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    Clinical Trial Results:
    Phase Ib / II study of BAY 1000394 in combination with cisplatin / etoposide or carboplatin / etoposide as first-line therapy in subjects with extensive disease small cell lung cancer

    Summary
    EudraCT number
    		 2011-004155-39
    Trial protocol
    		 FR  
    Global end of trial date
    08 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Mar 2017
    First version publication date
    19 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1000394/14858
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01573338
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    08 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the Phase Ib part of this study was to determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) dose of roniciclib (BAY1000394) in combination with cisplatin / etoposide or carboplatin / etoposide chemotherapy in 2 separate cohorts in parallel; The primary objective of the Phase II part of this study was to evaluate the response rate in subjects with extensive disease small cell lung cancer (SCLC) receiving first-line cisplatin / etoposide or carboplatin / etoposide chemotherapy in combination with roniciclib. Tumor response was evaluated based on Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Tumor measurements were made at baseline and then every 2 cycles, id est (i.e.) every 6 weeks based on 21-day cycles, until progressive disease occurred.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 Subjects received carboplatin 5 milligram per milliliter per minute (mg/mL/min) intravenous (IV) on Day 1 and Etoposide 100 milligram per meter square (mg/m^2) IV on Days 1-3 of a 21-day treatment cycle or Cisplatin 75mg/m^2 IV on Day 1 and Etoposide 100 mg/m^2 IV on Days 1-3 of a 21-day treatment cycle. A maximum of 6 cycles of carboplatin / etoposide or cisplatin / etoposide was administered unless there was tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Feb 2013
    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
    France: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    43
    EEA total number of subjects
    11
    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)
    26
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at multiple study centers in France, South Korea and United States, between 25 February 2013 (first subject first visit) and 25 March 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 58 subjects were screened, of these 15 subjects failed screening. Forty three (43) subjects were assigned to treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide
    Arm description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily (bid) for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roniciclib
    Investigational medicinal product code
    BAY1000394
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received roniciclib 2.5 mg orally twice daily for 3 days on / 4 days off schedule for 6 cycles (21 days each) in combination with chemotherapy and continued thereafter with roniciclib monotherapy.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin: Subjects received carboplatin 5 mg/mL/min IV on Day 1 of a 21-day treatment cycle. Carboplatin dose was calculated based on the Calvert’s formula = target area under curve (AUC) (5) * (estimated glomerular filtration rate [eGFR] [milliliter/minute] + 25). Etoposide: Subjects received etoposide 100 mg/m^2 as infusion for 3 days for 21-day treatment cycle (for 6 cycles).

    Arm title
    		 Roniciclib 2.5 mg bid / Cisplatin / Etoposide
    Arm description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roniciclib
    Investigational medicinal product code
    BAY1000394
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received roniciclib 2.5 mg orally twice daily for 3 days on / 4 days off schedule for 6 cycles (21 days each) in combination with chemotherapy and continued thereafter with roniciclib monotherapy.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin: Subjects received cisplatin 75 mg/m^2 as infusion on Day 1 of 21-days treatment cycle (for 6 cycles). Etoposide: Subjects received etoposide 100 mg/m^2 as infusion for 3 days for 21-day treatment cycle (for 6 cycles).

    Arm title
    		 Roniciclib 5 mg bid / Carboplatin / Etoposide
    Arm description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roniciclib
    Investigational medicinal product code
    BAY1000394
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received roniciclib 5 mg orally twice daily for 3 days on / 4 days off schedule for 6 cycles (21 days each) in combination with chemotherapy and continued thereafter with roniciclib monotherapy.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin: Subjects received carboplatin 5 mg/mL/min IV on Day 1 of a 21-day treatment cycle. Carboplatin dose was calculated based on the Calvert’s formula = target AUC (5) * (eGFR [milliliter/minute] + 25). Etoposide: Subjects received etoposide 100 mg/m^2 as infusion for 3 days for 21-day treatment cycle (for 6 cycles).

    Arm title
    		 Roniciclib 5 mg bid / Cisplatin / Etoposide
    Arm description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roniciclib
    Investigational medicinal product code
    BAY1000394
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received roniciclib 5 mg orally twice daily for 3 days on / 4 days off schedule for 6 cycles (21 days each) in combination with chemotherapy and continued thereafter with roniciclib monotherapy.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin: Subjects received cisplatin 75 mg/m^2 as infusion on Day 1 of 21-days treatment cycle (for 6 cycles). Etoposide: Subjects received etoposide 100 mg/m^2 as infusion for 3 days for 21-day treatment cycle (for 6 cycles).

    Number of subjects in period 1
    		Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Started
    4
    3
    24
    12
    Completed
    0
    0
    0
    0
    Not completed
    4
    3
    24
    12
         AE associated with clinical disease progression
    -
    -
    2
    -
         Physician decision
    -
    -
    1
    1
         Progressive disease- radiological progression
    1
    2
    15
    9
         Progressive disease- clinical progression
    1
    -
    1
    -
         Death
    -
    -
    2
    -
         Switching to other therapy
    1
    -
    -
    -
         AE un-associated with clinical disease progression
    1
    -
    1
    1
         Withdrawal by subject
    -
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roniciclib 2.5 mg bid / Carboplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily (bid) for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 2.5 mg bid / Cisplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 5 mg bid / Carboplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 5 mg bid / Cisplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide Total
    Number of subjects
    		 4 3 24 12 43
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68 ( 8 ) 59.3 ( 5.1 ) 60.6 ( 8.5 ) 59.3 ( 8.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2 5 5 14
        Male
    		 2 1 19 7 29

    End points

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    End points reporting groups
    Reporting group title
    Roniciclib 2.5 mg bid / Carboplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily (bid) for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 2.5 mg bid / Cisplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 5 mg bid / Carboplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 5 mg bid / Cisplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Subject analysis set title
    Safety analysis set SAF (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=43) included all subjects who received at least one dose of roniciclib.

    Subject analysis set title
    Pharmacokinetic (PK) analysis set (PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS (N=18) included subjects treated with at least one dose of active study medication who had valid PK data.

    Subject analysis set title
    Roniciclib, dose escalation 2.5 mg, 5 mg bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects (N=43) who received roniciclib 2.5 or 5 mg twice daily for 3 days on / 4 days off schedule in combination with chemotherapy.

    Primary: Response Rate

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    End point title
    		 Response Rate [1]
    End point description
    Response rate was defined as the percentage (%) of subjects with the best tumor response (confirmed partial response [PR] or confirmed complete response [CR]) that was achieved during or within 30 days after end of therapy. The total number of subjects with CR or PR divided by the total numbers of subjects in the safety population (included all subjects who received at least one dose of roniciclib) was ORR. CR = Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in shortaxis to greater than (<) 10 millimeter (mm). PR = At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 30 days after the last dose of study treatment
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [2]
    3 [3]
    24 [4]
    12 [5]
    Units: Percentage of subjects
        number (confidence interval 95%)
    75 (19.4 to 99.4)
    33.3 (0.8 to 90.6)
    87.5 (67.6 to 97.3)
    83.3 (51.6 to 97.9)
    Notes
    [2] - SAF
    [3] - SAF
    [4] - SAF
    [5] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [6]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly and another medical important serious event as judged by the investigator. Treatment-emergent adverse events (TEAEs) and Treatment-emergent serious adverse events (TESAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 30 days after the last dose of study treatment
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [7]
    3 [8]
    24 [9]
    12 [10]
    Units: Subjects
        TEAE
    4
    3
    24
    12
        TESAE
    0
    2
    13
    6
    Notes
    [7] - SAF
    [8] - SAF
    [9] - SAF
    [10] - SAF
    No statistical analyses for this end point

    Primary: Maximum Tolerated Dose (MTD)

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    End point title
    		 Maximum Tolerated Dose (MTD) [11]
    End point description
    MTD reflects highest dose of drug that did not cause an unacceptable side effect (= Dose limiting toxicity [DLT] in more than 30% of subjects). The MTD was the dose started at Level 1 and a modified 3+3 dose-escalation / de-escalation design was employed. Initially, 3 subjects were treated at Level 1. If 1 of the first 3 subjects experienced a DLT, another 3 subjects were added to this cohort. If none of 3 or up to 1 of 6 subjects experienced any DLT in Cycle 1 of Level 1, subsequent subjects would be treated at Level 2. If a DLT occurred in 2 subjects of one cohort, dose escalation would stop. Six subjects were to be treated at Level 2. If up to 1 of 6 subjects experienced any DLT in Cycle 1 of Level 2, Level 2 would be the MTD.
    End point type
    Primary
    End point timeframe
    From start of treatment up to first three weeks therapy
    Notes
    [11] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Roniciclib, dose escalation 2.5 mg, 5 mg bid
    Number of subjects analysed
    43 [12]
    Units: Milligram (mg)
        number (not applicable)
    5
    Notes
    [12] - SAF
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve From Zero to the Last Data Point Greater Than Lower Limit of Quantitation (LLOQ) of BAY1000394 in Plasma (AUC[0-tlast]) After Single Oral Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to the Last Data Point Greater Than Lower Limit of Quantitation (LLOQ) of BAY1000394 in Plasma (AUC[0-tlast]) After Single Oral Dose [13]
    End point description
    Area under the concentration versus time curve from zero to the last data point greater than (>) LLOQ (AUC[0-tlast]) after single dose of BAY1000394 were measured. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Primary
    End point timeframe
    Plasma samples were collected at pre-dose; 0.5, 1, 2, 4, 6, and 8 hours post-dose on Cycle 1, Day 8 (C1D8) and Cycle 2, Day 1 (C2D1)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does not allow to report only one treatment group in statistical analyses section (as here, data were evaluated between different time point C1D8 and C2D1; not between different reporting groups). Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [14]
    3 [15]
    6 [16]
    5 [17]
    Units: Microgram*hour per liter (mcg*h/L)
    geometric mean (geometric coefficient of variation)
        C1D8
    96.6 ( 20.3 )
    114 ( 32.8 )
    247 ( 51 )
    191 ( 19.8 )
        C2D1
    67.6 ( 18.5 )
    78.1 ( 47.3 )
    148 ( 38.4 )
    183 ( 20.2 )
    Attachments
    		 Untitled (Filename: Statistical Analyses_Primary_ AUC,0-tlast.DOCX)
    Notes
    [14] - PKS
    [15] - PKS
    [16] - PKS with evaluable subjects for this endpoint.
    [17] - PKS with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration (Cmax) of BAY1000394 in Plasma After Single Doses

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    End point title
    		 Maximum Observed Concentration (Cmax) of BAY1000394 in Plasma After Single Doses [18]
    End point description
    Maximum concentration of BAY1000394 in plasma after single dose administration. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Primary
    End point timeframe
    Plasma samples were collected at pre-dose, 0.5, 1, 2, 4, 6, and 8 hours post-dose on C1D8 and C2D1
    Notes
    [18] - 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: EudraCT database does not allow to report only one treatment group in statistical analyses section (as here, data were evaluated between different time point C1D8 and C2D1; not between different reporting groups). Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [19]
    3 [20]
    6 [21]
    5 [22]
    Units: Microgram per liter (mcg/L)
    geometric mean (geometric coefficient of variation)
        C1D8
    23.2 ( 31 )
    29.1 ( 71.5 )
    60.2 ( 51 )
    65.6 ( 40 )
        C2D1
    14.5 ( 26.9 )
    20.7 ( 64.2 )
    38.7 ( 75.9 )
    44.8 ( 18.2 )
    Attachments
    		 Untitled (Filename: Statistical Analyses_Primary_ Cmax.DOCX)
    Notes
    [19] - PKS
    [20] - PKS
    [21] - PKS with evaluable subjects for this endpoint.
    [22] - PKS with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    Disease control rate (DCR) was defined as the percentage of subjects who had a best response rating over the whole duration of the study of CR, PR, or SD according to RECIST 1.1. CR = Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in shortaxis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. SD = Steady state of disease. Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first subject until 3 years later, assessed every 6 weeks
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [23]
    2 [24]
    23 [25]
    11 [26]
    Units: Percentage of subjects
        number (confidence interval 95%)
    100 (47.3 to 100)
    66.7 (13.5 to 98.3)
    95.8 (81.7 to 99.8)
    91.7 (66.1 to 99.6)
    Notes
    [23] - SAF
    [24] - SAF with evaluable subjects for this endpoint.
    [25] - SAF with evaluable subjects for this endpoint.
    [26] - SAF with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) was defined as the time (days) from the date of first dose of study drug to death due to any cause. Subjects alive at the time of analysis were censored at their last contact date. Overall survival for subjects without any contact after first dose of study drug was censored at 1 day. In the below table, ‘99999’ indicates that data were not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of treatment until death (approximately up to 3 years), assessed every 3 months
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [27]
    3 [28]
    24 [29]
    12 [30]
    Units: Days
        median (confidence interval 95%)
    381.5 (238 to 99999)
    347 (195 to 99999)
    428 (281 to 734)
    341.5 (175 to 583)
    Notes
    [27] - SAF
    [28] - SAF
    [29] - SAF
    [30] - SAF
    No statistical analyses for this end point

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time to progression (TTP) was defined as the time (days) from the date of the first dose of study drug to the date of the first observed radiological disease progression. Time to progression for subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation. In the below table, ‘99999’ indicates that data were not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first subject until 3 years later, assessed every 6 weeks
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [31]
    3 [32]
    24 [33]
    12 [34]
    Units: Days
        median (confidence interval 95%)
    203 (157 to 241)
    164 (47 to 99999)
    227 (164 to 259)
    173 (145 to 217)
    Notes
    [31] - SAF
    [32] - SAF
    [33] - SAF
    [34] - SAF
    No statistical analyses for this end point

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    Progression-free survival (PFS) was defined as the time (days) from the date of the first dose of study drug to the date of the first observed radiological disease progression or death, whichever came first. Progression-free survival for subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation. In the below table, ‘99999’ indicates that data were not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first subject until 3 years later, assessed every 6 weeks
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    4 [35]
    3 [36]
    24 [37]
    12 [38]
    Units: Days
        median (confidence interval 95%)
    203 (157 to 241)
    164 (47 to 99999)
    218.5 (165 to 259)
    188 (145 to 217)
    Notes
    [35] - SAF
    [36] - SAF
    [37] - SAF
    [38] - SAF
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response (DOR) was defined as the time (days) from the date of first objective radiological response to the date that progressive disease was first objectively (radiologically) documented or death (if death occurred earlier than disease progression). DOR was evaluated only for subjects who achieved their confirmed best response as complete response or partial response. For subjects who had not progressed or died at the time of analysis, DOR was censored at their last date of evaluable scan. ‘99999’ indicates that data were not estimable due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of treatment of the first subject until 3 years later, assessed every 6 weeks
    End point values
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Number of subjects analysed
    3 [39]
    1 [40]
    21 [41]
    10 [42]
    Units: Days
        median (confidence interval 95%)
    169 (121 to 206)
    128 (0 to 99999)
    193 (131 to 224)
    154 (64 to 183)
    Notes
    [39] - SAF with evaluable subjects for this endpoint.
    [40] - SAF with evaluable subjects for this endpoint.
    [41] - SAF with evaluable subjects for this endpoint.
    [42] - SAF with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to 30 days after the last dose of study treatment
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Roniciclib 2.5 mg bid / Carboplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily for 3 days on / 4 days off schedule in||combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter||with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 2.5 mg bid / Cisplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 2.5 mg tablets orally twice daily for 3 days on / 4 days off schedule in||combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter||with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 5 mg bid / Carboplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in||combination with chemotherapy (carboplatin / etoposide) for 6 cycles (21 days each) and continued thereafter||with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Reporting group title
    Roniciclib 5 mg bid / Cisplatin / Etoposide
    Reporting group description
    		 Subjects received roniciclib 5 mg tablets orally twice daily for 3 days on / 4 days off schedule in||combination with chemotherapy (cisplatin / etoposide) for 6 cycles (21 days each) and continued thereafter||with roniciclib monotherapy. Study treatment continued until tumor progression, unacceptable toxicity, death, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

    Serious adverse events
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 3 (66.67%)
    13 / 24 (54.17%)
    6 / 12 (50.00%)
         number of deaths (all causes)
    3
    2
    17
    12
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 24 (12.50%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Roniciclib 2.5 mg bid / Carboplatin / Etoposide Roniciclib 2.5 mg bid / Cisplatin / Etoposide Roniciclib 5 mg bid / Carboplatin / Etoposide Roniciclib 5 mg bid / Cisplatin / Etoposide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    24 / 24 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    3 / 12 (25.00%)
         occurrences all number
    0
    1
    1
    4
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    2
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vascular pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    6 / 24 (25.00%)
    4 / 12 (33.33%)
         occurrences all number
    7
    3
    13
    14
    Chest discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    2
    Chills
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    2
    Discomfort
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    6 / 24 (25.00%)
    6 / 12 (50.00%)
         occurrences all number
    1
    1
    21
    20
    Injection site extravasation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    6
    Mucosal inflammation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    3
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    4
    3
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    4 / 24 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    6
    2
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    5 / 24 (20.83%)
    4 / 12 (33.33%)
         occurrences all number
    1
    1
    5
    7
    Dysphonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 24 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    6 / 24 (25.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    6
    6
    Dyspnoea exertional
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    0
    3
    Haemoptysis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    1
    2
    Hiccups
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Laryngeal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Wheezing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    1
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Depressed mood
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Hallucination
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    6 / 24 (25.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    1
    6
    4
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    3 / 24 (12.50%)
    2 / 12 (16.67%)
         occurrences all number
    1
    4
    3
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 24 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    5
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Lipase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    13 / 24 (54.17%)
    2 / 12 (16.67%)
         occurrences all number
    15
    14
    74
    3
    Platelet count decreased
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    12 / 24 (50.00%)
    5 / 12 (41.67%)
         occurrences all number
    12
    3
    56
    14
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    3
    Weight increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    5 / 24 (20.83%)
    2 / 12 (16.67%)
         occurrences all number
    11
    6
    7
    3
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Burns second degree
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Epicondylitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    0
    4
    Incision site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Radiation skin injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    0
    4
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aphasia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Ataxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cerebellar syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    3 / 24 (12.50%)
    5 / 12 (41.67%)
         occurrences all number
    3
    2
    4
    12
    Dysgeusia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    5
    0
    0
    7
    Head discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    12 / 24 (50.00%)
    6 / 12 (50.00%)
         occurrences all number
    1
    0
    36
    9
    Hemiparesis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypersomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Motor dysfunction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myoclonus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Visual field defect
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 4 (100.00%)
    2 / 3 (66.67%)
    15 / 24 (62.50%)
    7 / 12 (58.33%)
         occurrences all number
    12
    8
    44
    33
    Leukocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Leukopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 24 (12.50%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    3
    2
    Lymphopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    2
    Neutropenia
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    3 / 24 (12.50%)
    5 / 12 (41.67%)
         occurrences all number
    4
    4
    11
    14
    Thrombocytopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    6 / 24 (25.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    8
    43
    8
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Hypoacusis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ototoxicity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    1
    1
    0
    6
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vertigo positional
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Visual impairment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    4
    Abdominal pain upper
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    3 / 12 (25.00%)
         occurrences all number
    1
    0
    4
    3
    Constipation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    7 / 24 (29.17%)
    5 / 12 (41.67%)
         occurrences all number
    1
    0
    10
    5
    Diarrhoea
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    13 / 24 (54.17%)
    10 / 12 (83.33%)
         occurrences all number
    5
    18
    40
    19
    Dry mouth
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Eructation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    3 / 24 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Nausea
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    23 / 24 (95.83%)
    11 / 12 (91.67%)
         occurrences all number
    17
    9
    162
    56
    Oral pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Periodontal disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Retching
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 4 (100.00%)
    1 / 3 (33.33%)
    15 / 24 (62.50%)
    10 / 12 (83.33%)
         occurrences all number
    12
    7
    52
    42
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 4 (100.00%)
    2 / 3 (66.67%)
    12 / 24 (50.00%)
    6 / 12 (50.00%)
         occurrences all number
    5
    4
    20
    13
    Blister
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Dry skin
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    2
    Erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    4
    Hyperhidrosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    2
    1
    Nail disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 24 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    4 / 24 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 24 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Skin disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    3
    Chronic kidney disease
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nephropathy toxic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Renal failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Renal impairment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Renal vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    6
    0
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Joint stiffness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    5 / 24 (20.83%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    7
    4
    Neck pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 24 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Spinal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Candida infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Clostridium difficile infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Folliculitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    1
    3
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rash pustular
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tracheitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    7 / 24 (29.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    10
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 24 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    2
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    10 / 24 (41.67%)
    10 / 12 (83.33%)
         occurrences all number
    2
    2
    18
    19
    Dehydration
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 24 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 24 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    2
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 24 (4.17%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 24 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    7
    5
    Hypocalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 24 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    2
    2
    Hypoglycaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    7 / 24 (29.17%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    18
    5
    Hypomagnesaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    7 / 24 (29.17%)
    7 / 12 (58.33%)
         occurrences all number
    4
    20
    53
    18
    Hyponatraemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    6 / 24 (25.00%)
    3 / 12 (25.00%)
         occurrences all number
    2
    4
    15
    6
    Hypophagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 24 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 24 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2012
    Changed the roniciclib starting dose and dose levels, as well as dose modifications of roniciclib based on the updated results of first-in-man; clarified language concerning study design, sample size, dosing.
    28 Feb 2013
    Excluded anticoagulation therapy, clarified procedures for biomarker analysis, dose delays, and PK parameters.
    04 Sep 2013
    Reported the change of the Coordinating Investigator.
    22 Apr 2014
    Updated adequate contraceptive guidance to continue for 6 months after chemotherapy.
    11 Nov 2014
    Updated to include new clinical pharmacology data regarding involvement of Cytochrome P450 3A4 (CYP3A4) in roniciclib biotransformation.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Mar 2016
    The results of preliminary Phase 2 study (14615, 2013-004198-28) suggested that treatment with roniciclib in combination with chemotherapy had an unfavorable benefit-risk balance. Therefore, due to safety reasons it was decided to discontinue and terminate the roniciclib (14858, 2011-004155-39) project.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Occurrence of "±” in relation with geometric CV is auto-generated and cannot be deleted. Decimal places were automatically truncated if last decimal equals zero. ‘99999’ indicates that data were not estimable due to censored data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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