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    Clinical Trial Results:
    An Open-Label, Randomized, Parallel Group Study of Patients Treated with Paclitaxel with Standard Dosing versus Pharmacokinetic Guided Dose Adjustment in Patients with Advanced NSCLC

    Summary
    EudraCT number
    		 2010-023688-16
    Trial protocol
    		 DE  
    Global end of trial date
    25 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2018
    First version publication date
    05 Sep 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C-III-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01326767
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Central European Society for Anticancer Drug Research
    Sponsor organisation address
    Hanglüssgasse, 4/1-3, Wien, Austria, 1150
    Public contact
    Clinical trials information, Central European Society for Anticancer Drug Research, max.roessler@cesar.or.at
    Scientific contact
    Clinical trials information, Central European Society for Anticancer Drug Research, max.roessler@cesar.or.at
    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
    20 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the CEPAC-TDM study is to apply individualized paclitaxel dosing in patients with advanced NSCLC, as defined in Section 1.4. By applying the prespecified dosing algorithm, grade 4 neutropenia is predicted to be reduced from 15% with conventional dosing (i.e. paclitaxel 200 mg/m2 in combination with carboplatin or cisplatin at the predefined dose, given every three weeks) (Arm A) to 4% with individualized paclitaxel dosing (in combination with carboplatin or cisplatin at the predefined dose, given every three weeks) (Arm B) during the second treatment cycle. At the same time, progression-free survival (PFS) and overall survival (OS) must not be affected by individualized paclitaxel dosing.
    Protection of trial subjects
    As far as possible, patients were treated according to clinical routine. Study specific intervention was kept to a minimum. Patient specific dose modifications were designed to reduce adverse events.
    Background therapy
    		 Cisplatin / Carboplatin
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 317
    Country: Number of subjects enrolled
    Switzerland: 49
    Worldwide total number of subjects
    366
    EEA total number of subjects
    317
    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)
    199
    From 65 to 84 years
    167
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One study site in Switzerland participated in the study and 10 German study sites. Recruitment started on 25.03.2011 and ended at 25.04.2014 as the last patient was recruited.

    Pre-assignment
    Screening details
    		 The screening criteria were defined by the inclusion and exclusion criteria as defined in the study protocol.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding used

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard treatment arm (A)
    Arm description
    		 Chemotherapy will be administered according to the SmPC for Paclitaxel and Carboplatin (see Appendix 2-4), with initial doses according to Table 6.1.1. Dosing adaptation is performed according to specifications as outlined in Section 6.2. Rounding of chemotherapy dosage is left to the treating physician. The Body surface area (BSA) is calculated by the Dubois formula for Paclitaxel. A maximum BSA of 2.0 m2 may be used for dosing calculation according to local practice.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 on day 1 or 40 mg/m2 days 1 & 2 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC6 every three weeks for a maximum of 6 cycles

    Arm title
    		 Experimental treatment arm
    Arm description
    		 First-cycle Paclitaxel dose is adapted according to patient gender and age. Paclitaxel plasma levels will be determined 24 hours after the infusion, and paclitaxel TC>0.05 is calculated by using NONMEM. Individual paclitaxel dose adjustments for cycles two to six are done according to previous-cycle individual paclitaxel TC>0.05 and categorical neutropenia according to the algorithm. For each dose adaptation, only Paclitaxel TC>0.05 and neutrophil nadir from the prior cycle will be used for calculation. Missing values for Paclitaxel TC>0.05 or neutrophil nadir will be replaced by a value of 28 hours (Paclitaxel TC>0.05) and 1.5 G/L (neutrophil nadir), respectively. In case both Paclitaxel TC>0.05 and neutrophil nadir are missing, dose adaptations will be performed as recommended for the conventional treatment arm (Arm A). As a safety measure to prevent cumulative peripheral neuropathy, Paclitaxel dose increase is limited to a maximum of 320 mg/m2 in the experimental treatm. arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Individual dose adaptation based on PK values

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 on day 1 or 40 mg/m2 days 1 & 2 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC6 every three weeks for a maximum of 6 cycles

    Number of subjects in period 1
    		Standard treatment arm (A) Experimental treatment arm
    Started
    183
    183
    Completed
    183
    183
    Period 2
    Period 2 title
    Follow up period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard treatment arm (A)
    Arm description
    		 Chemotherapy will be administered according to the SmPC for Paclitaxel and Carboplatin (see Appendix 2-4), with initial doses according to Table 6.1.1. Dosing adaptation is performed according to specifications as outlined in Section 6.2. Rounding of chemotherapy dosage is left to the treating physician. The Body surface area (BSA) is calculated by the Dubois formula for Paclitaxel. A maximum BSA of 2.0 m2 may be used for dosing calculation according to local practice.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 on day 1 or 40 mg/m2 days 1 & 2 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC6 every three weeks for a maximum of 6 cycles

    Arm title
    		 Experimental treatment arm
    Arm description
    		 First-cycle Paclitaxel dose is adapted according to patient gender and age. Paclitaxel plasma levels will be determined 24 hours after the infusion, and paclitaxel TC>0.05 is calculated by using NONMEM. Individual paclitaxel dose adjustments for cycles two to six are done according to previous-cycle individual paclitaxel TC>0.05 and categorical neutropenia according to the algorithm. For each dose adaptation, only Paclitaxel TC>0.05 and neutrophil nadir from the prior cycle will be used for calculation. Missing values for Paclitaxel TC>0.05 or neutrophil nadir will be replaced by a value of 28 hours (Paclitaxel TC>0.05) and 1.5 G/L (neutrophil nadir), respectively. In case both Paclitaxel TC>0.05 and neutrophil nadir are missing, dose adaptations will be performed as recommended for the conventional treatment arm (Arm A). As a safety measure to prevent cumulative peripheral neuropathy, Paclitaxel dose increase is limited to a maximum of 320 mg/m2 in the experimental treatm. arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Individual dose adaptation based on PK values

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 on day 1 or 40 mg/m2 days 1 & 2 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC6 every three weeks for a maximum of 6 cycles

    Number of subjects in period 2
    		Standard treatment arm (A) Experimental treatment arm
    Started
    183
    183
    Completed
    183
    183

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Standard treatment arm (A)
    Reporting group description
    		 Chemotherapy will be administered according to the SmPC for Paclitaxel and Carboplatin (see Appendix 2-4), with initial doses according to Table 6.1.1. Dosing adaptation is performed according to specifications as outlined in Section 6.2. Rounding of chemotherapy dosage is left to the treating physician. The Body surface area (BSA) is calculated by the Dubois formula for Paclitaxel. A maximum BSA of 2.0 m2 may be used for dosing calculation according to local practice.

    Reporting group title
    Experimental treatment arm
    Reporting group description
    		 First-cycle Paclitaxel dose is adapted according to patient gender and age. Paclitaxel plasma levels will be determined 24 hours after the infusion, and paclitaxel TC>0.05 is calculated by using NONMEM. Individual paclitaxel dose adjustments for cycles two to six are done according to previous-cycle individual paclitaxel TC>0.05 and categorical neutropenia according to the algorithm. For each dose adaptation, only Paclitaxel TC>0.05 and neutrophil nadir from the prior cycle will be used for calculation. Missing values for Paclitaxel TC>0.05 or neutrophil nadir will be replaced by a value of 28 hours (Paclitaxel TC>0.05) and 1.5 G/L (neutrophil nadir), respectively. In case both Paclitaxel TC>0.05 and neutrophil nadir are missing, dose adaptations will be performed as recommended for the conventional treatment arm (Arm A). As a safety measure to prevent cumulative peripheral neuropathy, Paclitaxel dose increase is limited to a maximum of 320 mg/m2 in the experimental treatm. arm

    Reporting group values
    		 Standard treatment arm (A) Experimental treatment arm Total
    Number of subjects
    		 183 183 366
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    ITT Population
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ± 8.07 62.7 ± 7.59 -
    Gender categorical
    Units: Subjects
        Female
    		 55 65 120
        Male
    		 128 118 246
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is the primary analysis population for both safety and efficacy analyses, and is defined as patients who are randomized and receive at least one paclitaxel treatment.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population is defined as all patients in the ITT analysis population with no major protocol violations.

    Subject analysis sets values
    		 ITT PP
    Number of subjects
    366
    277
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    ITT Population
    Units: years
        arithmetic mean (standard deviation)
    63.3 ± 7.84
    63.2 ± 7.85
    Gender categorical
    Units: Subjects
        Female
    120
    89
        Male
    246
    188

    End points

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    End points reporting groups
    Reporting group title
    Standard treatment arm (A)
    Reporting group description
    		 Chemotherapy will be administered according to the SmPC for Paclitaxel and Carboplatin (see Appendix 2-4), with initial doses according to Table 6.1.1. Dosing adaptation is performed according to specifications as outlined in Section 6.2. Rounding of chemotherapy dosage is left to the treating physician. The Body surface area (BSA) is calculated by the Dubois formula for Paclitaxel. A maximum BSA of 2.0 m2 may be used for dosing calculation according to local practice.

    Reporting group title
    Experimental treatment arm
    Reporting group description
    		 First-cycle Paclitaxel dose is adapted according to patient gender and age. Paclitaxel plasma levels will be determined 24 hours after the infusion, and paclitaxel TC>0.05 is calculated by using NONMEM. Individual paclitaxel dose adjustments for cycles two to six are done according to previous-cycle individual paclitaxel TC>0.05 and categorical neutropenia according to the algorithm. For each dose adaptation, only Paclitaxel TC>0.05 and neutrophil nadir from the prior cycle will be used for calculation. Missing values for Paclitaxel TC>0.05 or neutrophil nadir will be replaced by a value of 28 hours (Paclitaxel TC>0.05) and 1.5 G/L (neutrophil nadir), respectively. In case both Paclitaxel TC>0.05 and neutrophil nadir are missing, dose adaptations will be performed as recommended for the conventional treatment arm (Arm A). As a safety measure to prevent cumulative peripheral neuropathy, Paclitaxel dose increase is limited to a maximum of 320 mg/m2 in the experimental treatm. arm
    Reporting group title
    Standard treatment arm (A)
    Reporting group description
    		 Chemotherapy will be administered according to the SmPC for Paclitaxel and Carboplatin (see Appendix 2-4), with initial doses according to Table 6.1.1. Dosing adaptation is performed according to specifications as outlined in Section 6.2. Rounding of chemotherapy dosage is left to the treating physician. The Body surface area (BSA) is calculated by the Dubois formula for Paclitaxel. A maximum BSA of 2.0 m2 may be used for dosing calculation according to local practice.

    Reporting group title
    Experimental treatment arm
    Reporting group description
    		 First-cycle Paclitaxel dose is adapted according to patient gender and age. Paclitaxel plasma levels will be determined 24 hours after the infusion, and paclitaxel TC>0.05 is calculated by using NONMEM. Individual paclitaxel dose adjustments for cycles two to six are done according to previous-cycle individual paclitaxel TC>0.05 and categorical neutropenia according to the algorithm. For each dose adaptation, only Paclitaxel TC>0.05 and neutrophil nadir from the prior cycle will be used for calculation. Missing values for Paclitaxel TC>0.05 or neutrophil nadir will be replaced by a value of 28 hours (Paclitaxel TC>0.05) and 1.5 G/L (neutrophil nadir), respectively. In case both Paclitaxel TC>0.05 and neutrophil nadir are missing, dose adaptations will be performed as recommended for the conventional treatment arm (Arm A). As a safety measure to prevent cumulative peripheral neuropathy, Paclitaxel dose increase is limited to a maximum of 320 mg/m2 in the experimental treatm. arm

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is the primary analysis population for both safety and efficacy analyses, and is defined as patients who are randomized and receive at least one paclitaxel treatment.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population is defined as all patients in the ITT analysis population with no major protocol violations.

    Primary: Grade 4 neutropenia at Day 15, Cycle 2

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    End point title
    		 Grade 4 neutropenia at Day 15, Cycle 2
    End point description
    The primary objective of the CEPAC-TDM study is to apply individualized paclitaxel dosing in patients with advanced NSCLC, as defined in Section 1.4. By applying the prespecified dosing algorithm, grade 4 neutropenia is predicted to be reduced from 15% with conventional dosing (i.e. paclitaxel 200 mg/m2 in combination with carboplatin at the predefined dose, given every three weeks) (Arm A) to 4% with individualized paclitaxel dosing (in combination with carboplatin at the predefined dose, given every three weeks) (Arm B) during the second treatment cycle. At the same time, progression-free survival (PFS) and overall survival (OS) must not be affected by individualized paclitaxel dosing.
    End point type
    Primary
    End point timeframe
    Grade 4 neutropenia Day 15, Cycle 2 (as identified from hematology safety laboratory)
    End point values
    		 Standard treatment arm (A) Experimental treatment arm ITT
    Number of subjects analysed
    138
    145
    366
    Units: Grade 4 neutropenia Cycle 2 Yes/No
    23
    23
    46
    Attachments
    		 Primary Endpoint
    Statistical analysis title
    		 Fisher exact test on primary endpoint
    Statistical analysis description
    Fisher exact test on percentage of subjects with Grade 4 neutropenia at Day 15, Cycle 2 (based on number of subjects with available information)
    Comparison groups
    Experimental treatment arm v Standard treatment arm (A)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8733
    Method
    		 Fisher exact
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Statistical analysis title
    		 Logistic regression on primary endpoint
    Statistical analysis description
    Baseline variables age (<65 vs. >=65), gender, tumor stage (IIIB, IV), smoking status (never smoked vs. former smoker vs. current smoker), tumor histology (non-squamous adenocarcinoma vs. squamous cell carcinoma), baseline ECOG performance status (0 vs. 1 vs. 2), prior treatment (yes/no), platinum drug (cisplatin, carboplatin), the presence of brain metastases at baseline assessment, and treatment group allocation (i.e. study arm) were taken as covariates
    Comparison groups
    Standard treatment arm (A) v Experimental treatment arm
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5847
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    A Cox regression model was applied for PFS that included the following covariates: treatment arm, age group (older than 65 or 65 vs. younger than 65), gender, tumor stage (IIIB vs. IV), smoking status, tumor histology (non-squamous adenocarcinoma vs. squamous cell carcinoma), Baseline ECOG (0 vs. 1 vs. 2), pre-treatment performed, platinum compound. Note that only the patients to be compared with respect to these parameters were included, e.g. only patients with non-squamous adenocarcinoma or squamous cell carcinoma.
    End point type
    Secondary
    End point timeframe
    Progression-free survival is the time from first administration of study medication to progression or death. Patients without progression or death were censored at their last available response assessment.
    End point values
    		 Standard treatment arm (A) Experimental treatment arm ITT
    Number of subjects analysed
    183
    183
    0 [1]
    Units: Days
        median (standard error)
    169 ± 0.039
    153 ± 0.038
    ±
    Notes
    [1] - No pooled analysis performed for whole ITT population
    Statistical analysis title
    		 Progression-free survival: Log-rank test
    Statistical analysis description
    Log-rank test for PFS to compare the two study arms in the ITT population
    Comparison groups
    Standard treatment arm (A) v Experimental treatment arm
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1786
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Progression-free survival: Cox regression
    Comparison groups
    Experimental treatment arm v Standard treatment arm (A)
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2896
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1468
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.4779

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    A Cox regression model was applied for OS that included the following covariates: treatment arm, age group (older than 65 or 65 vs. younger than 65), gender, tumor stage (IIIB vs. IV), smoking status, tumor histology (non-squamous adenocarcinoma vs. squamous cell carcinoma), Baseline ECOG (0 vs. 1 vs. 2), pre-treatment performed, platinum compound. Note that only the patients to be compared with respect to these parameters were included, e.g. only patients with non-squamous adenocarcinoma or squamous cell carcinoma.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is time from first administration of study medication to date of death. Patients that did not die were censored at last date patient was seen alive.
    End point values
    		 Standard treatment arm (A) Experimental treatment arm ITT
    Number of subjects analysed
    182
    183
    0 [2]
    Units: Days
        median (standard error)
    359 ± 0.04
    287 ± 0.039
    ±
    Notes
    [2] - No pooled analysis of overall survival performed for whole ITT population
    Statistical analysis title
    		 Overall survival: Log-rank test
    Comparison groups
    Standard treatment arm (A) v Experimental treatment arm
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0398
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Overall survival: Cox regression
    Comparison groups
    Standard treatment arm (A) v Experimental treatment arm
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0404
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.0136
         upper limit
    		 1.8247

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs have been assessed from first study drug administration to the End of treatment visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Standard treatment arm (A)
    Reporting group description
    		 Chemotherapy will be administered according to the SmPC for Paclitaxel and Carboplatin (see Appendix 2-4), with initial doses according to Table 6.1.1. Dosing adaptation is performed according to specifications as outlined in Section 6.2. Rounding of chemotherapy dosage is left to the treating physician. The Body surface area (BSA) is calculated by the Dubois formula for Paclitaxel. A maximum BSA of 2.0 m2 may be used for dosing calculation according to local practice.

    Reporting group title
    Experimental treatment arm (B)
    Reporting group description
    		 First-cycle Paclitaxel dose is adapted according to patient gender and age. Paclitaxel plasma levels will be determined 24 hours after the infusion, and paclitaxel TC>0.05 is calculated by using NONMEM. Individual paclitaxel dose adjustments for cycles two to six are done according to previous-cycle individual paclitaxel TC>0.05 and categorical neutropenia according to the algorithm. For each dose adaptation, only Paclitaxel TC>0.05 and neutrophil nadir from the prior cycle will be used for calculation. Missing values for Paclitaxel TC>0.05 or neutrophil nadir will be replaced by a value of 28 hours (Paclitaxel TC>0.05) and 1.5 G/L (neutrophil nadir), respectively. In case both Paclitaxel TC>0.05 and neutrophil nadir are missing, dose adaptations will be performed as recommended for the conventional treatment arm (Arm A). As a safety measure to prevent cumulative peripheral neuropathy, Paclitaxel dose increase is limited to a maximum of 320 mg/m2 in the experimental treatm. arm

    Serious adverse events
    		 Standard treatment arm (A) Experimental treatment arm (B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    114 / 183 (62.30%)
    127 / 183 (69.40%)
         number of deaths (all causes)
    111
    131
         number of deaths resulting from adverse events
    7
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Neoplasm malignant
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to meninges
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusive disease
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Multi-organ failure
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 183 (3.28%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 183 (2.19%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 183 (0.55%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Epistaxis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (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
    Pulmonary embolism
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Dyspnoea
         subjects affected / exposed
    4 / 183 (2.19%)
    8 / 183 (4.37%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemoptysis
         subjects affected / exposed
    2 / 183 (1.09%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder due to a general medical condition
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep disorder
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tachyarrhythmia
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 183 (3.83%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    9 / 9
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 183 (1.64%)
    5 / 183 (2.73%)
         occurrences causally related to treatment / all
    5 / 5
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 183 (0.00%)
    5 / 183 (2.73%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 183 (0.00%)
    7 / 183 (3.83%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (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
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    sepsis
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Infection
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    11 / 183 (6.01%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    2 / 13
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal abscess
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard treatment arm (A) Experimental treatment arm (B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 183 (78.69%)
    145 / 183 (79.23%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    10 / 183 (5.46%)
    11 / 183 (6.01%)
         occurrences all number
    17
    25
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    58 / 183 (31.69%)
    37 / 183 (20.22%)
         occurrences all number
    74
    40
    Peripheral sensory neuropathy
         subjects affected / exposed
    11 / 183 (6.01%)
    5 / 183 (2.73%)
         occurrences all number
    11
    5
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    19 / 183 (10.38%)
    43 / 183 (23.50%)
         occurrences all number
    32
    79
    Anaemia
         subjects affected / exposed
    24 / 183 (13.11%)
    20 / 183 (10.93%)
         occurrences all number
    32
    30
    Thrombocytopenia
         subjects affected / exposed
    2 / 183 (1.09%)
    11 / 183 (6.01%)
         occurrences all number
    2
    21
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    58 / 183 (31.69%)
    42 / 183 (22.95%)
         occurrences all number
    71
    45
    pain
         subjects affected / exposed
    13 / 183 (7.10%)
    12 / 183 (6.56%)
         occurrences all number
    19
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    28 / 183 (15.30%)
    25 / 183 (13.66%)
         occurrences all number
    40
    30
    Diarrhoea
         subjects affected / exposed
    16 / 183 (8.74%)
    18 / 183 (9.84%)
         occurrences all number
    18
    19
    Constipation
         subjects affected / exposed
    14 / 183 (7.65%)
    14 / 183 (7.65%)
         occurrences all number
    14
    15
    Vomiting
         subjects affected / exposed
    9 / 183 (4.92%)
    11 / 183 (6.01%)
         occurrences all number
    12
    18
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    13 / 183 (7.10%)
    15 / 183 (8.20%)
         occurrences all number
    14
    16
    Cough
         subjects affected / exposed
    12 / 183 (6.56%)
    14 / 183 (7.65%)
         occurrences all number
    12
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    27 / 183 (14.75%)
    34 / 183 (18.58%)
         occurrences all number
    27
    34
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    28 / 183 (15.30%)
    20 / 183 (10.93%)
         occurrences all number
    44
    32
    Arthralgia
         subjects affected / exposed
    12 / 183 (6.56%)
    7 / 183 (3.83%)
         occurrences all number
    15
    7
    Myalgia
         subjects affected / exposed
    12 / 183 (6.56%)
    8 / 183 (4.37%)
         occurrences all number
    16
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 183 (9.29%)
    11 / 183 (6.01%)
         occurrences all number
    17
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2011
    This amendment was prepared to implement a biomarker sub study to increase the scientific value of this study. This sub-study has been set up and is supervised by Dr. Holdenrieder (Institute for clinical Chemistry and clinical Pharmacology University Clinic Bonn, Sigmund-Freud-Str. 25 53105 Bonn, Germany). The aim of the study is to test biomarkers for their predictive and prognostic value as well as to determine if the kinetics of biomarker plasma levels allows monitoring of treatment success and toxicities. To minimized extra efforts for the patients, the time points for the blood analysis have been chosen in a way that no extra venipunctures are required. The blood draws for this sub-study will be done together with the ones for the main study.
    25 Jul 2013
    This amendment was prepared since the ongoing safety monitoring of the study showed, that the pharmacokinetic dose adaptation of paclitaxel (PTX), compared to the standard dosing in the conventional treatment arm A, in study patients receiving cisplatin leads to an increase of severe neutropenia. Although this did not result in an increase of infect-complications, the steering committee decided not to include any further patients, considered for cisplatin treatment.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27502710
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