 to 99999)
    98.0 (57.0 to 307.0)
    191.0 (101.0 to 465.0)
    99999 (99999 to 99999)
    ( to )
        FLT3 Mutation Negative [N=1, 0, 2, 1, 1, 0, 0]
    99999 (99999 to 99999)
    ( to )
    41.0 (22.0 to 60.0)
    99.0 (-99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=2, 0, 7, 27, 37, 3, 0]
    99999 (99999 to 99999)
    ( to )
    79.0 (22.0 to 99999)
    98.0 (58.0 to 307.0)
    191.0 (101.0 to 465.0)
    99999 (99999 to 99999)
    ( to )
    Notes
    [25] - Data could not be calculated due to low number of events.
    [26] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Duration of CR/CRh (DCRCRh)

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    End point title
    Duration of CR/CRh (DCRCRh)
    End point description
    DCRCRh was defined as the time from the date of first DCRCRh until the date of documented relapse for participants who achieved CR or CRh. For participants who achieved both CR and CRh, the first CR date or CRh date, whichever occurred first, was used. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis. DCRCRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "+/99999." DCRCRh was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [27]
    3
    13
    17
    3
    0 [28]
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    ( to )
    99999 (99999 to 99999)
    307.0 (56.0 to 99999)
    308.0 (101.0 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [27] - Data could not be calculated due to low number of events.
    [28] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse of any type for participants who achieved CRc or PR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." Duration of response was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    3
    3
    10
    32
    45
    6
    1
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=2, 3, 8, 30, 43, 6, 1]
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    88.0 (9.0 to 99999)
    141.0 (58.0 to 383.0)
    220.0 (111.0 to 482.0)
    59.0 (15.0 to 59.0)
    99999 (99999 to 99999)
        FLT3 Mutation Negative [N=1, 0, 2, 2, 2, 0, 0]
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    41.0 (22.0 to 60.0)
    109.5 (99.0 to 120.0)
    85.0 (-99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        All Participants [N=3, 3, 10, 32, 45, 6, 1]
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    79.0 (9.0 to 99999)
    126.0 (58.0 to 307.0)
    220.0 (85.0 to 482.0)
    59.0 (15.0 to 59.0)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to CR (TTCR)

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    End point title
    Time to CR (TTCR)
    End point description
    TTCR was defined as the time from the first dose of study drug until the date of first CR. The analysis population was the FAS. Only participants who achieved CR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [29]
    2
    7
    10
    1
    0 [30]
    Units: days
    median (full range (min-max))
        FLT3 Mutation Positive [N=0, 0, 2, 7, 10, 1, 0]
    99999 (99999 to 99999)
    ( to )
    171.5 (28 to 315)
    141.0 (29 to 364)
    93.0 (27 to 225)
    56.0 (56 to 56)
    ( to )
        FLT3 Mutation Negative [N=1, 0, 0, 0, 0, 0, 0]
    30.0 (30 to 30)
    ( to )
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=1, 0, 2, 7, 10, 1, 0]
    30.0 (30 to 30)
    ( to )
    171.5 (28 to 315)
    141.0 (29 to 364)
    93.0 (27 to 225)
    56.0 (56 to 56)
    ( to )
    Notes
    [29] - Data could not be calculated due to low number of events.
    [30] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Time to CRp (TTCRp)

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    End point title
    Time to CRp (TTCRp)
    End point description
    TTCRp was defined as the time from the first dose of study drug until the date of first CRp. TTCRp was evaluated for participants who achieved CRp. The analysis population was the FAS. Only participants who achieved CRp were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    0 [31]
    0 [32]
    1
    6
    12
    2
    0 [33]
    Units: days
    median (full range (min-max))
        FLT3 Mutation Positive [N=0, 0, 1, 6, 12, 2, 0]
    ( to )
    ( to )
    140.0 (140 to 140)
    195.0 (30 to 418)
    84.5 (28 to 392)
    29.0 (28 to 30)
    ( to )
        FLT3 Mutation Negative [N=0, 0, 0, 0, 0, 0, 0]
    ( to )
    ( to )
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=0, 0, 1, 6, 12, 2, 0]
    ( to )
    ( to )
    140.0 (140 to 140)
    195.0 (30 to 418)
    84.5 (28 to 392)
    29.0 (28 to 30)
    ( to )
    Notes
    [31] - Data could not be calculated due to low number of events.
    [32] - Data could not be calculated due to low number of events.
    [33] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Time to CRi (TTCRi)

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    End point title
    Time to CRi (TTCRi)
    End point description
    TTCRi was defined as the time from the first dose of study drug until the date of first CRi. TTCRi was evaluated for participants who achieved CRi. The analysis population was the FAS. Only participants who achieved CRi were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [34]
    7
    24
    31
    1
    0 [35]
    Units: days
    median (full range (min-max))
        FLT3 Mutation Positive [N=1, 0, 5, 23, 30, 1, 0]
    57.0 (57 to 57)
    ( to )
    57.0 (31 to 70)
    57.0 (26 to 170)
    39.5 (26 to 133)
    28.0 (28 to 28)
    ( to )
        FLT3 Mutation Negative [N=0, 0, 2, 1, 1, 0, 0]
    99999 (99999 to 99999)
    ( to )
    71.5 (71 to 72)
    30.0 (30 to 30)
    30.0 (30 to 30)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=1, 0, 7, 24, 31, 1, 0]
    57.0 (57 to 57)
    ( to )
    64.0 (31 to 72)
    43.5 (26 to 170)
    35.0 (26 to 133)
    28.0 (28 to 28)
    ( to )
    Notes
    [34] - Data could not be calculated due to low number of events.
    [35] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Time to First CR/CRh (TTFCRCRh)

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    End point title
    Time to First CR/CRh (TTFCRCRh)
    End point description
    TTFCRCRh was defined as the time from the first dose of study drug until the date of first either CR or CRh. TTFCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date or CRh date, whichever occurs first was used. The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis. TTFCRCRh was calculated only for participants who were FLT3 mutation positive.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [36]
    3
    13
    17
    3
    0 [37]
    Units: days
        median (full range (min-max))
    57.0 (57 to 57)
    ( to )
    57.0 (28 to 140)
    59.0 (29 to 280)
    57.0 (27 to 245)
    28.0 (28 to 30)
    ( to )
    Notes
    [36] - Data could not be calculated due to low number of events.
    [37] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Time to Best CR/CRh (TTBCRCRh)

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    End point title
    Time to Best CR/CRh (TTBCRCRh)
    End point description
    TTBCRCRh was defined as the time from the first dose of study drug until the first date that the best response of CR or CRh was achieved. TTBCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date was used. The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis. TTBCRCRh was calculated only for participants who were FLT3 mutation positive.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    1
    0 [38]
    3
    13
    17
    3
    0 [39]
    Units: days
        median (full range (min-max))
    57.0 (57 to 57)
    ( to )
    57.0 (28 to 315)
    63.0 (29 to 364)
    88.0 (27 to 245)
    30.0 (28 to 56)
    ( to )
    Notes
    [38] - Data could not be calculated due to low number of events.
    [39] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Time to CRc (TTCRc)

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    End point title
    Time to CRc (TTCRc)
    End point description
    TTCRc was defined as the time from the first dose of study drug until the date of first CRc. TTCRc was evaluated for participants who achieved CRc. The analysis population was the FAS. Only participants who achieved CRc were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    2
    0 [40]
    7
    27
    37
    3
    0 [41]
    Units: days
    median (full range (min-max))
        FLT3 Mutation Positive [N=1, 0, 5, 26, 36, 3, 0]
    57.0 (57 to 57)
    ( to )
    56.0 (28 to 64)
    30.0 (26 to 211)
    31.5 (26 to 197)
    28.0 (28 to 30)
    ( to )
        FLT3 Mutation Negative [N=1, 0, 2, 1, 1, 0, 0]
    30.0 (30 to 30)
    ( to )
    71.5 (71 to 72)
    30.0 (30 to 30)
    30.0 (30 to 30)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=2, 0, 7, 27, 37, 3, 0]
    43.5 (30 to 57)
    ( to )
    57.0 (28 to 72)
    30.0 (26 to 211)
    31.0 (26 to 197)
    28.0 (28 to 30)
    ( to )
    Notes
    [40] - Data could not be calculated due to low number of events
    [41] - Data could not be calculated due to low number of events
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    Time to Response (TTR)
    End point description
    TTR was defined as the time from the first dose of study drug until the date of either first CRc or PR. TTR was evaluated for participants who achieved CRc or PR. The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    3
    3
    10
    32
    45
    6
    1
    Units: days
    median (full range (min-max))
        FLT3 Mutation Positive [N=2, 3, 8, 30, 43, 6, 1]
    61.5 (29 to 94)
    57.0 (31 to 64)
    31.0 (28 to 59)
    29.0 (26 to 211)
    29.0 (26 to 197)
    28.0 (26 to 61)
    31.0 (31 to 31)
        FLT3 Mutation Negative [N=1, 0, 2, 2, 2, 0, 0]
    30.0 (30 to 30)
    99999 (99999 to 99999)
    71.5 (71 to 72)
    29.5 (29 to 30)
    29.5 (29 to 30)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        All Participants [N=3, 3, 10, 32, 45, 6, 1]
    30.0 (29 to 94)
    57.0 (31 to 64)
    43.5 (28 to 72)
    29.0 (26 to 211)
    29.0 (26 to 197)
    28.0 (26 to 61)
    31.0 (31 to 31)
    No statistical analyses for this end point

    Secondary: Time to Best Response (TTBR)

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    End point title
    Time to Best Response (TTBR)
    End point description
    TTBR was defined as the time from the first dose of study drug until the first disease assessment date when participant achieved best response. TTBR was evaluated in participants who achieved best response of CR, CRp, CRi, or PR. The analysis population was the FAS. Only participants who achieved CR, CRp, CRi, or PR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    3
    3
    10
    32
    45
    6
    1
    Units: days
    median (full range (min-max))
        FLT3 Mutation Positive [N=2, 3, 8, 30, 43, 6, 1]
    75.5 (57 to 94)
    57.0 (31 to 64)
    44.0 (28 to 315)
    43.5 (26 to 364)
    57.0 (26 to 245)
    29.0 (26 to 61)
    31.0 (31 to 31)
        FLT3 Mutation Negative [N=1, 0, 2, 2, 2, 0, 0]
    30.0 (30 to 30)
    99999 (99999 to 99999)
    71.5 (71 to 72)
    29.5 (29 to 30)
    29.5 (29 to 30)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        All Participants [N=3, 3, 10, 32, 45, 6, 1]
    57.0 (30 to 94)
    57.0 (31 to 64)
    58.0 (28 to 315)
    30.0 (26 to 364)
    56.0 (26 to 245)
    29.0 (26 to 61)
    31.0 (31 to 31)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from the date of first dose of study drug until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999." OS was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=14, 8, 12, 56, 89,10, 2]
    123.0 (17.0 to 267.0)
    199.5 (56.0 to 905.0)
    197.5 (61.0 to 329.0)
    246.0 (190.0 to 309.0)
    214.0 (126.0 to 264.0)
    157.0 (20.0 to 218.0)
    204.0 (51.0 to 357.0)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    99999 (227.0 to 99999)
    71.5 (5.0 to 180.0)
    136.0 (14.0 to 314.0)
    144.0 (83.0 to 195.0)
    67.0 (21.0 to 336.0)
    68.0 (8.0 to 249.0)
    89.0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    149.5 (31.0 to 267.0)
    95.0 (55.0 to 195.0)
    154.0 (74.0 to 299.0)
    216.0 (161.0 to 285.0)
    176.0 (124.0 to 253.0)
    128.5 (36.0 to 199.0)
    89.0 (51.0 to 357.0)
    No statistical analyses for this end point

    Secondary: Event Free Survival (EFS)

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    End point title
    Event Free Survival (EFS)
    End point description
    EFS was defined as the time from the date of first dose of study drug until the date of documented relapse, treatment failure or death from any cause, whichever occurred first. For a participant with none of these events, EFS was censored at the date of last relapse-free disease assessment. A participant without post-treatment disease assessment was censored at randomization date. Treatment failure included those participants who discontinued the treatment due to “progressive disease” or “lack of efficacy" without a previous response of CR, CRp, CRi or PR. Treatment failure date referred to the start of new anti-leukemia therapy or the last treatment evaluation date when new anti-leukemia therapy date was not available. For participants who were censored, last relapse-free disease assessment date referred to the participant’s last disease assessment date. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    16
    16
    24
    70
    100
    20
    3
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=14, 8, 12, 56, 89,10, 2]
    52.0 (14.0 to 88.0)
    109.0 (29.0 to 357.0)
    93.5 (61.0 to 127.0)
    112.0 (92.0 to 143.0)
    121.0 (92.0 to 155.0)
    85.0 (11.0 to 157.0)
    86.0 (51.0 to 121.0)
        FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]
    58.0 (-99999 to 99999)
    39.0 (5.0 to 67.0)
    74.0 (12.0 to 131.0)
    85.5 (37.0 to 126.0)
    45.0 (21.0 to 113.0)
    43.0 (8.0 to 83.0)
    71.0 (-99999 to 99999)
        All Participants [N=16, 16, 24, 70, 100, 20, 3]
    58.0 (19.0 to 88.0)
    55.5 (38.0 to 92.0)
    76.0 (61.0 to 119.0)
    108.0 (90.0 to 126.0)
    118.0 (88.0 to 140.0)
    65.0 (20.0 to 100.0)
    71.0 (51.0 to 121.0)
    No statistical analyses for this end point

    Secondary: Leukemia Free Survival (LFS)

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    End point title
    Leukemia Free Survival (LFS)
    End point description
    LFS was defined as the time from the date of first CRc until the date of documented relapse or death for participants who achieved CRc. For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRc were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." LFS was calculated using Kaplan-Meier method and therefore data are estimated.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    2
    0 [42]
    7
    27
    37
    3
    0 [43]
    Units: days
    median (confidence interval 95%)
        FLT3 Mutation Positive [N=1, 0, 5, 26, 36, 3, 0]
    242.0 (-99999 to 99999)
    ( to )
    98.0 (56.0 to 1126.0)
    98.0 (58.0 to 187.0)
    146.0 (47.0 to 247.0)
    296.0 (130.0 to 462.0)
    ( to )
        FLT3 Mutation Negative [N=1, 0, 2, 1, 1, 0, 0]
    99999 (99999 to 99999)
    ( to )
    41.0 (22.0 to 60.0)
    99.0 (-99999 to 99999)
    38.0 (-99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        All Participants [N=2, 0, 7, 27, 37, 3, 0]
    242.0 (-99999 to 99999)
    ( to )
    79.0 (22.0 to 1126.0)
    98.0 (58.0 to 187.0)
    146.0 (45.0 to 247.0)
    296.0 (130.0 to 462.0)
    ( to )
    Notes
    [42] - Data could not be calculated due to low number of events.
    [43] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved Transfusion Conversion

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    End point title
    Percentage of Participants Who Achieved Transfusion Conversion
    End point description
    Participants who achieved transfusion conversion were defined as participants who were transfusion dependent at baseline period but became transfusion independent at postbaseline period against participants who were transfusion dependent at baseline period. Participants were considered baseline transfusion dependent if there were RBC or platelet transfusions within the baseline period. Participants were considered postbaseline transfusion independent if they were on treatment >=84 days, and if there was one consecutive 56 days without any RBC or platelet transfusion within postbaseline period. If participants were on treatment >28 days but <84 days, and there was no RBC or platelet transfusion within postbaseline period, or on treatment <=28 days, postbaseline transfusion status was not evaluable. FAS, with participants who were was transfusion dependent at baseline & had evaluable postbaseline transfusion status. Data could not be calculated due to low number of events "+/-99999."
    End point type
    Secondary
    End point timeframe
    Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    7
    8
    16
    49
    63
    8
    2
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=6, 5, 8, 40, 57, 4, 1]
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    37.5 (8.5 to 75.5)
    27.5 (14.6 to 43.9)
    40.4 (27.6 to 54.2)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        FLT3 Mutation Negative [N=1, 3, 8, 9, 6, 4, 1]
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.5 (0.3 to 52.7)
    22.2 (2.8 to 60.0)
    33.3 (4.3 to 77.7)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        All Participants [N=7, 8, 16, 49, 63, 8, 2]
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    25.0 (7.3 to 52.4)
    26.5 (14.9 to 41.1)
    39.7 (27.6 to 52.8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved Transfusion Maintenance

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    End point title
    Percentage of Participants Who Achieved Transfusion Maintenance
    End point description
    Participants who achieved transfusion maintenance were defined as participants who were transfusion independent at baseline period and still maintained transfusion independent at postbaseline period against participants who were transfusion independent at baseline period. FAS, with participants who was transfusion independent at baseline and had evaluable postbaseline transfusion status. Data could not be calculated due to low number of events, and is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days
    End point values
    Gilteritinib 20 mg Gilteritinib 40 mg Gilteritinib 80 mg Gilteritinib 120 mg Gilteritinib 200 mg Gilteritinib 300 mg Gilteritinib 450 mg
    Number of subjects analysed
    0 [44]
    0 [45]
    1
    7
    10
    0 [46]
    1
    Units: percentage of participants
    number (confidence interval 95%)
        FLT3 Mutation Positive [N=0, 0, 1, 4, 10, 0, 1]
    ( to )
    ( to )
    100.0 (2.5 to 100.0)
    75.0 (19.4 to 99.4)
    80.0 (44.4 to 97.5)
    ( to )
    100.0 (2.5 to 100)
        FLT3 Mutation Negative [N=0, 0, 0, 3, 0, 0, 0]
    ( to )
    ( to )
    99999 (99999 to 99999)
    33.3 (0.8 to 90.6)
    99999 (99999 to 99999)
    ( to )
    99999 (99999 to 99999)
        All Participants [N=0, 0, 1, 7, 10, 0, 1]
    ( to )
    ( to )
    100.0 (2.5 to 100.0)
    57.1 (18.4 to 90.1)
    80.0 (44.4 to 97.5)
    ( to )
    100.0 (2.5 to 100.0)
    Notes
    [44] - Data could not be calculated due to low number of events.
    [45] - Data could not be calculated due to low number of events.
    [46] - Data could not be calculated due to low number of events.
    No statistical analyses for this end point

    Secondary: AUC24 of Gilteritinib in Co-administration with Voriconazole

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    End point title
    AUC24 of Gilteritinib in Co-administration with Voriconazole [47]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole. Data that could not be calculated due to a sample size of 1 is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Expansion Phase
    Number of subjects analysed
    1
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Cycle 2 day 1
    919.3 ± 99999
    No statistical analyses for this end point

    Secondary: Cmax of Gilteritinib in Co-administration with Voriconazole

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    End point title
    Cmax of Gilteritinib in Co-administration with Voriconazole [48]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole. Data that could not be calculated due to a sample size of 1 is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Expansion Phase
    Number of subjects analysed
    1
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 2 day 1
    63.79 ± 99999
    No statistical analyses for this end point

    Secondary: AUClast of Gilteritinib in Co-administration with Voriconazole

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    End point title
    AUClast of Gilteritinib in Co-administration with Voriconazole [49]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole. Data that could not be calculated due to a sample size of 1 is denoted as "+/-99999."
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Expansion Phase
    Number of subjects analysed
    1
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Cycle 2 day 1
    919.3 ± 99999
    No statistical analyses for this end point

    Secondary: Tmax of Gilteritinib in Co-administration with Voriconazole

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    End point title
    Tmax of Gilteritinib in Co-administration with Voriconazole [50]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.
    End point values
    Gilteritinib 20 mg in Expansion Phase
    Number of subjects analysed
    1
    Units: hours
    median (full range (min-max))
        Cycle 2 day 1
    2.08 (2.08 to 2.08)
    No statistical analyses for this end point

    Secondary: AUC24 of Midazolam Administered With and Without Gilteritinib

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    End point title
    AUC24 of Midazolam Administered With and Without Gilteritinib [51]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Midazolam Alone (Day -1) [N=15]
    66.55 ± 57.70
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=8]
    81.56 ± 65.84
    No statistical analyses for this end point

    Secondary: AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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    End point title
    AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [52]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Midazolam Alone (Day -1) [N=15]
    20.44 ± 24.80
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=8]
    23.10 ± 21.64
    No statistical analyses for this end point

    Secondary: Cmax of Midazolam Administered With and Without Gilteritinib

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    End point title
    Cmax of Midazolam Administered With and Without Gilteritinib [53]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: ng/mL
    arithmetic mean (standard deviation)
        Midazolam Alone (Day -1) [N=16]
    14.68 ± 8.923
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]
    18.45 ± 9.452
    No statistical analyses for this end point

    Secondary: Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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    End point title
    Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [54]
    End point description
    Plasma samples were used for pharmacokinetic assessments.The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: ng/mL
    arithmetic mean (standard deviation)
        Midazolam Alone (Day -1) [N=16]
    4.562 ± 2.858
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]
    5.053 ± 3.158
    No statistical analyses for this end point

    Secondary: AUClast of Midazolam Administered With and Without Gilteritinib

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    End point title
    AUClast of Midazolam Administered With and Without Gilteritinib [55]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Midazolam Alone (Day -1) [N=16]
    59.48 ± 59.49
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]
    82.44 ± 64.25
    No statistical analyses for this end point

    Secondary: AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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    End point title
    AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [56]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Midazolam Alone (Day -1) [N=16]
    17.05 ± 24.70
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]
    23.58 ± 22.07
    No statistical analyses for this end point

    Secondary: Tmax of Midazolam Administered With and Without Gilteritinib

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    End point title
    Tmax of Midazolam Administered With and Without Gilteritinib [57]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: hours
    median (full range (min-max))
        Midazolam Alone (Day -1) [N=16]
    0.5000 (0.367 to 2.00)
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]
    1.00 (0.317 to 4.13)
    No statistical analyses for this end point

    Secondary: Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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    End point title
    Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [58]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.
    End point values
    Gilteritinib 300 mg in Expansion Phase
    Number of subjects analysed
    16
    Units: hours
    median (full range (min-max))
        Midazolam Alone (Day -1) [N=16]
    0.5583 (0.483 to 2.00)
        Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]
    1.00 (0.317 to 4.13)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib [59]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=18]
    57650 ± 20386
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=13]
    51873 ± 18819
    No statistical analyses for this end point

    Secondary: Cmax of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Cmax of Cephalexin Administered With and Without Gilteritinib [60]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=20]
    17688 ± 6680
        Cephalexin + Gilteritinib (Cycle 1 day 15) [N=16]
    16075 ± 4606
    No statistical analyses for this end point

    Secondary: AUClast of Cephalexin Administered With and Without Gilteritinib

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    End point title
    AUClast of Cephalexin Administered With and Without Gilteritinib [61]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=20]
    53183 ± 26877
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=16]
    54963 ± 29531
    No statistical analyses for this end point

    Secondary: Tmax of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Tmax of Cephalexin Administered With and Without Gilteritinib [62]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: hours
    median (full range (min-max))
        Cephalexin Alone (Day -1) [N=20]
    1.500 (1.00 to 4.02)
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=16]
    1.483 (1.00 to 5.88)
    No statistical analyses for this end point

    Secondary: T1/2 of Cephalexin Administered With and Without Gilteritinib

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    End point title
    T1/2 of Cephalexin Administered With and Without Gilteritinib [63]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: hours
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=20]
    1.822 ± 0.5914
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=16]
    1.827 ± 0.7175
    No statistical analyses for this end point

    Secondary: Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib [64]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: L/h
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=18]
    9.713 ± 3.319
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=13]
    10.58 ± 2.977
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib [65]
    End point description
    Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
    Notes
    [65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: liters
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=18]
    24.07 ± 7.173
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=13]
    25.86 ± 5.346
    No statistical analyses for this end point

    Secondary: Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib [66]
    End point description
    Urine samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: mg
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=13]
    548.9 ± 523.7
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=10]
    448.8 ± 306.1
    No statistical analyses for this end point

    Secondary: Fraction of Drug Excreted into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib

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    End point title
    Fraction of Drug Excreted into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib [67]
    End point description
    Urine samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: percentage
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=13]
    109.8 ± 104.7
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=10]
    89.75 ± 61.21
    No statistical analyses for this end point

    Secondary: Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib

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    End point title
    Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib [68]
    End point description
    Urine samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.
    End point type
    Secondary
    End point timeframe
    Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.
    End point values
    Gilteritinib 200 mg in Expansion Phase
    Number of subjects analysed
    20
    Units: L/h
    arithmetic mean (standard deviation)
        Cephalexin Alone (Day -1) [N=13]
    8.784 ± 8.727
        Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=6]
    11.04 ± 8.430
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
    Adverse event reporting additional description
    The analysis population was the safety analysis set (SAF), which consisted of all participants who received at least 1 dose of study drug and excluded re-enrolled participants. The total number of deaths (all causes) includes deaths reported after the time frame above.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Gilterinib 20 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 40 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 120 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 80 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 200 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 300 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 450 mg in Escalation Phase
    Reporting group description
    Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

    Reporting group title
    Gilterinib 20 mg in Expansion Phase
    Reporting group description
    Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.

    Reporting group title
    Gilterinib 40 mg in Expansion Phase
    Reporting group description
    Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilterinib 80 mg in Expansion Phase
    Reporting group description
    Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilterinib 200 mg in Expansion Phase
    Reporting group description
    Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.

    Reporting group title
    Gilterinib 120 mg in Expansion Phase
    Reporting group description
    Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

    Reporting group title
    Gilterinib 300 mg in Expansion Phase
    Reporting group description
    Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.

    Serious adverse events
    Gilterinib 20 mg in Escalation Phase Gilterinib 40 mg in Escalation Phase Gilterinib 120 mg in Escalation Phase Gilterinib 80 mg in Escalation Phase Gilterinib 200 mg in Escalation Phase Gilterinib 300 mg in Escalation Phase Gilterinib 450 mg in Escalation Phase Gilterinib 20 mg in Expansion Phase Gilterinib 40 mg in Expansion Phase Gilterinib 80 mg in Expansion Phase Gilterinib 200 mg in Expansion Phase Gilterinib 120 mg in Expansion Phase Gilterinib 300 mg in Expansion Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    8 / 12 (66.67%)
    12 / 13 (92.31%)
    19 / 21 (90.48%)
    92 / 100 (92.00%)
    52 / 66 (78.79%)
    14 / 17 (82.35%)
         number of deaths (all causes)
    4
    2
    3
    3
    2
    3
    3
    10
    13
    21
    82
    53
    16
         number of deaths resulting from adverse events
    2
    2
    1
    0
    1
    1
    1
    3
    4
    11
    49
    23
    7
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    1 / 66 (1.52%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    4 / 100 (4.00%)
    3 / 66 (4.55%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    2 / 4
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis deep
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    3 / 13 (23.08%)
    5 / 21 (23.81%)
    20 / 100 (20.00%)
    9 / 66 (13.64%)
    4 / 17 (23.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
    0 / 8
    0 / 25
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
    0 / 5
    0 / 16
    0 / 9
    0 / 4
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system leukaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    2 / 66 (3.03%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    2 / 100 (2.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute graft versus host disease in intestine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute graft versus host disease in skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    3 / 100 (3.00%)
    1 / 66 (1.52%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    1 / 66 (1.52%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic graft versus host disease in skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft versus host disease in skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    2 / 66 (3.03%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    2 / 66 (3.03%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 21 (0.00%)
    4 / 100 (4.00%)
    1 / 66 (1.52%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 6
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    9 / 100 (9.00%)
    9 / 66 (13.64%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 13
    1 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    2 / 100 (2.00%)
    2 / 66 (3.03%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 21 (0.00%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 21 (4.76%)
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage