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    Clinical Trial Results:
    A Phase 3 Open-Label Randomized Study of Quizartinib Monotherapy Versus Salvage Chemotherapy in Subjects with FLT3-ITD Positive Acute Myeloid Leukemia (AML) Refractory to or Relapsed after First-Line Treatment with or without Hematopoietic Stem Cell Transplantation (HSCT) Consolidation

    Summary
    EudraCT number
    		 2013-004890-28
    Trial protocol
    		 GB   DE   IT   NL   ES   BE   HU   CZ   HR   PL  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    22 Mar 2019
    First version publication date
    22 Mar 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    AC220-007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02039726
    WHO universal trial number (UTN)
    		 U1111-1151-8078
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, After May 1, 2017, Basking Ridge, United States, 07920
    Public contact
    Global Clinical Leader, Daiichi Sankyo, Inc., 1 9089926400,
    Scientific contact
    Global Clinical Leader, Daiichi Sankyo, Inc., 1 9089926400,
    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
    22 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine whether quizartinib monotherapy prolongs overall survival (OS) compared to salvage chemotherapy in subjects with FLT3-ITD positive AML who are refractory to or have relapsed within 6 months, after first-line AML therapy.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Scientific research
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    United States: 118
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Hong Kong: 8
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Singapore: 2
    Worldwide total number of subjects
    367
    EEA total number of subjects
    188
    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)
    269
    From 65 to 84 years
    98
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of 563 patients assessed for eligibility, 367 were randomized and 335 received treatment

    Pre-assignment
    Screening details
    		 The study was conducted at 48 sites in Europe, 30 sites in North America, 11 sites in Asia, and 5 sites in Australia. The number of subjects enrolled in each region follows: Europe and Australia (195 patients), North America (141 patients), and Asia (31 patients).

    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
    		 Quizartinib monotherapy
    Arm description
    		 Patients received monotherapy with quizartinib dihydrochloride
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quizartinib
    Investigational medicinal product code
    Other name
    AC010220 x 2HCl
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet; 30 mg and 20 mg, Oral tablets for daily administration

    Arm title
    		 Salvage chemotherapy
    Arm description
    		 Patients received standard of care salvage chemotherapy (administered subcutaneously [LoDac] or intravenously [MEC and FLAG-IDA]),
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Salvage chemotherapy
    Investigational medicinal product code
    Other name
    Standard of care
    Pharmaceutical forms
    Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Solution for intravenous (IV) or subcutaneous (SC) administration. Standard of care, using commercially available product, per product packaging, including: - low dose cytarabine (LoDAC); - mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or - fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA).

    Number of subjects in period 1
    		Quizartinib monotherapy Salvage chemotherapy
    Started
    245
    122
    Received treatment (safety analysis set)
    241
    94 [1]
    Died
    88 [2]
    84 [3]
    Withdrew consent
    7 [4]
    22 [5]
    Dropped out with no reason specified
    2 [6]
    0 [7]
    Lost to follow-up
    3 [8]
    0 [9]
    Completed
    200
    106
    Not completed
    45
    16
         Still on Study
    45
    16
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These are interim results, laid out this way to show the patients who have not completed the trial as those who are continuing.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Quizartinib monotherapy
    Reporting group description
    		 Patients received monotherapy with quizartinib dihydrochloride

    Reporting group title
    Salvage chemotherapy
    Reporting group description
    		 Patients received standard of care salvage chemotherapy (administered subcutaneously [LoDac] or intravenously [MEC and FLAG-IDA]),

    Reporting group values
    		 Quizartinib monotherapy Salvage chemotherapy Total
    Number of subjects
    		 245 122 367
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 180 89 269
        From 65-84 years
    		 65 33 98
    Age continuous
    Median Age in Years
    Units: years
        median (full range (min-max))
    		 55.0 (19 to 81) 57.5 (18 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 132 58 190
        Male
    		 113 64 177

    End points

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    End points reporting groups
    Reporting group title
    Quizartinib monotherapy
    Reporting group description
    		 Patients received monotherapy with quizartinib dihydrochloride

    Reporting group title
    Salvage chemotherapy
    Reporting group description
    		 Patients received standard of care salvage chemotherapy (administered subcutaneously [LoDac] or intravenously [MEC and FLAG-IDA]),

    Primary: Overall Survival

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    End point title
    		 Overall Survival [1]
    End point description
    Time (weeks) from the date of randomization to the date of death due to any cause
    End point type
    Primary
    End point timeframe
    at the end of the trial (approximately 5 years, 2 months)
    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: The end of the trial has not occurred yet - these are interim results.
    End point values
    		 Quizartinib monotherapy Salvage chemotherapy
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: weeks
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [2] - The time point has not been reached for analysis of this endpoint.
    [3] - The end of the trial has not occurred yet - these are interim results
    No statistical analyses for this end point

    Primary: Overall Survival at Data Cut-off

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    End point title
    		 Overall Survival at Data Cut-off
    End point description
    OS is defined as the time (in weeks) from the date of randomization to the date of death due to any cause. Median and quartiles are calculated using the Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    At data cut off in February 2018 (approximately 3 years, 9 months)
    End point values
    		 Quizartinib monotherapy Salvage chemotherapy
    Number of subjects analysed
    245 [4]
    122 [5]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    27.0 (15.4 to 62.6)
    20.4 (8.3 to 39.6)
    Notes
    [4] - Intent to treat analysis set
    [5] - Intent to treat analysis set
    Statistical analysis title
    		 Hazard Ratio (Relative to Salvage Chemotherapy)
    Statistical analysis description
    Stratified analysis - stratification factors include prior therapy and response (Relapsed in ≤6 months (not post-HSCT), Refractory, or relapsed in ≤6 months post allogeneic HSCT), and pre-selected chemotherapy (High intensity chemotherapy [MEC or FLAG-IDA], or low intensity chemotherapy [LoDAC])
    Comparison groups
    Quizartinib monotherapy v Salvage chemotherapy
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0185
    Method
    		 p-value for HR=1 (1-Sided)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.758
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.584
         upper limit
    		 0.983
    Notes
    [6] - Interim analysis of the primary measure at the data cut off point in February 2018

    Secondary: Event-Free Survival

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    End point title
    		 Event-Free Survival
    End point description
    Time (weeks) from randomization until documented refractory disease, relapse after complete composite remission (CRc), or death from any cause, whichever is observed first
    End point type
    Secondary
    End point timeframe
    at the end of the trial (approximately 5 years, 2 months)
    End point values
    		 Quizartinib monotherapy Salvage chemotherapy
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: weeks
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [7] - The time point has not been reached for analysis of this endpoint.
    [8] - The time point has not been reached for analysis of this endpoint.
    No statistical analyses for this end point

    Secondary: Event-free survival at Data Cut-off

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    End point title
    		 Event-free survival at Data Cut-off
    End point description
    Event-free survival is defined as the time (in weeks) from randomization until documented refractory disease, relapse after complete composite remission (CRc), or death from any cause, whichever is observed first.
    End point type
    Secondary
    End point timeframe
    At data cut off in February 2018 (approximately 3 years, 9 months)
    End point values
    		 Quizartinib monotherapy Salvage chemotherapy
    Number of subjects analysed
    245 [9]
    122 [10]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    6.0 (0.1 to 19.7)
    3.7 (0.1 to 17.0)
    Notes
    [9] - Intent to treat analysis set
    [10] - Intent to treat analysis set
    Statistical analysis title
    		 Hazard Ratio (Relative to Salvage Chemotherapy)
    Statistical analysis description
    Stratified analysis - Stratification factors include prior therapy and response (Relapsed in ≤6 months not post-HSCT, Refractory, or relapsed in ≤6 months post allogeneic HSCT), and pre-selected chemotherapy (high intensity chemotherapy [MEC or FLAG-IDA], or low intensity chemotherapy [LoDAC]).
    Comparison groups
    Quizartinib monotherapy v Salvage chemotherapy
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.2034
    Method
    		 p-value for HR=1 (1-sided)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.898
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.697
         upper limit
    		 1.157
    Notes
    [11] - Interim analysis of the secondary measure at the data cut off point in February 2018

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Emergent Adverse Events (TEAEs) were collected from the first dose of study drug to 30 days after the last dose (or longer if assessed as treatment related), by the date of data cut-off, which was 22 Feb 2018.
    Adverse event reporting additional description
    Differences in treatment regimens make the TEAE collection period span multiple 28-day cycles in the quizartinib arm and only 1-2 weeks in the salvage chemotherapy arm. Consequently, the frequency of most TEAE categories is greater in the quizartinib arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Quizartinib monotherapy
    Reporting group description
    		 Patients receiving quizartinib monotherapy

    Reporting group title
    Salvage chemotherapy
    Reporting group description
    		 Patients receiving standard of care

    Serious adverse events
    		 Quizartinib monotherapy Salvage chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    168 / 241 (69.71%)
    37 / 94 (39.36%)
         number of deaths (all causes)
    80
    16
         number of deaths resulting from adverse events
    36
    11
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 241 (3.32%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    2 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular complication associated with device
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease in intestine
         subjects affected / exposed
    4 / 241 (1.66%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Graft versus host disease in liver
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in skin
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonitis
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    5 / 241 (2.07%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transfusion reaction
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    5 / 241 (2.07%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Headache
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Horner's syndrome
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 241 (2.07%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 241 (2.49%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    4 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    50 / 241 (20.75%)
    9 / 94 (9.57%)
         occurrences causally related to treatment / all
    21 / 65
    6 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    2 / 241 (0.83%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 241 (1.66%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (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
    5 / 241 (2.07%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (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
    5 / 241 (2.07%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    6 / 241 (2.49%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (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
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    4 / 241 (1.66%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    6 / 241 (2.49%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 241 (1.24%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 241 (0.83%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal skin infection
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenic infection
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    7 / 241 (2.90%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    4 / 12
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Peritonitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    22 / 241 (9.13%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 24
    1 / 3
         deaths causally related to treatment / all
    0 / 7
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    3 / 241 (1.24%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    16 / 241 (6.64%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    6 / 16
    1 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 241 (2.07%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Sinusitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    2 / 241 (0.83%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    4 / 241 (1.66%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 241 (2.07%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    6 / 241 (2.49%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cellulitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Quizartinib monotherapy Salvage chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    238 / 241 (98.76%)
    91 / 94 (96.81%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 241 (3.73%)
    8 / 94 (8.51%)
         occurrences all number
    9
    8
    Hypotension
         subjects affected / exposed
    32 / 241 (13.28%)
    10 / 94 (10.64%)
         occurrences all number
    39
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    34 / 241 (14.11%)
    10 / 94 (10.64%)
         occurrences all number
    38
    11
    Chills
         subjects affected / exposed
    15 / 241 (6.22%)
    7 / 94 (7.45%)
         occurrences all number
    15
    8
    Fatigue
         subjects affected / exposed
    67 / 241 (27.80%)
    18 / 94 (19.15%)
         occurrences all number
    81
    22
    Oedema peripheral
         subjects affected / exposed
    51 / 241 (21.16%)
    22 / 94 (23.40%)
         occurrences all number
    58
    26
    Pain
         subjects affected / exposed
    19 / 241 (7.88%)
    8 / 94 (8.51%)
         occurrences all number
    21
    8
    Pyrexia
         subjects affected / exposed
    88 / 241 (36.51%)
    42 / 94 (44.68%)
         occurrences all number
    130
    69
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    14 / 241 (5.81%)
    0 / 94 (0.00%)
         occurrences all number
    14
    0
    Graft versus host disease in skin
         subjects affected / exposed
    16 / 241 (6.64%)
    0 / 94 (0.00%)
         occurrences all number
    18
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    56 / 241 (23.24%)
    13 / 94 (13.83%)
         occurrences all number
    64
    14
    Dyspnoea
         subjects affected / exposed
    48 / 241 (19.92%)
    8 / 94 (8.51%)
         occurrences all number
    61
    11
    Epistaxis
         subjects affected / exposed
    28 / 241 (11.62%)
    8 / 94 (8.51%)
         occurrences all number
    34
    9
    Nasal congestion
         subjects affected / exposed
    9 / 241 (3.73%)
    5 / 94 (5.32%)
         occurrences all number
    9
    5
    Oropharyngeal pain
         subjects affected / exposed
    25 / 241 (10.37%)
    6 / 94 (6.38%)
         occurrences all number
    26
    7
    Pleural effusion
         subjects affected / exposed
    14 / 241 (5.81%)
    2 / 94 (2.13%)
         occurrences all number
    14
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 241 (7.88%)
    4 / 94 (4.26%)
         occurrences all number
    21
    4
    Confusional state
         subjects affected / exposed
    7 / 241 (2.90%)
    5 / 94 (5.32%)
         occurrences all number
    7
    5
    Insomnia
         subjects affected / exposed
    22 / 241 (9.13%)
    13 / 94 (13.83%)
         occurrences all number
    24
    13
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    32 / 241 (13.28%)
    4 / 94 (4.26%)
         occurrences all number
    46
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    26 / 241 (10.79%)
    1 / 94 (1.06%)
         occurrences all number
    41
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    18 / 241 (7.47%)
    4 / 94 (4.26%)
         occurrences all number
    24
    5
    Blood bilirubin increased
         subjects affected / exposed
    24 / 241 (9.96%)
    3 / 94 (3.19%)
         occurrences all number
    30
    6
    Blood creatinine increased
         subjects affected / exposed
    16 / 241 (6.64%)
    2 / 94 (2.13%)
         occurrences all number
    22
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    63 / 241 (26.14%)
    2 / 94 (2.13%)
         occurrences all number
    90
    2
    Neutrophil count decreased
         subjects affected / exposed
    31 / 241 (12.86%)
    14 / 94 (14.89%)
         occurrences all number
    46
    21
    Platelet count decreased
         subjects affected / exposed
    33 / 241 (13.69%)
    12 / 94 (12.77%)
         occurrences all number
    39
    20
    Weight decreased
         subjects affected / exposed
    27 / 241 (11.20%)
    5 / 94 (5.32%)
         occurrences all number
    31
    5
    White blood cell count decreased
         subjects affected / exposed
    35 / 241 (14.52%)
    14 / 94 (14.89%)
         occurrences all number
    45
    17
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    15 / 241 (6.22%)
    2 / 94 (2.13%)
         occurrences all number
    17
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    8 / 241 (3.32%)
    5 / 94 (5.32%)
         occurrences all number
    8
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    36 / 241 (14.94%)
    10 / 94 (10.64%)
         occurrences all number
    41
    10
    Dysgeusia
         subjects affected / exposed
    22 / 241 (9.13%)
    1 / 94 (1.06%)
         occurrences all number
    22
    1
    Headache
         subjects affected / exposed
    51 / 241 (21.16%)
    16 / 94 (17.02%)
         occurrences all number
    64
    19
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    86 / 241 (35.68%)
    29 / 94 (30.85%)
         occurrences all number
    131
    35
    Febrile neutropenia
         subjects affected / exposed
    41 / 241 (17.01%)
    19 / 94 (20.21%)
         occurrences all number
    47
    28
    Leukocytosis
         subjects affected / exposed
    14 / 241 (5.81%)
    3 / 94 (3.19%)
         occurrences all number
    14
    3
    Leukopenia
         subjects affected / exposed
    13 / 241 (5.39%)
    2 / 94 (2.13%)
         occurrences all number
    17
    2
    Neutropenia
         subjects affected / exposed
    48 / 241 (19.92%)
    11 / 94 (11.70%)
         occurrences all number
    77
    11
    Thrombocytopenia
         subjects affected / exposed
    62 / 241 (25.73%)
    20 / 94 (21.28%)
         occurrences all number
    84
    21
    Eye disorders
    Dry eye
         subjects affected / exposed
    13 / 241 (5.39%)
    1 / 94 (1.06%)
         occurrences all number
    13
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    11 / 241 (4.56%)
    5 / 94 (5.32%)
         occurrences all number
    13
    5
    Abdominal pain
         subjects affected / exposed
    30 / 241 (12.45%)
    15 / 94 (15.96%)
         occurrences all number
    33
    16
    Abdominal pain upper
         subjects affected / exposed
    18 / 241 (7.47%)
    0 / 94 (0.00%)
         occurrences all number
    21
    0
    Constipation
         subjects affected / exposed
    47 / 241 (19.50%)
    22 / 94 (23.40%)
         occurrences all number
    54
    29
    Diarrhoea
         subjects affected / exposed
    68 / 241 (28.22%)
    34 / 94 (36.17%)
         occurrences all number
    98
    42
    Dry mouth
         subjects affected / exposed
    13 / 241 (5.39%)
    3 / 94 (3.19%)
         occurrences all number
    14
    3
    Dyspepsia
         subjects affected / exposed
    20 / 241 (8.30%)
    6 / 94 (6.38%)
         occurrences all number
    20
    6
    Gingival bleeding
         subjects affected / exposed
    16 / 241 (6.64%)
    3 / 94 (3.19%)
         occurrences all number
    16
    3
    Nausea
         subjects affected / exposed
    114 / 241 (47.30%)
    39 / 94 (41.49%)
         occurrences all number
    164
    47
    Proctalgia
         subjects affected / exposed
    8 / 241 (3.32%)
    5 / 94 (5.32%)
         occurrences all number
    9
    5
    Stomatitis
         subjects affected / exposed
    39 / 241 (16.18%)
    18 / 94 (19.15%)
         occurrences all number
    39
    18
    Vomiting
         subjects affected / exposed
    80 / 241 (33.20%)
    20 / 94 (21.28%)
         occurrences all number
    116
    25
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    27 / 241 (11.20%)
    6 / 94 (6.38%)
         occurrences all number
    31
    8
    Pruritus
         subjects affected / exposed
    15 / 241 (6.22%)
    6 / 94 (6.38%)
         occurrences all number
    15
    8
    Rash
         subjects affected / exposed
    36 / 241 (14.94%)
    9 / 94 (9.57%)
         occurrences all number
    41
    10
    Skin lesion
         subjects affected / exposed
    14 / 241 (5.81%)
    1 / 94 (1.06%)
         occurrences all number
    14
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    15 / 241 (6.22%)
    39 / 94 (41.49%)
         occurrences all number
    16
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 241 (8.30%)
    3 / 94 (3.19%)
         occurrences all number
    24
    3
    Back pain
         subjects affected / exposed
    26 / 241 (10.79%)
    9 / 94 (9.57%)
         occurrences all number
    29
    9
    Muscle spasms
         subjects affected / exposed
    19 / 241 (7.88%)
    0 / 94 (0.00%)
         occurrences all number
    22
    0
    Musculoskeletal pain
         subjects affected / exposed
    19 / 241 (7.88%)
    6 / 94 (6.38%)
         occurrences all number
    20
    8
    Myalgia
         subjects affected / exposed
    15 / 241 (6.22%)
    2 / 94 (2.13%)
         occurrences all number
    16
    2
    Pain in extremity
         subjects affected / exposed
    25 / 241 (10.37%)
    6 / 94 (6.38%)
         occurrences all number
    26
    6
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 241 (0.83%)
    5 / 94 (5.32%)
         occurrences all number
    2
    5
    Device related infection
         subjects affected / exposed
    9 / 241 (3.73%)
    7 / 94 (7.45%)
         occurrences all number
    9
    7
    Enterococcal infection
         subjects affected / exposed
    1 / 241 (0.41%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5
    Pneumonia
         subjects affected / exposed
    11 / 241 (4.56%)
    6 / 94 (6.38%)
         occurrences all number
    11
    6
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 241 (7.05%)
    1 / 94 (1.06%)
         occurrences all number
    17
    1
    Urinary tract infection
         subjects affected / exposed
    18 / 241 (7.47%)
    0 / 94 (0.00%)
         occurrences all number
    26
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    48 / 241 (19.92%)
    10 / 94 (10.64%)
         occurrences all number
    62
    10
    Hyperglycaemia
         subjects affected / exposed
    15 / 241 (6.22%)
    7 / 94 (7.45%)
         occurrences all number
    17
    10
    Hypoalbuminaemia
         subjects affected / exposed
    17 / 241 (7.05%)
    7 / 94 (7.45%)
         occurrences all number
    33
    10
    Hypocalcaemia
         subjects affected / exposed
    27 / 241 (11.20%)
    10 / 94 (10.64%)
         occurrences all number
    36
    10
    Hypokalaemia
         subjects affected / exposed
    76 / 241 (31.54%)
    25 / 94 (26.60%)
         occurrences all number
    124
    45
    Hypomagnesaemia
         subjects affected / exposed
    36 / 241 (14.94%)
    7 / 94 (7.45%)
         occurrences all number
    56
    12
    Hyponatraemia
         subjects affected / exposed
    21 / 241 (8.71%)
    6 / 94 (6.38%)
         occurrences all number
    36
    6
    Hypophosphataemia
         subjects affected / exposed
    23 / 241 (9.54%)
    10 / 94 (10.64%)
         occurrences all number
    31
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Dec 2013
    The original protocol was amended prior to submission to the IND to incorporate the FDA’s concurrence of the proposed dosing regimen. Protocol Amendment 1 was the first protocol disseminated to IRBs and investigators.
    26 May 2015
    - Increased in the study duration to 36 months. - Clarified that quizartinib should be taken in the morning. - Changed the dose escalation schedule. - Changed the schedule for assessment of response. - FLT3-ITD allelic ratio cut-off changed to ≥3% from >3%. - Eligibility criteria clarified to state that subjects must be in first relapse or refractory (have not achieved a remission) to chemotherapy. Definition of duration of remission modified to allow the enrollment of subjects who relapsed 6 months after allogeneic transplant. - Bradycardia of less than 50 bpm added to the exclusion criteria. - Clarified the period to avoid pregnancy in the exclusion criteria. - The exclusion criterion of presence of a FLT3 D835 mutation at study enrollment was changed to exclude prior treatment with a FLT3 targeted therapy, including sorafenib or investigational FLT3 inhibitors. There were no changes in samples size due to this amendment. - Updated the packaging and storage information. - Added a table of P-glycoprotein inhibitors and inducers, - Added the requirement for a urine pregnancy test every 3 months during the treatment phase in women of child-bearing potential. - Specified that optional pharmacogenomic and pharmacoproteomic samples collected before dosing on Day 1 of Cycle 1 and at the end of treatment visit will be used for DNA, RNA, and PBMC isolation, in subjects who provided consent. - Clarified that an EOT case report form must be completed for subjects who discontinue quizartinib in order to proceed to HSCT. Clarified that for subjects receiving chemotherapy, the EOT visit is Day 29 of the last cycle. - Added an assessment of concomitant medications at the 30-Day Follow-up visit.
    06 Oct 2015
    - Changed the sponsor from Ambit Biosciences to DSI in all regions except Europe and to Daiichi Sankyo Development Limited in Europe. - Updated the total number of potential sites. - Clarified the following: age requirement, in inclusion criterion 2; that a local FLT3-ITD test may be used for enrollment after discussion with the Medical Monitor, if the central laboratory results are not available when the subject requires treatment initiation, in inclusion criterion 5; and that cases where subjects have been randomized and the FLT3-ITD local and central laboratory results were discordant, the subjects were permitted to continue quizartinib/salvage chemotherapy dosing. - Clarified that the sponsor will not have access to aggregate efficacy data, except when data from both treatment arms are combined. - Removed “Dispensing of quizartinib” and captured it as a footnote in the Schedules of Activities and Assessments. - Clarified expectations of when ECGs should occur. - Removed the detailed definition of the secondary efficacy endpoint. This information was included in statistical analysis plan. - Explained that Grade 3 or 4 QTcF prolongation events (average of triplicate ECG determinations by the central reading) should be reported within 24 hours.
    19 Nov 2015
    Updated exclusion criterion 9 to clarify that prior treatment with the multi-kinase inhibitor, midostaurin, was permitted.
    04 May 2016
    - Listed Daiichi Sankyo, Inc. as global sponsor due to organizational change in Europe. - Added information and clarified inclusion/exclusion criteria - Changed food and drug restrictions due to new data - Removed IB information - Updated the clinical exposure data - Added the following statement to the overall study design and plan, “the sponsor may allow subjects who did not receive quizartinib to crossover to the quizartinib monotherapy arm after database lock if the safety parameters in the eligibility criteria are met.” - Corrected the day of the planned quizartinib dose increase from Cycle 2 Day 2 to Cycle 2 Day 1. - Added that Competent Authority officials may identify conditions warranting study termination or site closure - Clarified and harmonized drug description, packaging, storage conditions and accountability - Changed ECG and PK sample collection times based on new information - Clarified that subjects undergoing HSCT will be evaluated by phone for the 30-Day Follow-up and Long-Term Follow-up
    15 Aug 2016
    - Made all necessary changes to switch the study design from an adaptive design to a traditional group sequential design - Increased the planned number of subjects to 363 to reach 280 events in a reasonable time - Adjusted efficacy objectives and endpoints to measure duration of CR and CRc - Changed protocol text to ensure descriptions and analysis of efficacy and safety endpoints were consistent throughout the protocol and the SAP - Revised planned analyses for subjects who underwent HSCT and removed pharmacoeconomic analysis - Clarified definition and added guidance for withdrawal of consent and lost to follow-up - Corrected ANC and/or platelet counts to match the Cheson IWG Response criteria - Clarified reporting requirements for SAE of QTcF prolongation - Defined sub-groups to be analyzed for primary and secondary efficacy endpoints
    30 Jun 2017
    - Removed AC220 throughout as this refers to the salt form (quizartinib dihydrochloride) and not the freebase (quizartinib), and corrected to quizartinib throughout. - Updated the Sponsor address and information for the DSI Medical Monitor. - Added a statement that the tasks performed by the SAC and the DMC during the interim analysis will be documented in the Interim Analysis Plan. - Added that safety data will be summarized by pre-defined sub-groups. - Clarified the definition and classification criteria for “No Response” subjects. - Provided a summary of findings from the Phase 1 Study of quizartinib following HSCT (Study 2689-CL-0011). - Added specific screening procedures, inclusion and exclusion criteria and schedule of activities and assessments for subjects crossing over from salvage chemotherapy to quizartinib. - Changed the site of peripheral blood screenings for FLT3-ITD testing from “Genoptix” to “Navigate BioPharma Services, Inc.” - Changed the frequency of urine pregnancy tests from monthly to every 3 months in subjects receiving quizartinib after HSCT - Added instructional language for subjects who discontinue salvage chemotherapy and do not qualify for cross-over - Added a description of the methodology for the Navigate FLT3-ITD mutation assay

    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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