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    Clinical Trial Results:
    Phase I-II study of F14512 in combination with cytarabine in patients 60 years old and older with acute myeloid leukemia.

    Summary
    EudraCT number
    		 2012-005241-20
    Trial protocol
    		 FR   IT   ES  
    Global end of trial date
    03 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2018
    First version publication date
    01 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F14512IN102G1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PIERRE FABRE MEDICAMENT
    Sponsor organisation address
    45 Place Abel Gance, Boulogne-Billancourt, France, 92100
    Public contact
    Clinical Trial Information Desk, PIERRE FABRE MEDICAMENT, contact_essais_cliniques@pierre-fabre.com
    Scientific contact
    Karim Keddad, Institut de Recherche Pierre Fabre 3 avenue Hubert Curien 31100 Toulouse, 33 534506169, karim.keddad@pierre-fabre.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
    10 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase I part: To determine the maximal tolerated dose (MTD) of F14512 administered as a three-hour daily infusion given for 5 consecutive days in combination with cytarabine 1 g/m²/day for 5 consecutive days in patients 60 years old or older with refractory or relapsing AML. Phase II part: To evaluate the efficacy of F14512 in combination with cytarabine (rate of complete remission [CR] and complete remission with incomplete blood recovery [CRi]) in AML patients 60 years old and older in first relapse or with refractory disease.
    Protection of trial subjects
    This study was performed in accordance with the principles stated in current version of the Declaration of Helsinki (1964 and subsequent amendments) and with the International Council for Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) (CPMP/ICH/135/95), and with related national regulations in biomedical research. All patients were informed of the aims, methods, objectives, and potential hazards of the study, and a signed informed consent form (ICF) was obtained from each patient prior to any study related procedures, or appropriate corrective actions have been implemented in case of failure. A specific patient informed consent, either on the same document or a separate document depending on the country, was also required for genetic research. The first study protocol in use (V2 : 15 February 2013), all of its 3 amendments (all substantial), and the patient information sheets, were reviewed by the appropriate IECs, including local IECs.
    Background therapy
    		 In both phases, the test product (F14512) was administered in combination with cytarabine F14512 (3-h daily infusion) was tested at the doses of 10 (DL 1), 15 (DL 1), 20 (DL 2), 26 (DL 3) and 34 mg/m²/day (DL 4) (Phase I) and 26 mg/m²/day (Phase II-induction) then 15 mg/m2/day (Phase II consolidation) : F14512 was administered as a 3 hour daily infusion, beginning 1 hour after the end of cytarabine infusion (1g/m2/day) for 5 consecutive days per 21-to-42-day cycle : until unacceptable toxicity/disease progression and up to a maximum of 6 cycles in phase I ; up to a maximum of 5 cycles (1 induction+4 consolidation or 2 induction+3 consolidation cycles) in phase II.
    Evidence for comparator
    		 The non-randomised, open-label design was typical for a Phase I to II oncology study with such objectives. There was no placebo control group as this would not have been ethical in this patient population. In first relapse, there is no single approach considered as standard and treatment is selected based on the age of the patient and the duration of the first complete response. In patients who are 60 years old or older, intermediate dose cytarabine alone or associated with another cytotoxic agent is commonly used. Results of a previous Phase I study of single-agent F14512 in patients with relapsed and refractory AML, together with demonstration of synergism between F14512 and cytarabine in preclinical models, constituted the rationale for testing this combination regimen in patients with AML.
    Actual start date of recruitment
    09 Apr 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 26 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    France: 70
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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)
    15
    From 65 to 84 years
    56
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 72 patients were registered (71 in France, 1 in Spain), and 71 patients were enrolled and treated (70 in France, 1 in Spain) : - 18 in Phase I part in 4 cohorts (3, 3, 6 and 6 patients were administered 15mg/m2/day, 20mg/m2/day, 26mg/m2/day and 34 mg/m2/day, respectively) - 53 in Phase II part (26mg/m2/day)

    Pre-assignment
    Screening details
    		 Eligible patients had AML (both phases) refractory after failure of 1 induction chemotherapy regimen or recurrence of disease < 3 months after CR, or (Phase I) relapsed AML, or (Phase II) first relapse after CR or CRi lasting 3 to 24 months ; were ≥60 years, with WHO PS ≤ 2, adequate liver and renal function and a LVEF≥45%.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I-15 mg
    Arm description
    		 Patients treated with F14512 at 15 mg/m2/day during the phase I dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    F14512
    Investigational medicinal product code
    F14512
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    F14512 was administered as a 3-hour daily infusion, beginning 1 hour after the end of cytarabine infusion, through a central venous catheter for 5 consecutive days

    Investigational medicinal product name
    cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 1 g/m²/day as a 2-hour daily infusion for 5 consecutive days

    Arm title
    		 Phase I-20 mg
    Arm description
    		 Patients treated with F14512 at 20 mg/m2/day during the Phase I dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    F14512
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 20 mg/m²/day administered as a 3-hour daily infusion, beginning 1 hour after the end of cytarabine infusion, through a central venous catheter for 5 consecutive days

    Investigational medicinal product name
    cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 1 g/m²/day administered as a 2-hour daily infusion for 5 consecutive days

    Arm title
    		 Phase I-26 mg
    Arm description
    		 Patients treated with F14512 26 mg/m2/day during Phase I-dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    F14512
    Investigational medicinal product code
    F14512
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doses of 26 mg/m²/day administered as a 3-hour daily infusion, beginning 1 hour after the end of cytarabine infusion, through a central venous catheter for 5 consecutive days

    Investigational medicinal product name
    cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 1 g/m²/day administered as a 2-hour daily infusion for 5 consecutive days.

    Arm title
    		 Phase I-34 mg
    Arm description
    		 Patients treated with F14512 at 34 mg/m2/day in the Phase I dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    F14512
    Investigational medicinal product code
    F14512
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 34 mg/m²/day administered as a 3-hour daily infusion, beginning 1 hour after the end of cytarabine infusion, through a central venous catheter for 5 consecutive days

    Investigational medicinal product name
    cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 1 g/m²/day administered as a 2-hour daily infusion for 5 consecutive days

    Arm title
    		 Phase II (26 mg)
    Arm description
    		 All patients treated in Phase II of the study. In this phase, all patients were treated with F14512 at the dose of 26 mg/m2/day during the induction cycle(s)
    Arm type
    		 Experimental

    Investigational medicinal product name
    F14512
    Investigational medicinal product code
    F14512
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 26 mg/m²/day administered as a 3-hour daily infusion, beginning 1 hour after the end of cytarabine infusion, through a central venous catheter for 5 consecutive days during the induction cycle(s) = 1st and (if haematological improvement) 2nd cycle. During the consolidation cycles, the dose was reduced to 15 mg/m2/day.

    Investigational medicinal product name
    cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 1 g/m²/day administered as a 2-hour daily infusion for 5 consecutive days

    Number of subjects in period 1
    		Phase I-15 mg Phase I-20 mg Phase I-26 mg Phase I-34 mg Phase II (26 mg)
    Started
    3
    3
    6
    6
    53
    Completed
    0
    0
    0
    0
    2
    Not completed
    3
    3
    6
    6
    51
         Adverse event, serious fatal
    -
    -
    -
    -
    1
         Physician decision
    -
    -
    -
    -
    1
         Psychological reason
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    1
    -
    2
         Maximum benefit obtained (complete response)
    -
    -
    2
    -
    -
         Maximum benefit obtained
    -
    -
    -
    -
    10
         Transplant
    -
    -
    -
    -
    4
         Lack of efficacy
    3
    3
    3
    6
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I-15 mg
    Reporting group description
    		 Patients treated with F14512 at 15 mg/m2/day during the phase I dose escalation

    Reporting group title
    Phase I-20 mg
    Reporting group description
    		 Patients treated with F14512 at 20 mg/m2/day during the Phase I dose escalation

    Reporting group title
    Phase I-26 mg
    Reporting group description
    		 Patients treated with F14512 26 mg/m2/day during Phase I-dose escalation

    Reporting group title
    Phase I-34 mg
    Reporting group description
    		 Patients treated with F14512 at 34 mg/m2/day in the Phase I dose escalation

    Reporting group title
    Phase II (26 mg)
    Reporting group description
    		 All patients treated in Phase II of the study. In this phase, all patients were treated with F14512 at the dose of 26 mg/m2/day during the induction cycle(s)

    Reporting group values
    		 Phase I-15 mg Phase I-20 mg Phase I-26 mg Phase I-34 mg Phase II (26 mg) Total
    Number of subjects
    		 3 3 6 6 53 71
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    All patients were to be >=60 years
    Units: years
        arithmetic mean (standard deviation)
    		 72 ± 4.9 67.5 ± 1.7 67.6 ± 4.6 70.2 ± 4.4 67.2 ± 4.0 -
    Gender categorical
    Units: Subjects
        Female
    		 0 1 2 1 24 28
        Male
    		 3 2 4 5 29 43
    Subject analysis sets

    Subject analysis set title
    Phase II ITT set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated in Phase II

    Subject analysis set title
    Phase II ITT subset of responders
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ITT subset of responders after induction cycle(s) of Phase II (i.e. with CR or CRi).

    Subject analysis sets values
    		 Phase II ITT set Phase II ITT subset of responders
    Number of subjects
    53
    20
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    All patients were to be >=60 years
    Units: years
        arithmetic mean (standard deviation)
    67.2 ± 4.0
    ±
    Gender categorical
    Units: Subjects
        Female
    24
        Male
    29

    End points

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    End points reporting groups
    Reporting group title
    Phase I-15 mg
    Reporting group description
    		 Patients treated with F14512 at 15 mg/m2/day during the phase I dose escalation

    Reporting group title
    Phase I-20 mg
    Reporting group description
    		 Patients treated with F14512 at 20 mg/m2/day during the Phase I dose escalation

    Reporting group title
    Phase I-26 mg
    Reporting group description
    		 Patients treated with F14512 26 mg/m2/day during Phase I-dose escalation

    Reporting group title
    Phase I-34 mg
    Reporting group description
    		 Patients treated with F14512 at 34 mg/m2/day in the Phase I dose escalation

    Reporting group title
    Phase II (26 mg)
    Reporting group description
    		 All patients treated in Phase II of the study. In this phase, all patients were treated with F14512 at the dose of 26 mg/m2/day during the induction cycle(s)

    Subject analysis set title
    Phase II ITT set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated in Phase II

    Subject analysis set title
    Phase II ITT subset of responders
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ITT subset of responders after induction cycle(s) of Phase II (i.e. with CR or CRi).

    Primary: Dose limiting toxicity (DLT)-Phase I

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    End point title
    		 Dose limiting toxicity (DLT)-Phase I [1] [2]
    End point description
    The maximal tolerated dose (MTD) was defined as the dose at which 2 out of 3 or 2 out of 6 patients experienced a DLT during the 1st cycle of administration
    End point type
    Primary
    End point timeframe
    1st cycle of administration (min 21 days, max 42 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 analysis planned. The conclusion were based on the number of patients with DLT in each dose level
    [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: There was no evaluation of DLT assessed in the single arm of the Phase II part of the trial (different objective from that of Phase I). Phase II part was conducted at the recommended dose determined in phase I (defined as the dose immediately below the MTD): 34 mg/m2/day was determined to be the MTD and 26 mg/m2/day the recommended dose for Phase II.
    End point values
    		 Phase I-15 mg Phase I-20 mg Phase I-26 mg Phase I-34 mg
    Number of subjects analysed
    3
    3
    6
    6
    Units: number of patients with DLTs
    0
    0
    0
    2
    No statistical analyses for this end point

    Primary: Overall response rate (ORR)-Phase II

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    End point title
    		 Overall response rate (ORR)-Phase II [3]
    End point description
    The ORR is defined as the rate of patients in complete remission (CR) or in complete remission with incomplete blood recovery (CRi) as assessed by the Investigator. The 95% CI was one-sided (left-sided).
    End point type
    Primary
    End point timeframe
    The ORR was evaluated in phase II, after one or (if haematological improvement after cycle 1) two cycles of induction.
    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 analysis planned. The conclusion were based on the descriptive values.
    End point values
    		 Phase II ITT set
    Number of subjects analysed
    Units: percentage
        number (confidence interval 95%)
    37.7 (26.6 to 100.0)
    No statistical analyses for this end point

    Secondary: ORR-Phase I

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    End point title
    		 ORR-Phase I [4]
    End point description
    The ORR was the rate of responders i.e. of patients in complete remission (CR) or complete remission with incomplete blood recovery (CRi) as assessed by the Investigator
    End point type
    Secondary
    End point timeframe
    The ORR in phase I was evaluated over the treatment period i.e. until unacceptable toxicity or disease progression up to a maximum of 6 cycles.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned. The conclusion were based on the descriptive values.
    End point values
    		 Phase I-15 mg Phase I-20 mg Phase I-26 mg Phase I-34 mg
    Number of subjects analysed
    3
    3
    6
    6
    Units: Percentage
        number (confidence interval 95%)
    33.3 (0.8 to 90.6)
    0 (0 to 70.8)
    50 (11.8 to 88.2)
    16.7 (0.4 to 64.1)
    No statistical analyses for this end point

    Secondary: Relapse-free survival (RFS)-Phase II

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    End point title
    		 Relapse-free survival (RFS)-Phase II
    End point description
    Time from date of CR/CRi to relapse or death whichever occurs first, or (in progression-free patients) to last disease assessment . Relapse was defined as an increase of bone marrow blasts ≥ 5% or reappearance of blasts in the blood; or development of extramedullary disease.
    End point type
    Secondary
    End point timeframe
    Post-remission treatment and follow-up periods.
    End point values
    		 Phase II ITT subset of responders
    Number of subjects analysed
    20
    Units: Months
        median (confidence interval 95%)
    7.5 (4.1 to 30.6)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)-Phase II

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    End point title
    		 Progression-free survival (PFS)-Phase II
    End point description
    Time from registration to disease progression, relapse or death whichever occurs first, or (in progression-free patients) to last disease assessment.
    End point type
    Secondary
    End point timeframe
    Whole study period from registration.
    End point values
    		 Phase II ITT set
    Number of subjects analysed
    53
    Units: Months
        median (confidence interval 95%)
    1.3 (1.1 to 3.2)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)-Phase II

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    End point title
    		 Overall survival (OS)-Phase II
    End point description
    Time from registration to death or date of last news if not died.
    End point type
    Secondary
    End point timeframe
    Whole study period from registration
    End point values
    		 Phase II ITT set
    Number of subjects analysed
    53
    Units: Months
        median (confidence interval 95%)
    6.7 (5.3 to 9.7)
    No statistical analyses for this end point

    Secondary: Duration of remission-Phase II

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    End point title
    		 Duration of remission-Phase II
    End point description
    Time from CR/CRi date to the date of relapse, or (in progression-free patients) of last disease assessment.
    End point type
    Secondary
    End point timeframe
    Post-remission treatment and follow-up periods
    End point values
    		 Phase II ITT subset of responders
    Number of subjects analysed
    Units: Months
        median (inter-quartile range (Q1-Q3))
    7.5 (5.7 to 30.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period (including 60 days of follow-up)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Phase I-15 mg
    Reporting group description
    		 Patients treated with F14512 at 15 mg/m2/day during the phase I dose escalation

    Reporting group title
    Phase I-20 mg
    Reporting group description
    		 Patients treated with F14512 mg/m2/day during the Phase I dose escalation

    Reporting group title
    Phase I-26 mg
    Reporting group description
    		 Patients treated with F14512 26 mg/m2/day during Phase I-dose escalation

    Reporting group title
    Phase I-34 mg
    Reporting group description
    		 Patients treated with F14512 at 34 mg/m2/day in the Phase I dose escalation

    Reporting group title
    Phase II (26 mg)
    Reporting group description
    		 All patients treated in Phase II of the study. In this phase, all patients were treated with F14512 at the dose of 26 mg/m2/day

    Serious adverse events
    		 Phase I-15 mg Phase I-20 mg Phase I-26 mg Phase I-34 mg Phase II (26 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    27 / 53 (50.94%)
         number of deaths (all causes)
    0
    1
    0
    0
    6
         number of deaths resulting from adverse events
    0
    0
    0
    0
    2
    Investigations
    Investigation
    Additional description: Abnormal transthoracic echocardiography of the aortic and mitral valves in the patient of Phase II concerned
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    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
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
    Additional description: Progression of the target disease (AML)
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    5 / 53 (9.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 5
    Injury, poisoning and procedural complications
    Septic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    6 / 53 (11.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiogenic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    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
    Pericarditis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar ataxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    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 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    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
    Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Bone marrow failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Cholecystitis acute
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Hidradenitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    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
    Enterococcal sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 53 (7.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    8 / 53 (15.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Device related infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Device related sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase I-15 mg Phase I-20 mg Phase I-26 mg Phase I-34 mg Phase II (26 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    53 / 53 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Cancer pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    5 / 53 (9.43%)
         occurrences all number
    0
    0
    2
    1
    7
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    6 / 53 (11.32%)
         occurrences all number
    0
    0
    1
    0
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    9 / 53 (16.98%)
         occurrences all number
    2
    1
    7
    2
    11
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    10 / 53 (18.87%)
         occurrences all number
    2
    1
    3
    0
    10
    Pyrexia
         subjects affected / exposed
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    4 / 6 (66.67%)
    1 / 6 (16.67%)
    13 / 53 (24.53%)
         occurrences all number
    4
    0
    7
    1
    16
    Catheter site inflammation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    0
    1
    Catheter site pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 53 (5.66%)
         occurrences all number
    2
    0
    1
    1
    3
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    0
    0
    4
    Implant site pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Thrombosis in device
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    6 / 53 (11.32%)
         occurrences all number
    1
    0
    0
    1
    6
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    2
    0
    0
    3
    Hiccups
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    9 / 53 (16.98%)
         occurrences all number
    1
    1
    0
    0
    9
    Hypoxia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    1
    0
    1
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    1
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    12 / 53 (22.64%)
         occurrences all number
    0
    2
    4
    3
    12
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    9 / 53 (16.98%)
         occurrences all number
    0
    0
    2
    1
    9
    Hallucination
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    1
    1
    3
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    1
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    0
    1
    0
    3
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    17 / 53 (32.08%)
         occurrences all number
    0
    0
    0
    1
    21
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    0
    1
    4
    Toxicity to various agents
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 53 (9.43%)
         occurrences all number
    0
    0
    0
    0
    7
    Arrhythmia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    20 / 53 (37.74%)
         occurrences all number
    4
    1
    5
    1
    25
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 3 (100.00%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    22 / 53 (41.51%)
         occurrences all number
    0
    3
    9
    5
    27
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Eye disorders
    Eye disorder
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    19 / 53 (35.85%)
         occurrences all number
    5
    2
    4
    2
    26
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    1 / 6 (16.67%)
    5 / 6 (83.33%)
    34 / 53 (64.15%)
         occurrences all number
    2
    2
    2
    5
    42
    Dry mouth
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 53 (3.77%)
         occurrences all number
    1
    0
    0
    1
    2
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    6 / 6 (100.00%)
    5 / 6 (83.33%)
    35 / 53 (66.04%)
         occurrences all number
    4
    1
    10
    5
    52
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    21 / 53 (39.62%)
         occurrences all number
    3
    1
    3
    2
    31
    Abdominal pain upper
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    9 / 53 (16.98%)
         occurrences all number
    1
    0
    0
    2
    12
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    17 / 53 (32.08%)
         occurrences all number
    1
    1
    3
    3
    20
    Dysphagia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    0
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    6 / 53 (11.32%)
         occurrences all number
    0
    0
    3
    0
    6
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    11 / 53 (20.75%)
         occurrences all number
    0
    0
    1
    1
    14
    Mouth ulceration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    0
    0
    0
    3
    Stomatitis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    13 / 53 (24.53%)
         occurrences all number
    1
    1
    3
    2
    15
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    2
    0
    3
    Anal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    0
    1
    2
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    6 / 53 (11.32%)
         occurrences all number
    0
    0
    0
    0
    6
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    1
    0
    0
    2
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 6 (66.67%)
    1 / 6 (16.67%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    6
    1
    6
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Toxic skin eruption
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    1
    0
    4
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    1
    1
    2
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    1
    0
    2
    Hidradenitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    0
    1
    Micturition disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    0
    1
    4
    Urinary tract disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in jaw
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    7 / 53 (13.21%)
         occurrences all number
    1
    0
    2
    0
    8
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    8 / 53 (15.09%)
         occurrences all number
    0
    0
    0
    0
    8
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    1
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    4 / 53 (7.55%)
         occurrences all number
    0
    1
    2
    1
    4
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    4 / 53 (7.55%)
         occurrences all number
    0
    0
    3
    1
    4
    Osteoarthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    1
    Infections and infestations
    Sialoadenitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    2
    1
    0
    3
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 53 (9.43%)
         occurrences all number
    0
    0
    0
    0
    8
    Bacterial infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    8 / 53 (15.09%)
         occurrences all number
    0
    0
    0
    0
    10
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    7 / 53 (13.21%)
         occurrences all number
    2
    0
    4
    1
    7
    Folliculitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 53 (9.43%)
         occurrences all number
    1
    0
    0
    0
    5
    Fungal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    8 / 53 (15.09%)
         occurrences all number
    0
    0
    0
    0
    9
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    4
    Pneumonia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 53 (5.66%)
         occurrences all number
    2
    0
    0
    1
    3
    Laryngitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Device related infection
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    1
    2
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Anorectal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    1
    0
    0
    2
    Streptococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    0
    3
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    1
    0
    2
    Anorectal cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    0
    1
    Oral infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Lung infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    0
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    16 / 53 (30.19%)
         occurrences all number
    2
    1
    2
    0
    18
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    0
    1
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    0
    0
    2
    Malnutrition
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    2
    1
    Fluid retention
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2013
    Completion of the definition of DLT. Correction of a discrepancy between the synopsis and the protocol regarding the exclusion criteria number 10. Correction of the volume of rinse of the catheter following the end of F14512 infusion. Addition of specifications for F14512 preparation. Correction of the labelling of the study drugs F14512 and Cytarabine. Modification of the reporting modalities of SAEs and the SAE report form. Addition of pharmaceutical information about the non-modified associated product Cytarabine following the addition of a second supplier.
    28 Apr 2014
    combination (F14512 plus cytarabine) showed similar results in first relapsed and refractory patients.  Extension of the follow-up phase until documentation of death from any cause.  Modification of the PK sampling in Phase II regarding the results of Phase I and modification of the volume of bone marrow sample for Specification of the RD determined during Phase I, to be tested during Phase II (26 mg/m²/day of F14512). Definition of specific criteria allowing 1 re-induction cycle and consolidation cycles, for Phase II, as well as the rules of study drugs administration: dose of F14512 and cytarabine and number of cycles. Extension of the inclusion criteria of Phase II to patients who had refractory AML after failure of 1 induction chemotherapy regimen or who had recurrence of disease < 3 months after CR. In Phase I, the rate of response of thePD assessments (Phase I and Phase II). Withdrawal of PBMC sample collection. Study manager was appointed and head statistician was changed. Modification of the blood sampling procedures for PK assessment. Correction of the results of efficacy of the first-in-man Phase I study. Extension of the list of participating countries. The number of sites was increased in order to recruit the 50 patients in Phase II. Update of the version of the IB. Update of the version of the World Medical Association Declaration of Helsinki (October 2013).
    03 Feb 2015
    Extension of the recruitment period in order to obtain the 50 patients requested by the protocol in the ongoing Phase II part.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    03 Mar 2017
    Due to the discontinuation of the development of F14512 in the indication of AML, and, as described in the study protocol, the sponsor decided to proceed with an early termination of the trial on 03 March 2017. All the patients had finished the study treatment period at time of trial early termination. The date of the last study drug administration was 24 October 2015.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No limitations and caveats for Phase I of the trial: 26 mg/M2/day was defined as the recommended dose for Phase II. The early termination of Phase II is not a limitation as all patients had completed the treatment period + 60 days evaluation period.
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