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    Clinical Trial Results:
    Phase II randomized trial of the Polo-like kinase 1 inhibitor BI 6727 monotherapy versus investigator’s choice chemotherapy in ovarian cancer patients resistant or refractory to platinum-based cytotoxic therapy

    Summary
    EudraCT number
    		 2009-015770-35
    Trial protocol
    		 FR   ES   BE   SE   SK  
    Global end of trial date
    03 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1230.18
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01121406
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.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
    15 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of intravenous infusion of volasertib (BI 6727) monotherapy given once every 3 weeks compared to investigator’s choice chemotherapy in platinum-refractory or -resistant ovarian cancer patients
    Protection of trial subjects
    Written informed consent was obtained from all the patients before the enrollment and the study was approved by the Ethic Committee and Competent Authority (EC/CA) before start and were conducted in accordance with Declaration of Helsinki, International Conference on Harmonisation (ICH) , Good Clinical Practise (GCP) and Boehringer Ingelheim (BI) Standard operating Procedures (SOP).
    Background therapy
    		 -
    Evidence for comparator
    		 Investigator’s choice chemotherapy
    Actual start date of recruitment
    23 Apr 2010
    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
    Belgium: 13
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Sweden: 10
    Worldwide total number of subjects
    122
    EEA total number of subjects
    122
    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)
    76
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The "Not completed" category in the Subject Disposition table represents " Treatment permanently discontinued" and "The reasons for non-completion" in the table represent "Reason for treatment discontinuation". 24 patients switched to Volasertib (BI 6727) due to disease progression or occurrence of toxicity.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label design was used

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Volasertib (BI 6727)
    Arm description
    		 Volasertib (BI 6727 300 mg) was administered as intravenous infusion over 2 hours at Day 1 of each 21-day treatment course. Treatment was to be administered until disease progression or occurrence of toxicity leading to treatment discontinuation. Patients withdrawn from volasertib treatment could receive a treatment according to investigator’s choice. The patients were to be followed for survival status. One patient was randomised to the Volasertib (BI 6727) arm, however this patient was not treated. Consequently, number of subject that started is 55 but only 54 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Volasertib
    Investigational medicinal product code
    BI 6727
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infusion over 2 hours at Day 1 of each treatment course

    Arm title
    		 Cytotoxic
    Arm description
    		 Patients received a non-platinum cytotoxic single agent. The investigator chose the most appropriate drug according to patient status (previous chemotherapy effects, cumulative toxic effects, performance status, and nutritional status), the product Summary of Product Characteristics (SPC), and the local standard of care. The following non-platinum regimens were recommended because they are regarded efficacious and safe in patients with resistant ovarian cancer: -Pegylated liposomal doxorubicin (PLD): 40 mg/m² at Day 1 (1 course = 28 days) - Topotecan: 1.25 mg/m² from Days 1 to 5 (1 course = 21 days), or 4 mg/m² at Days 1, 8, and 15 (1 course = 28 days) - Paclitaxel: 80 mg/m² at Days 1, 8, 15, and 21 (1 course = 28 days) - Gemcitabine: 1000 mg/m² at Days 1 and 8 (1 course = 21 days)
    Arm type
    		 Investigator’s choice chemotherapy

    Investigational medicinal product name
    Pegylated liposomal doxorubicin (PLD)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m² at Day 1 (1 course = 28 days)

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.25 mg/m² from Days 1 to 5 (1 course = 21 days), or 4 mg/m² at Days 1, 8, and 15 (1 course = 28 days)

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m² at Days 1, 8, 15, and 21 (1 course = 28 days)

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m² at Days 1 and 8 (1 course = 21 days)

    Number of subjects in period 1
    		Volasertib (BI 6727) Cytotoxic
    Started
    54
    55
    Completed
    0
    0
    Not completed
    54
    55
         Refused continuation of study med.
    1
    2
         Wors. or AE of underlying cancer disease
    4
    6
         Adverse event, non-fatal
    3
    10
         Other reason
    2
    6
         Progressive disease (PD) RECIST
    44
    28
         Non−compliant with protocol
    -
    2
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Volasertib (BI 6727)
    Reporting group description
    		 Volasertib (BI 6727 300 mg) was administered as intravenous infusion over 2 hours at Day 1 of each 21-day treatment course. Treatment was to be administered until disease progression or occurrence of toxicity leading to treatment discontinuation. Patients withdrawn from volasertib treatment could receive a treatment according to investigator’s choice. The patients were to be followed for survival status. One patient was randomised to the Volasertib (BI 6727) arm, however this patient was not treated. Consequently, number of subject that started is 55 but only 54 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Cytotoxic
    Reporting group description
    		 Patients received a non-platinum cytotoxic single agent. The investigator chose the most appropriate drug according to patient status (previous chemotherapy effects, cumulative toxic effects, performance status, and nutritional status), the product Summary of Product Characteristics (SPC), and the local standard of care. The following non-platinum regimens were recommended because they are regarded efficacious and safe in patients with resistant ovarian cancer: -Pegylated liposomal doxorubicin (PLD): 40 mg/m² at Day 1 (1 course = 28 days) - Topotecan: 1.25 mg/m² from Days 1 to 5 (1 course = 21 days), or 4 mg/m² at Days 1, 8, and 15 (1 course = 28 days) - Paclitaxel: 80 mg/m² at Days 1, 8, 15, and 21 (1 course = 28 days) - Gemcitabine: 1000 mg/m² at Days 1 and 8 (1 course = 21 days)

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.
    Reporting group values
    		 Volasertib (BI 6727) Cytotoxic Total
    Number of subjects
    		 54 55
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS) consisted of all patients who received at least one administration of the trial drug and is the population used for Baseline characteristics.
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ± 9.88 60.9 ± 9.26 -
    Gender, Male/Female
    Treated set (TS) consisted of all patients who received at least one administration of the trial drug and is the population used for Baseline characteristics.
    Units: participants
        Female
    		 54 55 109
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Volasertib (BI 6727)
    Reporting group description
    		 Volasertib (BI 6727 300 mg) was administered as intravenous infusion over 2 hours at Day 1 of each 21-day treatment course. Treatment was to be administered until disease progression or occurrence of toxicity leading to treatment discontinuation. Patients withdrawn from volasertib treatment could receive a treatment according to investigator’s choice. The patients were to be followed for survival status. One patient was randomised to the Volasertib (BI 6727) arm, however this patient was not treated. Consequently, number of subject that started is 55 but only 54 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Cytotoxic
    Reporting group description
    		 Patients received a non-platinum cytotoxic single agent. The investigator chose the most appropriate drug according to patient status (previous chemotherapy effects, cumulative toxic effects, performance status, and nutritional status), the product Summary of Product Characteristics (SPC), and the local standard of care. The following non-platinum regimens were recommended because they are regarded efficacious and safe in patients with resistant ovarian cancer: -Pegylated liposomal doxorubicin (PLD): 40 mg/m² at Day 1 (1 course = 28 days) - Topotecan: 1.25 mg/m² from Days 1 to 5 (1 course = 21 days), or 4 mg/m² at Days 1, 8, and 15 (1 course = 28 days) - Paclitaxel: 80 mg/m² at Days 1, 8, 15, and 21 (1 course = 28 days) - Gemcitabine: 1000 mg/m² at Days 1 and 8 (1 course = 21 days)

    Subject analysis set title
    Cytotoxic to volasertib switch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients of the cytotoxic arm who switched to treatment with Volasertib (BI 6727).

    Primary: Disease Control Rate (DCR) at week 24 according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1

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    End point title
    		 Disease Control Rate (DCR) at week 24 according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1
    End point description
    DCR was defined as the proportion of patients who had an overall response of complete response (CR), partial response (PR), or stable disease (SD).
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [1]
    55 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    30.6 (18 to 43.2)
    43.1 (29.5 to 56.7)
    Notes
    [1] - TS
    [2] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Kaplan Meier estimates and confidence intervals (CI) were calculated using Greenwood’s variance estimate within each treatment arm and the asymptotic CI for the difference in the rates found. The time was censored in those cases where there was no death or progression until the last trial visit. 95% CI using Greenwood´s variance estimate. Volasertib (BI 6727) minus Cytotoxic.
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Difference in Kaplan−Meier DC rates
    Point estimate
    -12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.1
         upper limit
    		 6
    Notes
    [3] - Exploratory

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Progression-free survival of a patient was based on the investigator’s assessment; it was defined as the number of days from the date of randomisation until the date of either disease progression or death from any cause, whichever occurred first. Definition of disease progression according to RECIST version 1.1; Patients with measurable tumour lesions at baseline, Target-lesions: at least a 20% increase in the sum of diameters of target lesions, the sum of diameters must also demonstrate an absolute increase of at least 5 mm,taking as reference the smallest sum on study, or appearance of 1 or more new lesions. Non-target lesions: unequivocal progression of existing non-target lesions or appearance of 1 or more new lesions Patients with non-measurable tumour lesions at baseline, Non-target lesions: requires unequivocal progression of existing non-target lesions or appearance of 1 or more new lesions
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, death or study discontinuation; Up to 213 weeks
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [4]
    55 [5]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    13.1 (6.6 to 30.1)
    20.6 (11.6 to 30.7)
    Notes
    [4] - TS
    [5] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727) /Cytotoxic.
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.53

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as time from randomisation to death irrespective of the cause of the death.
    End point type
    Secondary
    End point timeframe
    From randomization until death or study discontinuation; Up to 213 weeks
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [6]
    55 [7]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    60.1 (31.3 to 95.4)
    68.6 (28.7 to 119.4)
    Notes
    [6] - TS
    [7] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.42

    Secondary: Best Overall Response

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    End point title
    		 Best Overall Response
    End point description
    Best overall response (BOR) is defined as the best response recorded at any time from the date of randomisation until the end of treatment. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.
    End point type
    Secondary
    End point timeframe
    Time from the date of randomisation until study completion/discontinuation; Up to 213 weeks
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [8]
    55 [9]
    Units: participants
    number (not applicable)
        CR- Measurable disease
    0
    0
        PR- Measurable disease
    7
    8
        SD- Measurable disease
    24
    24
        PD- Measurable disease
    14
    10
        Missing- Measurable disease
    0
    2
        CR- Non-measurable disease
    0
    1
        Non-CR/Non-PD- Non-measurable disease
    6
    9
        PD- Non-measurable disease
    3
    0
        Missing- Non-measurable disease
    0
    1
    Notes
    [8] - TS
    [9] - TS
    No statistical analyses for this end point

    Secondary: Biological progression-free survival based on serum cancer antigen 125 (CA-125) according to the Gynaecologic Cancer Intergroup (GCIG) criteria

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    End point title
    		 Biological progression-free survival based on serum cancer antigen 125 (CA-125) according to the Gynaecologic Cancer Intergroup (GCIG) criteria
    End point description
    Biological PFS including assessment of CA-125 levels was defined as the time from randomisation until the first occurrence of progressive disease according to CA-125, progressive disease according to radiological evidence, or death. Also according to the below criterias, - In patients with radiological measurable disease, disease progression during study treatment could not be declared on the basis of CA-125 alone. - Patients with elevated CA-125 pre-treatment and normalization of CA-125 had to show evidence of CA-125 ≥ to two times the upper normal limit on two occasions at least one week apart or - Patients with elevated CA-125 pre-treatment, which never normalized, had to show evidence of CA-125 ≥ to two times the nadir value on two occasions at least one week apart or - Patients with CA-125 in the normal range pre-treatment had to show evidence of CA-125 ≥ to two times the upper normal limit on two occasions at least one week apart.
    End point type
    Secondary
    End point timeframe
    At screening and every 6 weeks thereafter (Up to 213 weeks)
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [10]
    55 [11]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    13.1 (6.6 to 25.6)
    20.6 (11.6 to 30)
    Notes
    [10] - TS
    [11] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.7

    Secondary: Time to deterioration in global health status/Quality of life (QOL)

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    End point title
    		 Time to deterioration in global health status/Quality of life (QOL)
    End point description
    Time to deterioration in global health status/Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires. The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. 99999 is the "Missing value"; Missing median or percentiles signify that a sufficient number of events have not yet occurred to produce these estimates.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks (Up to 213 weeks)
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [12]
    55 [13]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (12.3 to 99999)
    39.6 (13.1 to 47.2)
    Notes
    [12] - TS
    [13] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic.
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.61

    Secondary: Time to deterioration in fatigue/Quality of life (QOL)

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    End point title
    		 Time to deterioration in fatigue/Quality of life (QOL)
    End point description
    Time to deterioration in fatigue/Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires. The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. 99999 is the "Missing value"; Missing median or percentiles signify that a sufficient number of events have not yet occurred to produce these estimates.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks (Up to 213 weeks)
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [14]
    55 [15]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (18.3 to 99999)
    67.1 (12.4 to 99999)
    Notes
    [14] - TS
    [15] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status atbaseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.65

    Secondary: Time to deterioration in pain/ Quality of life (QOL)

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    End point title
    		 Time to deterioration in pain/ Quality of life (QOL)
    End point description
    Time to deterioration in pain/ Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires. The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. 99999 is the "Missing value"; Missing median or percentiles signify that a sufficient number of events have not yet occurred to produce these estimates.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks (Up to 213 weeks)
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [16]
    55 [17]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (16.6 to 99999)
    54.1 (25 to 99999)
    Notes
    [16] - TS
    [17] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.93

    Secondary: Time to deterioration in abdominal bloating/ Quality of life (QOL)

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    End point title
    		 Time to deterioration in abdominal bloating/ Quality of life (QOL)
    End point description
    time to deterioration in abdominal bloating/ Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires. The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. 99999 is the "Missing value"; Missing median or percentiles signify that a sufficient number of events have not yet occurred to produce these estimates.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks (Up to 213 weeks )
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [18]
    55 [19]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (12.9 to 99999)
    47.2 (17.3 to 67.1)
    Notes
    [18] - TS
    [19] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.47

    Secondary: Time to deterioration in the three most troublesome disease specific symptoms/ Quality of life (QOL)

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    End point title
    		 Time to deterioration in the three most troublesome disease specific symptoms/ Quality of life (QOL)
    End point description
    Three most troublesome disease specific symptoms, defined by the patient at baseline. Patients that have defined more than 3 most troublesome symptoms have not been taken into account in the analysis. Quality of life (QOL) and symptom control assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OV28, and individual symptom questionnaires. The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. 99999 is the "Missing value"; Missing median or percentiles signify that a sufficient number of events have not yet occurred to produce these estimates.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks (Up to 213 weeks)
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [20]
    55 [21]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    18.9 (6.3 to 99999)
    Notes
    [20] - TS
    [21] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cox proportional−hazards regression model, stratified by disease status at baseline (measurable vs. non measurable disease) and platinum resistant vs platinum refractory disease at baseline. HR calculated as Volasertib (BI 6727)/ Cytotoxic
    Comparison groups
    Volasertib (BI 6727) v Cytotoxic
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.77

    Secondary: Clinically relevant changes in laboratory and ECG data

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    End point title
    		 Clinically relevant changes in laboratory and ECG data
    End point description
    Clinically relevant changes in laboratory and ECG data
    End point type
    Secondary
    End point timeframe
    From first treatment administration to 21 days after the last drug administration (Up to 1403 days)
    End point values
    		 Volasertib (BI 6727) Cytotoxic Cytotoxic to volasertib switch
    Number of subjects analysed
    54 [22]
    55 [23]
    24 [24]
    Units: percentage of participants
    number (not applicable)
        Blood alkaline phosphatase increased
    3.7
    12.7
    8.3
        Blood creatinine increased
    9.3
    3.6
    0
        Platelet count decreased
    9.3
    0
    8.3
        Alanine aminotransferase increased
    1.9
    9.1
    4.2
        Aspartate aminotransferase increased
    3.7
    5.5
    4.2
        Blood uric acid increased
    1.9
    5.5
    0
        Gamma−glutamyltransferase increased
    3.7
    5.5
    4.2
        Alanine aminotransferase abnormal
    0
    0
    4.2
        Electrocardiogram QT prolonged
    0
    0
    4.2
        Haemoglobin decreased
    3.7
    3.6
    4.2
        Neutrophil count decreased
    1.9
    0
    4.2
        Troponin I increased
    0
    0
    4.2
        Blood lactate dehydrogenase increased
    3.7
    0
    0
        Blood magnesium decreased
    3.7
    0
    0
        White blood cell count decreased
    3.7
    0
    0
        Blood urea increased
    1.9
    3.6
    0
        Alanine aminotransferase decreased
    1.9
    0
    0
        Blood bilirubin increased
    1.9
    0
    0
        Blood creatine phosphokinase decreased
    1.9
    0
    0
        Blood potassium decreased
    1.9
    0
    0
        Hepatic enzyme increased
    1.9
    0
    0
        Aspartate aminotransferase abnormal
    0
    1.8
    0
        Transaminases increased
    0
    1.8
    0
    Notes
    [22] - TS
    [23] - TS
    [24] - TS
    No statistical analyses for this end point

    Secondary: AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for CD 10899 BS

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    End point title
    		 AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for CD 10899 BS [25]
    End point description
    AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for CD 10899 BS (metabolite of Volasertib BI 6727) Pharmacokinetic set (PKS): All evaluable patients were to be included in the pharmacokinetic analysis. A patient was considered not evaluable if they had an important protocol violation relevant to the evaluation of pharmacokinetics or had insufficient data.
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [26]
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    204 ± 65.3
    Notes
    [26] - PKS
    No statistical analyses for this end point

    Secondary: AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for BI 6727 BS

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    End point title
    		 AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for BI 6727 BS [27]
    End point description
    AUC (0-24); area under the concentration-time curve in plasma over the time interval from 0 to 24 hours for BI 6727 BS.
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [28]
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    2140 ± 25.5
    Notes
    [28] - PKS
    No statistical analyses for this end point

    Secondary: AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for BI 6727 BS

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    End point title
    		 AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for BI 6727 BS [29]
    End point description
    AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for BI 6727 BS
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    49 [30]
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    6240 ± 29.8
    Notes
    [30] - PKS
    No statistical analyses for this end point

    Secondary: AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for CD 10899 BS

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    End point title
    		 AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for CD 10899 BS [31]
    End point description
    AUC (0-inf); area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity for CD 10899 BS (metabolite of Volasertib BI 6727)
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [32]
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1400 ± 35.8
    Notes
    [32] - PKS
    No statistical analyses for this end point

    Secondary: Cmax; maximum measured concentration of BI 6727 BS in plasma

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    End point title
    		 Cmax; maximum measured concentration of BI 6727 BS in plasma [33]
    End point description
    Cmax; maximum measured concentration of BI 6727 BS in plasma
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [34]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    341 ± 42.2
    Notes
    [34] - PKS
    No statistical analyses for this end point

    Secondary: Cmax; maximum measured concentration of CD 10899 BS in plasma

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    End point title
    		 Cmax; maximum measured concentration of CD 10899 BS in plasma [35]
    End point description
    Cmax; maximum measured concentration of CD 10899 BS (metabolite of Volasertib BI 6727) in plasma
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [36]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    10.8 ± 63.4
    Notes
    [36] - PKS
    No statistical analyses for this end point

    Secondary: tmax; time from dosing to maximum measured concentration of BI 6727 BS in plasma

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    End point title
    		 tmax; time from dosing to maximum measured concentration of BI 6727 BS in plasma [37]
    End point description
    tmax; time from dosing to maximum measured concentration of BI 6727 BS in plasma
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [38]
    Units: hours
        median (full range (min-max))
    2 (1.83 to 3)
    Notes
    [38] - PKS
    No statistical analyses for this end point

    Secondary: tmax; time from dosing to maximum measured concentration of CD 10899 BS in plasma

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    End point title
    		 tmax; time from dosing to maximum measured concentration of CD 10899 BS in plasma [39]
    End point description
    tmax; time from dosing to maximum measured concentration of CD 10899 BS (metabolite of Volasertib BI 6727) in plasma
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [40]
    Units: hours
        median (full range (min-max))
    6.07 (3.83 to 24.3)
    Notes
    [40] - PKS
    No statistical analyses for this end point

    Secondary: t1/2; Terminal half-life of BI 6727 BS in plasma

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    End point title
    		 t1/2; Terminal half-life of BI 6727 BS in plasma [41]
    End point description
    t1/2; Terminal half-life of BI 6727 BS in plasma
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    51 [42]
    Units: hours
        geometric mean (geometric coefficient of variation)
    143 ± 21.3
    Notes
    [42] - PKS
    No statistical analyses for this end point

    Secondary: CL; total clearance of BI 6727 BS in plasma after intravenous administration

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    End point title
    		 CL; total clearance of BI 6727 BS in plasma after intravenous administration [43]
    End point description
    CL; total clearance of BI 6727 BS in plasma after intravenous administration
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    49 [44]
    Units: mL/min
        geometric mean (geometric coefficient of variation)
    801 ± 29.8
    Notes
    [44] - PKS
    No statistical analyses for this end point

    Secondary: MRT; Mean residence time of BI 6727 BS in the body

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    End point title
    		 MRT; Mean residence time of BI 6727 BS in the body [45]
    End point description
    MRT; Mean residence time of BI 6727 BS in the body
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    49 [46]
    Units: hours
        geometric mean (geometric coefficient of variation)
    118 ± 31.2
    Notes
    [46] - PKS
    No statistical analyses for this end point

    Secondary: Vss;apparent volume of distribution at steady state following intravenous administration for BI 6727 BS

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    End point title
    		 Vss;apparent volume of distribution at steady state following intravenous administration for BI 6727 BS [47]
    End point description
    Vss;apparent volume of distribution at steady state following intravenous administration for BI 6727 BS
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    49 [48]
    Units: Litres
        geometric mean (geometric coefficient of variation)
    5690 ± 25.8
    Notes
    [48] - PKS
    No statistical analyses for this end point

    Secondary: t1/2; Terminal half-life of CD 10899 BS in plasma

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    End point title
    		 t1/2; Terminal half-life of CD 10899 BS in plasma [49]
    End point description
    t1/2; Terminal half-life of CD 10899 (metabolite of Volasertib BI 6727) BS in plasma
    End point type
    Secondary
    End point timeframe
    -0.083 hours (h), 2h, 4h, 6h, 24h, 168h and 336 h after first drug administration
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the statistics are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 Volasertib (BI 6727)
    Number of subjects analysed
    53 [50]
    Units: hours
        geometric mean (geometric coefficient of variation)
    146 ± 21.5
    Notes
    [50] - PKS
    No statistical analyses for this end point

    Secondary: Biomarkers and Pharmacogenetics Analysis (Optional)

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    End point title
    		 Biomarkers and Pharmacogenetics Analysis (Optional)
    End point description
    This endpoint has not been statistically analysed in the study report
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    0 [51]
    0 [52]
    Units: NA
        number (not applicable)
    Notes
    [51] - Endpoint has not been statistically analysed in the study report
    [52] - Endpoint has not been statistically analysed in the study report
    No statistical analyses for this end point

    Secondary: Biological tumour response based on serum cancer antigen 125 (CA-125) according to the Gynaecologic Cancer Intergroup (GCIG) criteria

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    End point title
    		 Biological tumour response based on serum cancer antigen 125 (CA-125) according to the Gynaecologic Cancer Intergroup (GCIG) criteria
    End point description
    Patients were to have a pre-treatment CA-125 of at least twice the upper limit of normal to be considered for CA-125 response. Patients were not evaluable by CA-125 if they had received mouse antibodies or if they had undergone medical and/or surgical interference with their peritoneum or pleura during the previous 28 days. In eligible patients, a CA-125 response was defined as the moment the CA- 25 was reduced by 50%, with this being confirmed with a consecutive CA-125 assessment not earlier than 28 days after the previous one. Biological response rate based on serum CA-125 levels was assessed according to the guidelines by the Gynaecologic Cancer Intergroup. Monitoring of blood levels of the tumour marker CA-125 was performed at screening and every 6 weeks thereafter.
    End point type
    Secondary
    End point timeframe
    At screening and every 6 weeks thereafter (Up to 213 weeks)
    End point values
    		 Volasertib (BI 6727) Cytotoxic
    Number of subjects analysed
    54 [53]
    55 [54]
    Units: participants
    number (not applicable)
        Yes
    10
    12
        No
    33
    23
        Not evaluable
    4
    11
        Missing
    7
    9
    Notes
    [53] - TS
    [54] - TS
    No statistical analyses for this end point

    Secondary: Incidence and intensity of adverse events according to the United States National Cancer Institute (US NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

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    End point title
    		 Incidence and intensity of adverse events according to the United States National Cancer Institute (US NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
    End point description
    Incidence and intensity of adverse events according to the United States National Cancer Institute (US NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
    End point type
    Secondary
    End point timeframe
    From first treatment administration to 21 days after the last drug administration (Up to 1403 days)
    End point values
    		 Volasertib (BI 6727) Cytotoxic Cytotoxic to volasertib switch
    Number of subjects analysed
    54 [55]
    55 [56]
    24 [57]
    Units: participants
    number (not applicable)
        Grade 1
    4
    3
    1
        Grade 2
    6
    19
    3
        Grade 3
    16
    25
    9
        Grade 4
    25
    5
    6
        Grade 5
    3
    3
    3
    Notes
    [55] - TS
    [56] - TS
    [57] - TS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first treatment administration to 21 days after the last drug administration (Up to 1403 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Volasertib (BI 6727)
    Reporting group description
    		 Volasertib (BI 6727 300 mg) was administered as intravenous infusion over 2 hours at Day 1 of each 21-day treatment course. Treatment was to be administered until disease progression or occurrence of toxicity leading to treatment discontinuation. Patients withdrawn from volasertib treatment could receive a treatment according to investigator's choice. The patients were to be followed for survival status.

    Reporting group title
    Cytotoxic to Volasertib Switch
    Reporting group description
    		 Patients of the cytotoxic arm who switched to treatment with Volasertib (BI 6727).

    Reporting group title
    Cytotoxic
    Reporting group description
    		 Patients received a non-platinum cytotoxic single agent. The investigator chose the most appropriate drug according to patient status previous chemotherapy effects, cumulative toxic effects, performance status, and nutritional status), the product Summary of Product Characteristics (SPC), and the local standard of care. The following non-platinum regimens were recommended because they are regarded efficacious and safe in patients with resistant ovarian cancer: Pegylated liposomal doxorubicin (PLD): 40 mg/m² at Day 1 (1 course = 28 days) Topotecan: 1.25 mg/m² from Days 1 to 5 (1 course = 21 days), or 4 mg/m² at Days 1, 8, and 15 (1 course = 28 days) Paclitaxel: 80 mg/m² at Days 1,8, 15, and 21 (1 course = 28 days) Gemcitabine: 1000 mg/m² at Days 1 and 8 (1 course = 21 days)

    Serious adverse events
    		 Volasertib (BI 6727) Cytotoxic to Volasertib Switch Cytotoxic
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 54 (44.44%)
    12 / 24 (50.00%)
    19 / 55 (34.55%)
         number of deaths (all causes)
    46
    20
    49
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to heart
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tumour invasion
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Poor venous access
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Euthanasia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Multi-organ failure
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstruction
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic reaction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 24 (8.33%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 24 (8.33%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pyelocaliectasis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Volasertib (BI 6727) Cytotoxic to Volasertib Switch Cytotoxic
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 54 (98.15%)
    21 / 24 (87.50%)
    53 / 55 (96.36%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 24 (4.17%)
    3 / 55 (5.45%)
         occurrences all number
    3
    1
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
    5 / 55 (9.09%)
         occurrences all number
    1
    1
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 24 (8.33%)
    7 / 55 (12.73%)
         occurrences all number
    5
    2
    8
    Blood creatinine increased
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    6
    0
    2
    Blood uric acid increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    2
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
    3 / 55 (5.45%)
         occurrences all number
    1
    1
    3
    Platelet count decreased
         subjects affected / exposed
    5 / 54 (9.26%)
    2 / 24 (8.33%)
    0 / 55 (0.00%)
         occurrences all number
    10
    2
    0
    Weight decreased
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    4
    0
    2
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    1
    0
    4
    Headache
         subjects affected / exposed
    8 / 54 (14.81%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    10
    0
    4
    Neuropathy peripheral
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    8 / 55 (14.55%)
         occurrences all number
    2
    0
    9
    Paraesthesia
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    3
    0
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    1
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 54 (53.70%)
    5 / 24 (20.83%)
    20 / 55 (36.36%)
         occurrences all number
    50
    5
    30
    Neutropenia
         subjects affected / exposed
    34 / 54 (62.96%)
    7 / 24 (29.17%)
    17 / 55 (30.91%)
         occurrences all number
    138
    15
    36
    Leukopenia
         subjects affected / exposed
    15 / 54 (27.78%)
    2 / 24 (8.33%)
    8 / 55 (14.55%)
         occurrences all number
    43
    3
    19
    Lymphopenia
         subjects affected / exposed
    7 / 54 (12.96%)
    0 / 24 (0.00%)
    8 / 55 (14.55%)
         occurrences all number
    14
    0
    16
    Thrombocytopenia
         subjects affected / exposed
    26 / 54 (48.15%)
    4 / 24 (16.67%)
    4 / 55 (7.27%)
         occurrences all number
    63
    9
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 54 (33.33%)
    4 / 24 (16.67%)
    26 / 55 (47.27%)
         occurrences all number
    28
    4
    45
    Mucosal inflammation
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 24 (4.17%)
    7 / 55 (12.73%)
         occurrences all number
    7
    1
    12
    Fatigue
         subjects affected / exposed
    4 / 54 (7.41%)
    4 / 24 (16.67%)
    12 / 55 (21.82%)
         occurrences all number
    4
    5
    21
    Chest pain
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 24 (4.17%)
    2 / 55 (3.64%)
         occurrences all number
    4
    1
    2
    Oedema peripheral
         subjects affected / exposed
    8 / 54 (14.81%)
    3 / 24 (12.50%)
    5 / 55 (9.09%)
         occurrences all number
    9
    4
    5
    Pyrexia
         subjects affected / exposed
    5 / 54 (9.26%)
    4 / 24 (16.67%)
    4 / 55 (7.27%)
         occurrences all number
    6
    5
    4
    Pain
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 24 (4.17%)
    4 / 55 (7.27%)
         occurrences all number
    2
    1
    6
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 24 (8.33%)
    0 / 55 (0.00%)
         occurrences all number
    2
    2
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    6 / 54 (11.11%)
    3 / 24 (12.50%)
    7 / 55 (12.73%)
         occurrences all number
    6
    4
    8
    Abdominal pain
         subjects affected / exposed
    13 / 54 (24.07%)
    5 / 24 (20.83%)
    20 / 55 (36.36%)
         occurrences all number
    16
    5
    33
    Abdominal distension
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    5
    0
    2
    Ascites
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 24 (8.33%)
    3 / 55 (5.45%)
         occurrences all number
    1
    2
    3
    Intestinal obstruction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    1
    0
    4
    Dyspepsia
         subjects affected / exposed
    6 / 54 (11.11%)
    0 / 24 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    7
    0
    2
    Diarrhoea
         subjects affected / exposed
    15 / 54 (27.78%)
    2 / 24 (8.33%)
    12 / 55 (21.82%)
         occurrences all number
    26
    3
    16
    Constipation
         subjects affected / exposed
    16 / 54 (29.63%)
    5 / 24 (20.83%)
    13 / 55 (23.64%)
         occurrences all number
    23
    6
    14
    Vomiting
         subjects affected / exposed
    15 / 54 (27.78%)
    2 / 24 (8.33%)
    18 / 55 (32.73%)
         occurrences all number
    26
    7
    32
    Stomatitis
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    3
    0
    3
    Rectal haemorrhage
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 24 (4.17%)
    1 / 55 (1.82%)
         occurrences all number
    3
    1
    1
    Nausea
         subjects affected / exposed
    19 / 54 (35.19%)
    5 / 24 (20.83%)
    25 / 55 (45.45%)
         occurrences all number
    35
    7
    36
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 54 (14.81%)
    1 / 24 (4.17%)
    4 / 55 (7.27%)
         occurrences all number
    13
    1
    4
    Dyspnoea
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    5 / 55 (9.09%)
         occurrences all number
    5
    0
    6
    Epistaxis
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 24 (4.17%)
    5 / 55 (9.09%)
         occurrences all number
    4
    4
    6
    Oropharyngeal pain
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    16 / 54 (29.63%)
    4 / 24 (16.67%)
    12 / 55 (21.82%)
         occurrences all number
    16
    4
    12
    Erythema
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    1
    0
    4
    Hair colour changes
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 24 (8.33%)
    0 / 55 (0.00%)
         occurrences all number
    1
    2
    0
    Nail toxicity
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    0
    0
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    2
    0
    5
    Rash
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    6 / 55 (10.91%)
         occurrences all number
    2
    0
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
    3 / 55 (5.45%)
         occurrences all number
    0
    1
    3
    Anxiety
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
    4 / 55 (7.27%)
         occurrences all number
    2
    1
    4
    Insomnia
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 24 (8.33%)
    4 / 55 (7.27%)
         occurrences all number
    6
    2
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 24 (8.33%)
    4 / 55 (7.27%)
         occurrences all number
    5
    2
    6
    Back pain
         subjects affected / exposed
    7 / 54 (12.96%)
    2 / 24 (8.33%)
    7 / 55 (12.73%)
         occurrences all number
    11
    3
    7
    Myalgia
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 24 (4.17%)
    5 / 55 (9.09%)
         occurrences all number
    9
    1
    5
    Muscle spasms
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 24 (8.33%)
    2 / 55 (3.64%)
         occurrences all number
    4
    2
    2
    Pain in extremity
         subjects affected / exposed
    3 / 54 (5.56%)
    3 / 24 (12.50%)
    3 / 55 (5.45%)
         occurrences all number
    5
    4
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 24 (4.17%)
    2 / 55 (3.64%)
         occurrences all number
    4
    1
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    5 / 55 (9.09%)
         occurrences all number
    3
    0
    7
    Rhinitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 54 (20.37%)
    1 / 24 (4.17%)
    14 / 55 (25.45%)
         occurrences all number
    15
    1
    18
    Hyperglycaemia
         subjects affected / exposed
    4 / 54 (7.41%)
    0 / 24 (0.00%)
    5 / 55 (9.09%)
         occurrences all number
    9
    0
    7
    Hyperkalaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    1
    0
    8
    Hyperuricaemia
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 24 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    3
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 24 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    3
    0
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    1
    0
    5
    Hypokalaemia
         subjects affected / exposed
    7 / 54 (12.96%)
    1 / 24 (4.17%)
    2 / 55 (3.64%)
         occurrences all number
    9
    1
    4
    Hypomagnesaemia
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 24 (4.17%)
    4 / 55 (7.27%)
         occurrences all number
    4
    1
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2010
    Amendment 1 introduced accurate recommendations for the management of QTcF interval prolongation and ventricular tachyarrhythmia.
    27 Sep 2010
    - Amendment 2 added drug-related QTcF prolongation >60 ms from baseline or drug-related prolongation of absolute QTcF >500 ms as a further unacceptable volasertib toxicity. - Amendment 2 detailed in the ECG investigations section that supervision of the patient had to be performed by an intensive care unit physician. - Amendment 2 corrected footnote 9 in the flow chart for screening and the first treatment course: safety laboratory had to be performed within 7 days prior to the start of the study treatment. - Amendment 2 corrected the time interval given in inclusion criterion 3: patients with disease progression occurring up to 4 weeks after the last administration of platinum-based therapy were considered as platinum refractory - Amendment 2 specified the conditions for patient cross-over from Arm B to volasertib treatment and described the procedures and recommendations for these patients. - Amendment 2 clarified that the interim analysis of safety was conducted by a data safety management board that was independent from the sponsor. - Amendment 2 added the collection of information on the type of progression before the patient was entered into the trial to the section on demographics and history.
    13 Dec 2010
    Amendment 3 further specified the conditions for patient cross-over from Arm B to volasertib treatment and clarified the procedures for ECG monitoring in these patients.
    29 Mar 2011
    Amendment 4 was implemented to facilitate the procedures for dispensing the commercial cytotoxic agents in the comparator arm and allowed the drugs to the dispensed by the pharmacy service of the site as marketed in each country with the approved local label and appropriate documentation.
    20 Feb 2012
    - Amendment 5 prolonged the duration of the trial until September 2012 due to some non-progressing patients still being on treatment. - Amendment 5 updated details on specified optional tumour biopsy biomarker testing on samples collected during the study. - Amendment 5 included guidance and procedures to complement AE reporting of DILI.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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