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    Clinical Trial Results:
    A randomized, double blind, placebo-controlled, multicenter phase II study to evaluate efficacy and safety of roniciclib in subjects with extensive-stage disease small cell lung cancer (SCLC) who are receiving cisplatin + etoposide or carboplatin + etoposide as first-line therapy

    Summary
    EudraCT number
    2013-004198-28
    Trial protocol
    DE   BE   HU   IT   PL  
    Global end of trial date
    25 May 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1000394/14615
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02161419
    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
    25 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to compare roniciclib with placebo in addition to background treatment with chemotherapy (either cisplatin + etoposide or carboplatin + etoposide) in terms of progression free survival (PFS) in small cell lung cancer (SCLC) subjects.
    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 background treatment with chemotherapy (either cisplatin + etoposide or carboplatin + etoposide) in terms of progression free survival in SCLC subjects.
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 9
    Country: Number of subjects enrolled
    Poland: 16
    Worldwide total number of subjects
    142
    EEA total number of subjects
    101
    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)
    84
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 32 centers, enrolled subjects in 9 countries between 30 July 2014 (first subject first visit) and 07 April 2016 (last subject last visit). Primary completion date of the study was 31 December 2015.

    Pre-assignment
    Screening details
    A total of 172 subjects were screened, of these 30 subjects failed screening. The remaining 142 subjects were randomized and 140 subjects received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Roniciclib (BAY1000394) 10 mg
    Arm description
    Subjects received roniciclib 5 milligram (mg) (2 * 2.5 mg tablet) orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin/etoposide or 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 (2 * 2.5 mg tablet) orally twice daily for 3 days on / 4 days off schedule for 6 cycles (21 days each) 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 milligram per square meter (mg/m^2) as infusion for 6 cycles (21 days each). Etoposide: Subjects received etoposide 100 mg/m^2 as infusion for 3 days for up to 6 cycles (21 days each). Carboplatin: Subjects received carboplatin as infusion for 6 cycles (21 days each). Carboplatin dose is calculated based on the Calvert’s formula = target area under curve (AUC) (5) x (estimated glomerular filtration rate [eGFR] [milliliter/minute] + 25).

    Arm title
    Placebo
    Arm description
    Subjects received placebo matched to roniciclib tablets orally twice daily for 3 days on / 4 days off schedule along with chemotherapy (carboplatin/etoposide or cisplatin/etoposide) for 6 cycles (21 days each).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to roniciclib tablets orally twice daily for 3 days on / 4 days off schedule for 6 cycles (21 days each).

    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 for 6 cycles (21 days each). Etoposide: Subjects received etoposide 100 mg/m^2 as infusion for 3 days for up to 6 cycles (21 days each). Carboplatin: Subjects received carboplatin as infusion for 6 cycles (21 days each). Carboplatin dose is calculated based on the Calvert’s formula = target area under curve (AUC) (5) x (estimated glomerular filtration rate [eGFR] [milliliter/minute] + 25).

    Number of subjects in period 1
    Roniciclib (BAY1000394) 10 mg Placebo
    Started
    71
    71
    Treated
    70
    70
    Completed
    47
    58
    Not completed
    24
    13
         Physician decision
    4
    -
         Protocol driven decision point
    -
    1
         Protocol violation
    1
    1
         Withdrawal by subject
    6
    4
         Study drug never administered
    1
    1
         Deterioration of general conditions
    -
    1
         Switching to other therapy
    1
    1
         AE unassociated with clinical disease progression
    10
    3
         Lost to follow-up
    -
    1
         Intolerance
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roniciclib (BAY1000394) 10 mg
    Reporting group description
    Subjects received roniciclib 5 milligram (mg) (2 * 2.5 mg tablet) orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin/etoposide or 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
    Placebo
    Reporting group description
    Subjects received placebo matched to roniciclib tablets orally twice daily for 3 days on / 4 days off schedule along with chemotherapy (carboplatin/etoposide or cisplatin/etoposide) for 6 cycles (21 days each).

    Reporting group values
    Roniciclib (BAY1000394) 10 mg Placebo Total
    Number of subjects
    71 71 142
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.5 ± 8.9 62.4 ± 7.5 -
    Gender categorical
    Units: Subjects
        Female
    28 27 55
        Male
    43 44 87
    Eastern cooperative oncology group (ECOG) Performance Status (PS)
    ECOG PS was measured in a scale from 0 to grade 5, where 0= Fully active, able to carry on all pre-diseases performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours, 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair and 5= dead.
    Units: Subjects
        Score 0
    25 20 45
        Score 1
    46 51 97
    Type of chemo combination therapy
    Subjects received roniciclib along with chemotherapy (carboplatin/etoposide or cisplatin/etoposide) for 6 cycles (21 days each).
    Units: Subjects
        Missing
    1 1 2
        Carboplatin / Etoposide
    44 44 88
        Cisplatin / Etoposide
    26 26 52

    End points

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    End points reporting groups
    Reporting group title
    Roniciclib (BAY1000394) 10 mg
    Reporting group description
    Subjects received roniciclib 5 milligram (mg) (2 * 2.5 mg tablet) orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin/etoposide or 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
    Placebo
    Reporting group description
    Subjects received placebo matched to roniciclib tablets orally twice daily for 3 days on / 4 days off schedule along with chemotherapy (carboplatin/etoposide or cisplatin/etoposide) for 6 cycles (21 days each).

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (N= 142) included all subjects who were randomized.

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was defined as the time (days) from the date of randomization to the date of the first observed radiological disease progression or death due to any cause, whichever occurs first. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. PFS for subjects without tumor progression at the time of analysis was censored at their last date of tumor evaluation before the data base cut-off date. Median, percentile and other 95% confidence intervals (CIs) computed using Kaplan-Meier estimates.
    End point type
    Primary
    End point timeframe
    From date of randomization of the first subject until disease progression or start of new anti-tumor therapy after discontinuation of study drug (assessed every 6 weeks)
    End point values
    Roniciclib (BAY1000394) 10 mg Placebo
    Number of subjects analysed
    71 [1]
    71 [2]
    Units: days
        median (confidence interval 95%)
    149 (129 to 168)
    166 (139 to 170)
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    Roniciclib v Placebo: Stratified
    Statistical analysis description
    The two treatment groups (roniciclib plus chemotherapy and placebo plus chemotherapy) were compared using a one-sided stratified log-rank test stratified by gender (female / male). Hazard ratio and 95% CI were based on Cox Regression Model, stratified by gender.
    Comparison groups
    Roniciclib (BAY1000394) 10 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.8653 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.242
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.881
    Notes
    [3] - Hazard ratio < 1 indicates superiority of Roniciclib over Placebo.
    [4] - One-sided p-value was calculated from log rank test. P-value was manually rounded.

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival was defined as the time (days) from the date of randomization to death due to any cause. Subjects alive at the time of analysis were censored at their last contact date. Here, 99999 denotes that data was not calculated as value cannot be estimated due to censored data. Median and 95% confidence interval were computed using Kaplan-Meier estimates. In the below table, ‘99999’ indicates that values were not estimated due to censored data.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until death, assessed every 2 months
    End point values
    Roniciclib (BAY1000394) 10 mg Placebo
    Number of subjects analysed
    71 [5]
    71 [6]
    Units: days
        median (confidence interval 95%)
    324 (240 to 432)
    323 (287 to 99999)
    Notes
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    Roniciclib v Placebo: Stratified
    Statistical analysis description
    The two treatment groups (roniciclib plus chemotherapy and placebo plus chemotherapy) were compared using a one-sided stratified log-rank test stratified by gender (female / male). Hazard ratio and 95% CI were based on Cox Regression Model, stratified by gender.
    Comparison groups
    Roniciclib (BAY1000394) 10 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.8691 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.785
         upper limit
    2.606
    Notes
    [7] - Hazard ratio < 1 indicates superiority of Roniciclib over Placebo.
    [8] - One-sided p-value was calculated from log rank test. P-value was manually rounded.

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    TTP was defined as the time (days) from date of randomization to date of first observed radiological progression. TTP for subjects without tumor progression at the time of analysis will be censored at their last date of tumor evaluation. Median and 95% confidence interval were computed using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    From date of randomization of the first subject until disease progression or start of new anti-tumor therapy after discontinuation of study drug (assessed every 6 weeks)
    End point values
    Roniciclib (BAY1000394) 10 mg Placebo
    Number of subjects analysed
    71 [9]
    71 [10]
    Units: days
        median (confidence interval 95%)
    164 (139 to 174)
    167 (145 to 171)
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    Roniciclib v Placebo: Stratified
    Statistical analysis description
    The two treatment groups (roniciclib plus chemotherapy and placebo plus chemotherapy) were compared using a one-sided stratified log-rank test stratified by gender (female / male). Hazard ratio and 95% CI were based on Cox Regression Model, stratified by gender.
    Comparison groups
    Placebo v Roniciclib (BAY1000394) 10 mg
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.59 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.665
         upper limit
    1.648
    Notes
    [11] - Hazard ratio < 1 indicates superiority of Roniciclib over Placebo.
    [12] - One-sided p-value was calculated from log rank test. P-value was manually rounded.

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    Objective response of a subject was defined as the best tumor response: complete response or partial response observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria. Objective response rate was defined as the percentage of subjects with complete response or partial response.
    End point type
    Secondary
    End point timeframe
    From date of randomization of the first subject until disease progression or start of new anti-tumor therapy after discontinuation of study drug (assessed every 6 weeks)
    End point values
    Roniciclib (BAY1000394) 10 mg Placebo
    Number of subjects analysed
    71 [13]
    71 [14]
    Units: percentage of subjects
        number (confidence interval 95%)
    60.6 (48.3 to 72)
    74.6 (62.9 to 84.2)
    Notes
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    Roniciclib v Placebo
    Statistical analysis description
    Objective response rate was analyzed using the Cochran-Mantel-Haenszel test. The two treatment groups (roniciclib plus chemotherapy and placebo plus chemotherapy) were compared using a one-sided stratified log-rank test stratified by gender (female / male). Hazard ratio and 95% CI were based on Cox Regression Model, stratified by gender.
    Comparison groups
    Roniciclib (BAY1000394) 10 mg v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9685
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference
    Point estimate
    -14.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.34
         upper limit
    0.06

    Secondary: Best Overall Response

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    End point title
    Best Overall Response
    End point description
    Best overall response of a subject was defined as the best tumor response across timepoints: Complete response, Partial response, Stable disease or Progressive disease observed during trial period assessed according to the RECIST version 1.1 criteria. Complete response was defined as disappearance of tumor lesions, Partial response was defined as a decrease of at least 30% in the sum of tumor lesion sizes, Stable disease was defined as steady state of disease and Progressive disease was defined as an increase of at least 20% in the sum of tumor lesions sizes.
    End point type
    Secondary
    End point timeframe
    From date of randomization of the first subject until disease progression or start of new anti-tumor therapy after discontinuation of study drug (assessed every 6 weeks)
    End point values
    Roniciclib (BAY1000394) 10 mg Placebo
    Number of subjects analysed
    71 [15]
    71 [16]
    Units: percentage of subjects
    number (confidence interval 95%)
        Complete response
    1.4 (0 to 7.6)
    0 (0 to 0)
        Partial response
    59.2 (46.8 to 70.7)
    74.6 (62.9 to 84.2)
        Stable disease
    12.7 (6 to 22.7)
    15.5 (8 to 26)
        Progressive disease
    4.2 (0.9 to 11.9)
    5.6 (1.6 to 13.8)
        Not evaluable
    22.5 (13.5 to 34)
    4.2 (0.9 to 11.9)
    Notes
    [15] - FAS
    [16] - FAS
    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
    Adverse event reporting additional description
    Survival of subjects after treatment discontinuation for the overall survival efficacy endpoint was noted. Deaths later than 30 days after treatment discontinuation (which cannot be counted as adverse event) was noted. In total 42 and 36 deaths for roniciclib and placebo in the study, but only 9 and 3 due to adverse events.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Roniciclib (BAY1000394) 10 mg
    Reporting group description
    Subjects received roniciclib 5 mg (2 * 2.5 mg tablets) orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin/etoposide or 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
    Placebo
    Reporting group description
    Subjects received placebo matched to roniciclib tablets orally twice daily for 3 days on / 4 days off schedule in combination with chemotherapy (carboplatin/etoposide or cisplatin/etoposide) for 6 cycles (21 days each) and continued thereafter with placebo 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 (BAY1000394) 10 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 70 (57.14%)
    27 / 70 (38.57%)
         number of deaths (all causes)
    42
    36
         number of deaths resulting from adverse events
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombosis
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 70 (8.57%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 70 (5.71%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Roniciclib (BAY1000394) 10 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 70 (100.00%)
    69 / 70 (98.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 70 (2.86%)
    6 / 70 (8.57%)
         occurrences all number
    2
    7
    Hypotension
         subjects affected / exposed
    10 / 70 (14.29%)
    1 / 70 (1.43%)
         occurrences all number
    12
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    13 / 70 (18.57%)
    11 / 70 (15.71%)
         occurrences all number
    27
    17
    Oedema peripheral
         subjects affected / exposed
    11 / 70 (15.71%)
    2 / 70 (2.86%)
         occurrences all number
    15
    2
    Chest pain
         subjects affected / exposed
    5 / 70 (7.14%)
    10 / 70 (14.29%)
         occurrences all number
    5
    12
    Fatigue
         subjects affected / exposed
    28 / 70 (40.00%)
    17 / 70 (24.29%)
         occurrences all number
    61
    30
    Pyrexia
         subjects affected / exposed
    6 / 70 (8.57%)
    11 / 70 (15.71%)
         occurrences all number
    6
    14
    Pain
         subjects affected / exposed
    5 / 70 (7.14%)
    4 / 70 (5.71%)
         occurrences all number
    5
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 70 (14.29%)
    2 / 70 (2.86%)
         occurrences all number
    13
    2
    Anxiety
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 70 (2.86%)
         occurrences all number
    8
    2
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    6 / 70 (8.57%)
    1 / 70 (1.43%)
         occurrences all number
    10
    1
    Neutrophil count decreased
         subjects affected / exposed
    13 / 70 (18.57%)
    16 / 70 (22.86%)
         occurrences all number
    52
    65
    Platelet count decreased
         subjects affected / exposed
    19 / 70 (27.14%)
    7 / 70 (10.00%)
         occurrences all number
    59
    20
    Weight decreased
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 70 (7.14%)
         occurrences all number
    4
    5
    White blood cell count decreased
         subjects affected / exposed
    7 / 70 (10.00%)
    3 / 70 (4.29%)
         occurrences all number
    17
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 70 (44.29%)
    26 / 70 (37.14%)
         occurrences all number
    84
    64
    Thrombocytopenia
         subjects affected / exposed
    16 / 70 (22.86%)
    9 / 70 (12.86%)
         occurrences all number
    42
    22
    Leukopenia
         subjects affected / exposed
    6 / 70 (8.57%)
    2 / 70 (2.86%)
         occurrences all number
    12
    4
    Neutropenia
         subjects affected / exposed
    28 / 70 (40.00%)
    30 / 70 (42.86%)
         occurrences all number
    107
    69
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 70 (2.86%)
         occurrences all number
    5
    2
    Dyspnoea
         subjects affected / exposed
    12 / 70 (17.14%)
    4 / 70 (5.71%)
         occurrences all number
    15
    7
    Oropharyngeal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 70 (14.29%)
    6 / 70 (8.57%)
         occurrences all number
    10
    6
    Headache
         subjects affected / exposed
    17 / 70 (24.29%)
    6 / 70 (8.57%)
         occurrences all number
    27
    8
    Paraesthesia
         subjects affected / exposed
    7 / 70 (10.00%)
    6 / 70 (8.57%)
         occurrences all number
    11
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 70 (5.71%)
    4 / 70 (5.71%)
         occurrences all number
    11
    6
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 70 (0.00%)
    6 / 70 (8.57%)
         occurrences all number
    0
    6
    Vertigo
         subjects affected / exposed
    5 / 70 (7.14%)
    3 / 70 (4.29%)
         occurrences all number
    9
    5
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 70 (11.43%)
    5 / 70 (7.14%)
         occurrences all number
    10
    8
    Constipation
         subjects affected / exposed
    9 / 70 (12.86%)
    16 / 70 (22.86%)
         occurrences all number
    17
    23
    Diarrhoea
         subjects affected / exposed
    30 / 70 (42.86%)
    12 / 70 (17.14%)
         occurrences all number
    79
    18
    Vomiting
         subjects affected / exposed
    44 / 70 (62.86%)
    15 / 70 (21.43%)
         occurrences all number
    118
    27
    Stomatitis
         subjects affected / exposed
    5 / 70 (7.14%)
    5 / 70 (7.14%)
         occurrences all number
    7
    6
    Nausea
         subjects affected / exposed
    46 / 70 (65.71%)
    34 / 70 (48.57%)
         occurrences all number
    173
    86
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 70 (1.43%)
         occurrences all number
    6
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    20 / 70 (28.57%)
    23 / 70 (32.86%)
         occurrences all number
    25
    29
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 70 (14.29%)
    8 / 70 (11.43%)
         occurrences all number
    14
    10
    Arthralgia
         subjects affected / exposed
    3 / 70 (4.29%)
    4 / 70 (5.71%)
         occurrences all number
    4
    5
    Musculoskeletal pain
         subjects affected / exposed
    3 / 70 (4.29%)
    4 / 70 (5.71%)
         occurrences all number
    3
    4
    Pain in extremity
         subjects affected / exposed
    7 / 70 (10.00%)
    3 / 70 (4.29%)
         occurrences all number
    8
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    8 / 70 (11.43%)
    6 / 70 (8.57%)
         occurrences all number
    19
    8
    Hyponatraemia
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 70 (7.14%)
         occurrences all number
    6
    9
    Decreased appetite
         subjects affected / exposed
    20 / 70 (28.57%)
    15 / 70 (21.43%)
         occurrences all number
    35
    16
    Hypomagnesaemia
         subjects affected / exposed
    23 / 70 (32.86%)
    9 / 70 (12.86%)
         occurrences all number
    93
    20
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    0 / 70 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    6
    Urinary tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    5 / 70 (7.14%)
         occurrences all number
    1
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2014
    The following modifications were done in the inclusion criteria regarding contraception. • Adequate contraception for subjects had to be ensured during chemotherapy treatment and for at least 6 months after end of chemotherapy. • The partners of sexually active subjects should had been advised to use adequate contraception during the six cycles of chemotherapy.
    03 Sep 2014
    The following modifications were done: • Concomitant therapies were revised, and one specification on dose modification was changed. • A cautionary provision on the use of strong Cytochrome P450 3A4 (CYP3A4) modifiers was added.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Feb 2016
    Study was terminated after evaluation of primary completion data.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Decimal places were automatically truncated if last decimal equals zero. ‘99999’ in the posting indicates that values were not estimated due to censored data.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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