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    Clinical Trial Results:
    A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia (AML)

    Summary
    EudraCT number
    2016-003353-16
    Trial protocol
    DE  
    Global end of trial date
    21 Feb 2019

    Results information
    Results version number
    v1
    This version publication date
    17 Oct 2019
    First version publication date
    17 Oct 2019
    Other versions
    v2

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-339-1559
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02343939
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study will evaluate the efficacy, safety, and tolerability of entospletinib (ENTO) when administered as monotherapy or in combination with chemotherapy in adults with acute myeloid leukemia (AML).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 133
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Germany: 5
    Worldwide total number of subjects
    148
    EEA total number of subjects
    5
    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)
    56
    From 65 to 84 years
    83
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in the United States, Canada, and Germany. The first participant was screened on 01 July 2015.

    Pre-assignment
    Screening details
    233 participants were screened.

    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
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Arm description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Arm description
    Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Arm description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Arm description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Arm description
    As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Arm description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Arm description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group C Phase 1b/2 ENTO 400 mg
    Arm description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Arm title
    Group C Phase 1b ENTO 800 mg
    Arm description
    Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    GS-9973, ENTO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet(s) administered orally every 12 hours

    Number of subjects in period 1 [1]
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Started
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Completed
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Not completed
    3
    48
    5
    6
    8
    17
    14
    35
    7
         Death
    -
    15
    4
    2
    5
    11
    8
    22
    1
         Investigator's discretion
    -
    -
    -
    1
    -
    -
    1
    -
    -
         Treatment Failure
    -
    -
    -
    -
    -
    -
    2
    1
    -
         Study terminated by sponsor
    -
    27
    -
    1
    1
    5
    3
    4
    -
         Consent withdrawn by subject
    3
    6
    1
    2
    2
    -
    -
    8
    6
         Adverse Event
    -
    -
    -
    -
    -
    1
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three participants who were enrolled but not treated are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Reporting group description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Reporting group title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Reporting group description
    Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Reporting group title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Reporting group description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Reporting group description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Reporting group description
    As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Reporting group description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Reporting group description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group C Phase 1b/2 ENTO 400 mg
    Reporting group description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group title
    Group C Phase 1b ENTO 800 mg
    Reporting group description
    Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg Total
    Number of subjects
    3 50 5 6 8 17 14 35 7 145
    Age categorical
    Units: Subjects
        < 65 Years
    3 32 0 1 1 1 0 17 0 55
        ≥ 65 years
    0 18 5 5 7 16 14 18 7 90
    Gender categorical
    Units: Subjects
        Female
    1 21 2 2 2 7 3 18 5 61
        Male
    2 29 3 4 6 10 11 17 2 84
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 2 0 0 0 0 0 2 0 4
        Not Hispanic or Latino
    3 48 5 6 7 15 13 33 7 137
        Not Permitted
    0 0 0 0 1 2 1 0 0 4
    Race
    Units: Subjects
        White/Caucasian
    3 44 3 6 6 14 11 31 7 125
        Black or African American
    0 5 2 0 1 0 1 2 0 11
        Asian
    0 0 0 0 0 0 0 1 0 1
        Other
    0 1 0 0 0 0 1 1 0 3
        Not Permitted
    0 0 0 0 1 3 1 0 0 5

    End points

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    End points reporting groups
    Reporting group title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Reporting group description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Reporting group title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Reporting group description
    Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Reporting group title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Reporting group description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Reporting group description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Reporting group description
    As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Reporting group description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Reporting group description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group C Phase 1b/2 ENTO 400 mg
    Reporting group description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group title
    Group C Phase 1b ENTO 800 mg
    Reporting group description
    Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Subject analysis set title
    Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Subject analysis set title
    Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Subject analysis set title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Subject analysis set title
    Group C Phase 1b ENTO 400 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 1b ENTO 800 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with relapsed/refractory (R/R) acute myeloid leukemia (AML) received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants R/R AML with mixed-lineage leukemia (MLL) received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Subject analysis set title
    Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with previously untreated AML who were unfit for chemotherapy or hypomethylating agents or refused chemotherapy or hypomethylating agent received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Primary: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)

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    End point title
    Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) [1] [2]
    End point description
    DLTs refer to toxicities experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLT assessment was applicable only for Phase 1b and Phase 2 safety run-in participants. The DLT Analysis Set included all participants who received 21 days of ENTO (applicable to all groups) and all doses of cytarabine and daunorubicin in Group A Phase 1b, decitabine in Group B Phase 1b, or azacitidine in Group B Phase 2 safety run-in during the DLT assessment window; or experienced a DLT during the DLT assessment window.
    End point type
    Primary
    End point timeframe
    Group A: Cycle 0 Day 1 to Cycle 2 Day 28; Group B: Cycle 0 Day 1 to Cycle 1 Day 28; Group C: Cycle 1 Day 1 to Cycle 1 Day 28 (Cycle length: for Cycle 0 = 14 days, for all other cycles = 28 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to include data only for the specified arms.
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    6
    3
    6
    6
    6
    6
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.0
    0.0
    16.7
    0.0
    0.0
    16.7
    No statistical analyses for this end point

    Primary: Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction

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    End point title
    Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction [3]
    End point description
    Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Morphologic CR included CR and cytogenetic CR (CRc). CR required all of the following: < 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/microliter (mcL); Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. The Full Analysis Set included all participants who received at least 1 dose of study drug with treatment designated according to the planned treatment.
    End point type
    Primary
    End point timeframe
    At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: Percentage of Participants
        number (confidence interval 95%)
    66.7 (9.4 to 99.2)
    66.7 (29.9 to 92.5)
    46.3 (30.7 to 62.6)
    0.0 (0.0 to 52.2)
    16.7 (0.4 to 64.1)
    25.0 (3.2 to 65.1)
    0.0 (0.0 to 19.5)
    7.1 (0.2 to 33.9)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 45.9)
    15.4 (1.9 to 45.4)
    11.1 (0.3 to 48.2)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Composite Complete Remission at the End of Induction

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    End point title
    Percentage of Participants With Composite Complete Remission at the End of Induction [4]
    End point description
    Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Composite complete remission included CR, CRc, and morphologic complete remission with incomplete blood count recovery (CRi). CR required all of the following: < 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. Participants in the Full Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (29.2 to 100)
    77.8 (40 to 97.2)
    65.9 (49.4 to 79.9)
    40.0 (5.3 to 85.3)
    50.0 (11.8 to 88.2)
    25.0 (3.2 to 65.1)
    23.5 (6.8 to 49.9)
    14.3 (1.8 to 42.8)
    14.3 (0.4 to 57.9)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 45.9)
    15.4 (1.9 to 45.4)
    11.1 (0.3 to 48.2)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Overall Response at the End of Induction

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    End point title
    Percentage of Participants With Overall Response at the End of Induction [5]
    End point description
    Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Overall response included CR, CRc, CRi, and partial remission (PR). CR required all of the following: < 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. PR required all of the following: ≥ 50% decrease in blasts in bone marrow aspirate to a range of 5% to 25%; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; Independent of transfusions; and A value of ≤ 5% blasts was also considered a PR if Auer rods were detected. Participants in the Full Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (29.2 to 100)
    77.8 (40 to 97.2)
    70.7 (54.5 to 83.9)
    40.0 (5.3 to 85.3)
    50.0 (11.8 to 88.2)
    25.0 (3.2 to 65.1)
    23.5 (6.8 to 49.9)
    14.3 (1.8 to 42.8)
    14.3 (0.4 to 57.9)
    0.0 (0 to 41)
    0.0 (0 to 45.9)
    15.4 (1.9 to 45.4)
    11.1 (0.3 to 48.2)
    No statistical analyses for this end point

    Secondary: Duration of Exposure of Entospletinib

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    End point title
    Duration of Exposure of Entospletinib
    End point description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    First dose date up to approximately 3 years
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Units: weeks
        median (full range (min-max))
    8.6 (6.1 to 10.0)
    7.1 (0.9 to 72.9)
    13.7 (1.6 to 50.9)
    15.4 (1.9 to 58.9)
    10.1 (1.3 to 39.4)
    13.9 (1.9 to 40.0)
    10.1 (0.9 to 47.0)
    4.4 (1.4 to 15.6)
    7.6 (2.0 to 9.0)
    No statistical analyses for this end point

    Secondary: Event Free Survival (EFS)

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    End point title
    Event Free Survival (EFS)
    End point description
    EFS was defined as the time interval from the start of the study therapy until the date of treatment failure, acute myeloid leukemia (AML) relapse, or death from any cause, whichever occurred first. Participants who received other anti-cancer therapy (prior to the event if any) were censored. Median EFS was analyzed using Kaplan-Meier (KM) method. Participants in the Full Analysis Set were analyzed. 999 = not reached due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    First dose date up to approximately 3 years
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    1.9 (0.9 to 1.9)
    9.0 (2.3 to 999)
    2.2 (0.5 to 4.7)
    2.9 (1.1 to 7.7)
    2.3 (0.5 to 9.0)
    3.2 (0.5 to 4.2)
    2.4 (2.1 to 3.9)
    1.8 (0.9 to 1.9)
    1.8 (0.5 to 1.9)
    1.0 (0.7 to 2.8)
    1.0 (0.8 to 2.7)
    1.7 (0.8 to 1.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time interval from the start of the study therapy to death from any cause. Median OS was analyzed using KM method. Participants in the Full Analysis Set were analyzed. 999 = not reached due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    First dose date up to approximately 3 years
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b ENTO 400 mg + Cytarabine + Daunorubicin Group A Phase 2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b ENTO 400 mg Group C Phase 1b ENTO 800 mg Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML)
    Number of subjects analysed
    3
    9
    41
    5
    6
    8
    17
    14
    7
    7
    6
    13
    9
    Units: months
        median (confidence interval 95%)
    37.1 (9.1 to 999)
    34.1 (1.2 to 999)
    999 (16.8 to 999)
    3.2 (0.8 to 12.7)
    5.3 (2.4 to 999)
    6.9 (1.4 to 999)
    7.3 (2.4 to 999)
    6.2 (3.2 to 10.2)
    5.9 (0.9 to 6.3)
    5.6 (0.5 to 8.4)
    8.2 (0.7 to 24.3)
    7.9 (3.3 to 11.9)
    2.2 (1.0 to 4.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events

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    End point title
    Percentage of Participants Experiencing Treatment-Emergent Adverse Events
    End point description
    Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    First dose date up to the last dose date plus 30 days (maximum: 18 months)
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Units: Percentage of Participants
        number (not applicable)
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Laboratory Abnormalities

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    End point title
    Percentage of Participants Who Experienced Laboratory Abnormalities
    End point description
    Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    First dose date up to the last dose date plus 30 days (maximum: 18 months)
    End point values
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Number of subjects analysed
    3
    50
    5
    6
    8
    17
    14
    35
    7
    Units: Percentage of Participants
    number (not applicable)
        Any Laboratory Abnormality
    100
    100
    100
    100
    100
    94.1
    100
    100
    100
        Grade 3 or 4 Laboratory Abnormalities
    100
    98.0
    100
    100
    85.7
    94.1
    92.9
    82.9
    85.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    - All-Cause Mortality: First dose date up to approximately 36 months. - Adverse Events: First dose date up to the last dose date plus 30 days (maximum: 18 months)
    Adverse event reporting additional description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin
    Reporting group description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy).

    Reporting group title
    Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin
    Reporting group description
    Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m^2 on Days 1-7 and daunorubicin 60 mg/m^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy). Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles.

    Reporting group title
    Group B Phase 1b ENTO 200 mg + Decitabine
    Reporting group description
    Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 1b ENTO 400 mg + Decitabine
    Reporting group description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator’s discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In)
    Reporting group description
    As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Decitabine (Randomized)
    Reporting group description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized)
    Reporting group description
    Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles.

    Reporting group title
    Group C Phase 1b/2 ENTO 400 mg
    Reporting group description
    Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Reporting group title
    Group C Phase 1b ENTO 800 mg
    Reporting group description
    Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor.

    Serious adverse events
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    23 / 50 (46.00%)
    5 / 5 (100.00%)
    5 / 6 (83.33%)
    7 / 8 (87.50%)
    11 / 17 (64.71%)
    7 / 14 (50.00%)
    19 / 35 (54.29%)
    4 / 7 (57.14%)
         number of deaths (all causes)
    2
    21
    5
    4
    5
    12
    11
    30
    6
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    13 / 50 (26.00%)
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    3 / 8 (37.50%)
    8 / 17 (47.06%)
    0 / 14 (0.00%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    11 / 16
    5 / 6
    5 / 7
    3 / 4
    8 / 14
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Group B Phase 1b ENTO 200 mg + Decitabine Group B Phase 1b ENTO 400 mg + Decitabine Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Group C Phase 1b/2 ENTO 400 mg Group C Phase 1b ENTO 800 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    50 / 50 (100.00%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    7 / 8 (87.50%)
    17 / 17 (100.00%)
    14 / 14 (100.00%)
    33 / 35 (94.29%)
    7 / 7 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 50 (14.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    4 / 17 (23.53%)
    5 / 14 (35.71%)
    6 / 35 (17.14%)
    1 / 7 (14.29%)
         occurrences all number
    1
    8
    0
    0
    3
    6
    11
    8
    1
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    12 / 50 (24.00%)
    0 / 5 (0.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    12
    0
    3
    0
    3
    0
    2
    1
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    3
    0
    2
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    0
    0
    Embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    2 / 3 (66.67%)
    29 / 50 (58.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    4 / 8 (50.00%)
    6 / 17 (35.29%)
    4 / 14 (28.57%)
    4 / 35 (11.43%)
    3 / 7 (42.86%)
         occurrences all number
    3
    35
    2
    3
    4
    9
    5
    4
    3
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    14 / 50 (28.00%)
    3 / 5 (60.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    9 / 17 (52.94%)
    6 / 14 (42.86%)
    10 / 35 (28.57%)
    3 / 7 (42.86%)
         occurrences all number
    1
    16
    3
    1
    2
    10
    6
    10
    3
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    9 / 50 (18.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    2
    2
    3
    1
    5
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    5 / 14 (35.71%)
    4 / 35 (11.43%)
    0 / 7 (0.00%)
         occurrences all number
    0
    9
    0
    0
    0
    5
    5
    4
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    4 / 35 (11.43%)
    0 / 7 (0.00%)
         occurrences all number
    0
    10
    1
    0
    0
    0
    1
    4
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    1
    0
    2
    1
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    3
    4
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    1
    0
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    2
    0
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    2
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    1
    0
    Catheter site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    0
    Catheter site rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Catheter site dermatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Device related thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Performance status decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    16 / 50 (32.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    4 / 14 (28.57%)
    7 / 35 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    16
    2
    1
    1
    2
    4
    8
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    1
    2
    0
    1
    0
    3
    0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    6
    1
    0
    1
    2
    0
    2
    1
    Delirium
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    2
    0
    2
    0
    1
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    0
    1
    0
    1
    1
    0
    Hallucination
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    0
    0
    0
    Mental status changes
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Apathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    4 / 35 (11.43%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    1
    0
    0
    1
    1
    4
    1
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    0
    0
    5
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Transfusion reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    2
    0
    Eye contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pelvic fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular access complication
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    26 / 50 (52.00%)
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    3 / 8 (37.50%)
    5 / 17 (29.41%)
    7 / 14 (50.00%)
    9 / 35 (25.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    38
    3
    3
    3
    7
    10
    10
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 50 (36.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    7 / 17 (41.18%)
    5 / 14 (35.71%)
    4 / 35 (11.43%)
    1 / 7 (14.29%)
         occurrences all number
    0
    25
    2
    2
    3
    12
    11
    4
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    16 / 50 (32.00%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
    4 / 17 (23.53%)
    2 / 14 (14.29%)
    6 / 35 (17.14%)
    2 / 7 (28.57%)
         occurrences all number
    0
    24
    2
    2
    3
    4
    5
    6
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    12 / 50 (24.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
    4 / 14 (28.57%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    0
    3
    7
    7
    3
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    7 / 14 (50.00%)
    2 / 35 (5.71%)
    2 / 7 (28.57%)
         occurrences all number
    0
    9
    1
    1
    1
    1
    13
    2
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    4 / 35 (11.43%)
    2 / 7 (28.57%)
         occurrences all number
    0
    13
    0
    0
    4
    0
    7
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 50 (16.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    3 / 35 (8.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    11
    0
    0
    4
    1
    6
    3
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    4 / 17 (23.53%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    1
    1
    2
    4
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 50 (4.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    3
    3
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    1
    2
    0
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    2 / 35 (5.71%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    2
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    3
    2
    1
    0
    Weight increased
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0
    0
    0
    2
    0
    0
    0
    Troponin I increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    1
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    1
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    2
    0
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    4 / 14 (28.57%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    7
    0
    0
    Lymphocyte count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Troponin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Spleen palpable
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ultrasound liver abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
    3 / 14 (21.43%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    1
    0
    1
    3
    3
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 50 (12.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    2
    1
    3
    2
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 50 (10.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    0
    2
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    2
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    1
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Arrhythmia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    20 / 50 (40.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
    4 / 14 (28.57%)
    10 / 35 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    23
    2
    3
    2
    6
    4
    10
    1
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 50 (36.00%)
    1 / 5 (20.00%)
    4 / 6 (66.67%)
    3 / 8 (37.50%)
    5 / 17 (29.41%)
    5 / 14 (35.71%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    21
    1
    4
    4
    5
    6
    5
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    7 / 35 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    16
    1
    3
    0
    3
    2
    7
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    1 / 14 (7.14%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    0
    0
    4
    1
    3
    0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 50 (22.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    11
    0
    0
    0
    2
    1
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 50 (14.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    1
    1
    0
    2
    0
    2
    0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    3
    2
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    2 / 14 (14.29%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    2
    2
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    1
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    3
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    2
    0
    Wheezing
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    1
    0
    Atelectasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 50 (6.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    Sinus pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Rales
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Lung infiltration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Paranasal sinus hyposecretion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rhonchi
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 3 (66.67%)
    36 / 50 (72.00%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    4 / 14 (28.57%)
    8 / 35 (22.86%)
    0 / 7 (0.00%)
         occurrences all number
    2
    53
    3
    3
    2
    3
    4
    12
    0
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    24 / 50 (48.00%)
    3 / 5 (60.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
    6 / 14 (42.86%)
    10 / 35 (28.57%)
    3 / 7 (42.86%)
         occurrences all number
    0
    28
    3
    4
    2
    8
    10
    11
    3
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    2
    3
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pancytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    20 / 50 (40.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 14 (14.29%)
    6 / 35 (17.14%)
    2 / 7 (28.57%)
         occurrences all number
    1
    29
    2
    3
    0
    3
    2
    6
    2
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    14 / 50 (28.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    5 / 35 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    17
    0
    0
    0
    1
    1
    5
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 50 (22.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    2 / 17 (11.76%)
    3 / 14 (21.43%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    12
    0
    1
    3
    2
    4
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    3 / 35 (8.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    0
    4
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    2
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    1
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Encephalopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Parosmia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 14 (7.14%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 50 (20.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    1 / 35 (2.86%)
    0 / 7 (0.00%)
         occurrences all number
    0
    10
    0
    0
    0
    1
    0
    1
    0
    Dry eye
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 50 (8.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    1
    4
    0
    1
    0
    0
    0
    2
    0
    Eye pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    0
    Scleral hyperaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Eye haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eye oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Optic nerve cupping
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ulcerative keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 50 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 50 (4.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 14 (0.00%)
    2 / 35 (5.71%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    2
    0
    2
    0
    Hypoacusis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 50 (2.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 14 (0.00%)
    0 / 35 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 3 (100.00%)
    34 / 50 (68.00%)
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    4 / 8 (50.00%)
    5 / 17 (29.41%)
    7 / 14 (50.00%)
    15 / 35 (42.86%)
    2 / 7 (28.57%)
         occurrences all number
    4
    49
    4
    5
    4
    6
    9
    15
    3
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    34 / 50 (68.00%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    3 / 8 (37.50%)
    9 / 17 (52.94%)
    4 / 14 (28.57%)
    14 / 35 (40.00%)
    4 / 7 (57.14%)
         occurrences all number
    2
    55
    1
    4
    4
    16
    9
    14
    4
    Constipation