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    Clinical Trial Results:
    A Phase 2 Multicenter, Randomized, Double-Blind, Placebo Controlled Trial of the FLT3 Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects with FLT3/ITD AML in First Complete Remission

    Summary
    EudraCT number
    		 2016-001643-39
    Trial protocol
    		 HU   ES   CZ   PL   PT   SE   GR   DK   HR   FR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    04 May 2022
    First version publication date
    04 May 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    2215-CL-0302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02927262
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical trial Disclosure, Astellas Pharma Global Development, Inc, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical trial Disclosure, Astellas Pharma Global Development, Inc, 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
    Interim
    Date of interim/final analysis
    25 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 May 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Main objective of the trial: The primary objective of this study was to compare RFS between participants with FMS-like tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) without transplant and who were randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a 2-year period.
    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
    10 Jan 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 18
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    98
    EEA total number of subjects
    42
    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)
    53
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult participants diagnosed with FLT3/ITD AML in first CR1, including complete remission with incomplete platelet recovery (CRp) and complete remission with incomplete hematologic recovery (CRi) for whom a decision not to proceed with transplantation was made, or a suitable donor could not be identified, were enrolled in this study

    Pre-assignment
    Screening details
    		 Randomization was stratified based on: Age (<60 or ≥60 years), Geographic region (North America or Europe or Rest of the world), Presence of MRD at screening (yes or no), Use of FLT3-inhibiting agents during induction/consolidation (yes or no).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gilteritinib
    Arm description
    		 Participants received gilteritinib 120 milligrams (mg) (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-specified discontinuation criterion was met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gilteritinib
    Investigational medicinal product code
    Other name
    ASP2215
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib 120 mg (three tablets of 40 mg) orally, QD for up to 2 years or until a discontinuation criterion was met.

    Arm title
    		 Placebo
    Arm description
    		 Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-specified discontinuation criterion was met.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a discontinuation criterion was met.

    Number of subjects in period 1
    		Gilteritinib Placebo
    Started
    63
    35
    Completed
    20
    12
    Not completed
    43
    23
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    3
    -
         Disease Relapse
    23
    18
         Adverse event, non-fatal
    7
    1
         Miscellaneous
    5
    4
         Ongoing
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gilteritinib
    Reporting group description
    		 Participants received gilteritinib 120 milligrams (mg) (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-specified discontinuation criterion was met.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-specified discontinuation criterion was met.

    Reporting group values
    		 Gilteritinib Placebo Total
    Number of subjects
    		 63 35 98
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.4 ± 11.0 59.9 ± 13.9 -
    Sex: Female, Male
    Units: Participants
        Female
    		 31 20 51
        Male
    		 32 15 47
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 17 10 27
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 38 22 60
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 8 3 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 3 9
        Not Hispanic or Latino
    		 50 29 79
        Unknown or Not Reported
    		 7 3 10
    Age (<60 or ≥60 years)
    Units: Subjects
        < 60 years
    		 24 13 37
        ≥ 60 years
    		 39 22 61
    Geographic Region
    Geographical region was categorized as Europe, North America and Rest of the World.
    Units: Subjects
        North America
    		 5 4 9
        Europe
    		 40 20 60
        Rest of the world
    		 18 11 29
    Presence of MRD
    Presence of MRD (yes/no) at screening per interatcive response technology (IRT) at randomization was reported. The presence of MRD will be “Yes” if log10-transformed overall FLT3/ITD mutation ratio was greater than -4
    Units: Subjects
        MRD = Yes
    		 8 6 14
        MRD = No
    		 55 29 84
    Use of FLT3-inhibitors
    Use of FLT3 inhibitor (yes/no) during induction/consolidation per IRT at randomization was reported.
    Units: Subjects
        Use of FLT3 Inhibitor = Yes
    		 12 10 22
        Use of FLT3 Inhibitor = No
    		 51 25 76

    End points

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    End points reporting groups
    Reporting group title
    Gilteritinib
    Reporting group description
    		 Participants received gilteritinib 120 milligrams (mg) (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-specified discontinuation criterion was met.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-specified discontinuation criterion was met.

    Primary: Relapse-free Survival (RFS) per Independent Review Committee (IRC) Adjudication

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    End point title
    		 Relapse-free Survival (RFS) per Independent Review Committee (IRC) Adjudication
    End point description
    RFS was defined as time from the date of randomization until the date of documented relapse or death from any cause, whichever occurred first. Relapse after complete remission (CR) [including complete remission with incomplete platelet recovery (CRp) & Complete remission with incomplete hematologic recovery (CRi)], was defined as bone marrow blasts 5% or higher (not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary blast foci as per Revised International Working Group (IWG) criteria. Participants were classified as: CRi, if they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 × 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence was not required. CRp, if they achieved CR except for incomplete platelet recovery (< 100 × 10^9/L). RFS was estimated using Kaplan-Meier estimates. 99999 denotes upper limit was not estimable due to low number of events.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of documented relapse, or death; (Median time on study drug was 427 days for gilteritinib group and 212 days for placebo group) The full analysis set (FAS) consisted of all participants who were randomized.
    End point values
    		 Gilteritinib Placebo
    Number of subjects analysed
    63
    35
    Units: Months
        median (confidence interval 95%)
    24.02 (14.06 to 99999)
    15.84 (3.02 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Gilteritinib
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.163 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.738
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.407
         upper limit
    		 1.336
    Notes
    [1] - Hazard ratio (HR), Cox proportional hazards model (CHM)
    [2] - HR & 95% CI are based on CHM. Assuming proportional hazards, HR < 1 indicates a reduction in hazard rate in favor of gilteritinib arm. Stratification factors:age, geographic region, presence of MRD at screening, use of FLT3 inhibiting agents per IRT.

    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 randomization until the date of death from any cause. OS was estimated using Kaplan-Meiers method. Analysis Population: FAS Population 99999 denotes median and upper limit were not estimable due to low number of events.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death from any cause; (Median time on study drug was 427 days for gilteritinib group and 212 days for placebo group)
    End point values
    		 Gilteritinib Placebo
    Number of subjects analysed
    63
    35
    Units: Months
        median (confidence interval 95%)
    99999 (30.42 to 99999)
    99999 (43.56 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Gilteritinib v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.627 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 2.364
    Notes
    [3] - HR & 95%CI are based on CHM. Assuming proportional hazards, HR < 1 indicates a reduction in hazard rate in favor of gilteritinib arm. Stratification factors:age, geographic region, presence of MRD at screening, use of FLT3 inhibiting agents per IRT.

    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 randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause, whichever occurred first. Relapse after CR (including CRp and CRi), was defined as bone marrow blasts 5% or higher (not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary blast foci as per Revised IWG criteria. Participants were classified as: CRi, if they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 × 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence was not required. CRp, if they achieved CR except for incomplete platelet recovery (< 100 × 10^9/L). EFS was estimated using Kaplan-Meier's method. Analysis Population: FAS Population
    End point type
    Secondary
    End point timeframe
    From date of randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause; (Median time on study drug was 427 days for gilteritinib and 212 days for placebo)
    End point values
    		 Gilteritinib Placebo
    Number of subjects analysed
    63
    35
    Units: Months
        median (confidence interval 95%)
    14.06 (9.89 to 23.72)
    6.74 (2.86 to 21.95)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Gilteritinib v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.296 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.862
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.455
    Notes
    [4] - HR & 95%CI are based on CHM. Assuming proportional hazards, HR < 1 indicates a reduction in hazard rate in favor of gilteritinib arm. Stratification factors: age, geographic region, presence of MRD at screening, use of FLT3 inhibiting agents per IRT.

    Secondary: Change from Baseline in Quantitative Minimal Residual Disease Measured as Log10-transformed Overall FLT3/ITD Mutation Ratio at Months 3, 6, 12, 24/End of Treatment (EoT)

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    End point title
    		 Change from Baseline in Quantitative Minimal Residual Disease Measured as Log10-transformed Overall FLT3/ITD Mutation Ratio at Months 3, 6, 12, 24/End of Treatment (EoT)
    End point description
    MRD was measured from bone marrow samples. FLT3/ITD mutation ratio was measured in relation to total FLT3. For a participant with multiple ITD mutations, the overall FLT3/ITD mutation ratio was calculated from the sum of all ITD mutations. Analysis Population: FAS population with available data at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline and months 3, 6, 12, 24/EoT
    End point values
    		 Gilteritinib Placebo
    Number of subjects analysed
    48
    22
    Units: Ratio
    arithmetic mean (standard deviation)
        Month 3 (n = 48, 22)
    0.14 ± 0.96
    0.14 ± 1.46
        Month 6 (n = 44, 17)
    0.07 ± 0.92
    -0.17 ± 0.79
        Month 12 (n = 32, 14)
    -0.11 ± 0.60
    -0.34 ± 0.67
        Month 24/EoT (n = 28, 14)
    -0.12 ± 1.08
    0.23 ± 1.63
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Month 3
    Comparison groups
    Gilteritinib v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [5]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [5] - 2-sided P-value from analysis of covariance (ANCOVA) including treatment, age group, geographic region and use of FLT3-inhibiting agents per IRT as fixed factors and baseline score as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Month 6
    Comparison groups
    Gilteritinib v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.415 [6]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [6] - 2-sided P-value from ANCOVA including treatment, age group, geographic region and use of FLT3-inhibiting agents per IRT as fixed factors and baseline score as covariate.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Month 12
    Comparison groups
    Gilteritinib v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.271 [7]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [7] - 2-sided P-value from ANCOVA including treatment, age group, geographic region and use of FLT3-inhibiting agents per IRT as fixed factors and baseline score as covariate.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Month 24/EoT
    Comparison groups
    Gilteritinib v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.179 [8]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [8] - 2-sided P-value from ANCOVA including treatment, age group, geographic region and use of FLT3-inhibiting agents per IRT as fixed factors and baseline score as covariate.

    Secondary: Number of Participants With Adverse Events (AE)

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    End point title
    		 Number of Participants With Adverse Events (AE)
    End point description
    AE:any untoward medical occurrence in participants administered study treatment (ST)/had undergone study procedures & did not necessarily have a causal relationship with treatment. Abnormalities was defined as AE only if met 1 of the criteria:Induced clinical signs/symptoms, required active intervention, required interruption or discontinuation of ST, abnormality or investigational value was clinically significant. Serious AE:resulted in death, was life threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/birth defect, required hospitalization or prolongation of hospitalization, other medically important events. Treatment-emergent AE:recorded on treatment ≤ 30 days from last ST. Relapse: defined in Outcome Measure #1. Grades(Gr) based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) (Gr 1=mild, Gr 2=moderate, Gr 3 =severe, Gr 4 =life threatening, Gr 5 =death).
    End point type
    Secondary
    End point timeframe
    From first dose date up to 30 days after last dose or data cut-off date 25-May 2021 (Maximum treatment duration was 744 days) The safety analysis set (SAF) consisted of all randomized participants who received at least one dose of study drug.
    End point values
    		 Gilteritinib Placebo
    Number of subjects analysed
    62
    35
    Units: Participants
        TEAE
    58
    33
        Drug-Related TEAE
    51
    20
        TEAE before Relapse
    57
    28
        Drug-Related TEAE before Relapse
    51
    15
        Serious TEAE
    24
    14
        Drug-Related Serious TEAE
    10
    3
        TEAE Leading to Death
    1
    1
        Drug-Related TEAE Leading to Death
    0
    1
        TEAE Leading to Withdrawal of Treatment
    15
    6
        Drug-Related TEAE Leading to Treatment Withdrawal
    5
    2
        TEAE Leading to Dose Reduction
    15
    1
        Drug-Related TEAE Leading to Dose Reduction
    14
    1
        TEAE Leading to Dose Interruption
    35
    4
        Drug-Related TEAE Leading to Dose Interruption
    31
    1
        Grade 3 or Higher TEAE
    42
    18
        Grade 3 or Higher Drug-related TEAE
    33
    4
        Death
    20
    11
    No statistical analyses for this end point

    Secondary: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score

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    End point title
    		 Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score
    End point description
    ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. 1-Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2-Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3-Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4-Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5-Dead. Number of participants with ECOG PS was reported. ECOG PS grades with zero participants were not reported. Analysis Population: Safety population with available data at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, months 2, 3, 4, 5, 6, 8, 10. 12, 14, 16, 18, 20, 22 and 24/EoT
    End point values
    		 Gilteritinib Placebo
    Number of subjects analysed
    62
    35
    Units: Participants
        Baseline: Grade 0 (n = 62, 35)
    39
    22
        Baseline: Grade 1 (n = 62, 35)
    23
    13
        Month 2: Grade 0 (n = 54, 28)
    38
    18
        Month 2: Grade 1 (n = 54, 28)
    16
    9
        Month 2: Grade 2 (n = 54, 28)
    0
    1
        Month 3: Grade 0 (n = 52, 25)
    33
    20
        Month 3: Grade 1 (n = 52, 25)
    19
    4
        Month 3: Grade 2 (n = 52, 25)
    0
    1
        Month 4: Grade 0 (n = 49, 22)
    37
    16
        Month 4: Grade 1 (n = 49, 22)
    12
    6
        Month 5: Grade 0 (n = 46, 21)
    35
    17
        Month 5: Grade 1 (n = 46, 21)
    11
    4
        Month 6: Grade 0 (n = 43, 19)
    32
    17
        Month 6: Grade 1 (n = 43, 19)
    11
    2
        Month 8: Grade 0 (n = 41, 18)
    32
    12
        Month 8: Grade 1 (n = 41, 18)
    8
    6
        Month 8: Grade 2 (n = 41, 18)
    1
    0
        Month 10: Grade 0 (n = 37, 17)
    29
    14
        Month 10: Grade 1 (n = 37, 17)
    8
    3
        Month 12: Grade 0 (n= 35, 17)
    24
    14
        Month 12: Grade 1 (n= 35, 17)
    11
    3
        Month 14: Grade 0 (n = 30, 16)
    21
    13
        Month 14: Grade 1 (n = 30, 16)
    9
    3
        Month 16: Grade 0 (n = 28, 13)
    22
    11
        Month 16: Grade 1 (n = 28, 13)
    4
    2
        Month 16: Grade 2 (n = 28, 13)
    2
    0
        Month 18: Grade 0 (n = 27, 14)
    19
    13
        Month 18: Grade 1 (n = 27, 14)
    8
    1
        Month 20: Grade 0 (n = 25, 14)
    18
    13
        Month 20: Grade 1 (n = 25, 14)
    7
    1
        Month 22: Grade 0 (n = 24, 13)
    20
    11
        Month 22: Grade 1 (n = 24, 13)
    4
    2
        Month 24/EoT: Grade 0 (n = 51, 28)
    34
    20
        Month 24/EoT: Grade 1 (n = 51, 28)
    14
    6
        Month 24/EoT: Grade 2 (n = 51, 28)
    1
    0
        Month 24/EoT: Grade 3 (n = 51, 28)
    1
    1
        Month 24/EoT: Grade 4 (n = 51, 28)
    1
    1
    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 or data cut-off date 25-May-2021 (Maximum treatment duration was 744 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a discontinuation criterion was met.

    Reporting group title
    Gilteritinib
    Reporting group description
    		 Participants received gilteritinib 120 mg (three tablets of 40 mg) orally, QD for up to 2 years or until a discontinuation criterion was met.

    Serious adverse events
    		 Placebo Gilteritinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 35 (40.00%)
    24 / 62 (38.71%)
         number of deaths (all causes)
    11
    20
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    5 / 35 (14.29%)
    7 / 62 (11.29%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia recurrent
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic mastocytosis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thymoma
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Neurogenic shock
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperleukocytosis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal haemorrhage
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Gilteritinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 35 (91.43%)
    53 / 62 (85.48%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 35 (2.86%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 35 (8.57%)
    10 / 62 (16.13%)
         occurrences all number
    4
    10
    Malaise
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 35 (11.43%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Pyrexia
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 62 (3.23%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 35 (5.71%)
    9 / 62 (14.52%)
         occurrences all number
    2
    12
    Dyspnoea
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 62 (6.45%)
         occurrences all number
    2
    5
    Epistaxis
         subjects affected / exposed
    1 / 35 (2.86%)
    4 / 62 (6.45%)
         occurrences all number
    1
    5
    Oropharyngeal pain
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 62 (1.61%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 62 (6.45%)
         occurrences all number
    2
    5
    Restlessness
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    8 / 62 (12.90%)
         occurrences all number
    3
    17
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    7 / 62 (11.29%)
         occurrences all number
    1
    12
    Blood bilirubin increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    18 / 62 (29.03%)
         occurrences all number
    1
    37
    Blood creatinine increased
         subjects affected / exposed
    1 / 35 (2.86%)
    5 / 62 (8.06%)
         occurrences all number
    2
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 35 (0.00%)
    7 / 62 (11.29%)
         occurrences all number
    0
    7
    Neutrophil count decreased
         subjects affected / exposed
    3 / 35 (8.57%)
    12 / 62 (19.35%)
         occurrences all number
    5
    46
    Platelet count decreased
         subjects affected / exposed
    4 / 35 (11.43%)
    12 / 62 (19.35%)
         occurrences all number
    10
    24
    Weight increased
         subjects affected / exposed
    2 / 35 (5.71%)
    8 / 62 (12.90%)
         occurrences all number
    4
    11
    White blood cell count decreased
         subjects affected / exposed
    3 / 35 (8.57%)
    6 / 62 (9.68%)
         occurrences all number
    3
    24
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 62 (1.61%)
         occurrences all number
    3
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 35 (11.43%)
    8 / 62 (12.90%)
         occurrences all number
    4
    9
    Headache
         subjects affected / exposed
    1 / 35 (2.86%)
    5 / 62 (8.06%)
         occurrences all number
    1
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 35 (14.29%)
    5 / 62 (8.06%)
         occurrences all number
    8
    8
    Leukopenia
         subjects affected / exposed
    1 / 35 (2.86%)
    7 / 62 (11.29%)
         occurrences all number
    1
    8
    Neutropenia
         subjects affected / exposed
    1 / 35 (2.86%)
    10 / 62 (16.13%)
         occurrences all number
    1
    32
    Thrombocytopenia
         subjects affected / exposed
    4 / 35 (11.43%)
    11 / 62 (17.74%)
         occurrences all number
    4
    17
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 35 (2.86%)
    5 / 62 (8.06%)
         occurrences all number
    1
    5
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 35 (5.71%)
    5 / 62 (8.06%)
         occurrences all number
    2
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 35 (2.86%)
    7 / 62 (11.29%)
         occurrences all number
    1
    8
    Diarrhoea
         subjects affected / exposed
    3 / 35 (8.57%)
    5 / 62 (8.06%)
         occurrences all number
    3
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 62 (6.45%)
         occurrences all number
    3
    4
    Nausea
         subjects affected / exposed
    7 / 35 (20.00%)
    8 / 62 (12.90%)
         occurrences all number
    7
    10
    Stomatitis
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 62 (4.84%)
         occurrences all number
    3
    3
    Vomiting
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 62 (3.23%)
         occurrences all number
    2
    3
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 35 (2.86%)
    4 / 62 (6.45%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    2 / 35 (5.71%)
    6 / 62 (9.68%)
         occurrences all number
    2
    6
    Rash
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Skin lesion
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 62 (6.45%)
         occurrences all number
    3
    6
    Back pain
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 62 (3.23%)
         occurrences all number
    4
    2
    Bone pain
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 35 (2.86%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Herpes zoster
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 62 (1.61%)
         occurrences all number
    2
    2
    Influenza
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 35 (17.14%)
    7 / 62 (11.29%)
         occurrences all number
    11
    11
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 62 (4.84%)
         occurrences all number
    3
    3
    Otitis media
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 62 (4.84%)
         occurrences all number
    2
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 62 (3.23%)
         occurrences all number
    5
    7
    Hyperuricaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    4 / 62 (6.45%)
         occurrences all number
    1
    7

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2017
    The changes included: Add requirement for central hematology assessment during the first month on treatment at Days 1, 8, 15 & 29, as well as during all regularly scheduled visits beginning at Month 2. To collect hematology assessments at all the same times as other routine laboratory assessments to ensure identification of relapse at the earliest time point.
    25 Apr 2019
    The changes included: The study is changed from a phase 3 to phase 2. Prior text indicating target numbers for enrollment based on an adaptive design is modified to remove the adaptive design element and provide approximate enrollment numbers moving forward. The interim analysis that was originally planned is removed. Inclusion criterion 3 makes note of a diagnostic test that was previously under development but is now available. The revision reflects this change in the diagnostic test status. The duration of treatment no longer includes the requirement for a 3-year follow-up (to start after the 30-day follow-up) or for 80% of the subjects to have a relapse-free survival (RFS) event, whichever comes first. The primary analysis hypothesis test on the primary endpoint of RFS is changed from the Wald test based on stratified Cox-proportional hazards model to a stratified log-rank test, and the stratified Cox-proportional hazards model is then used as sensitivity analysis. A weighted statistics model (CHW method) will no longer be applied to the primary endpoint analysis. Language is added to clarify the conditions under which unblinding could occur, including in the event of documented relapse.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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