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    Clinical Trial Results:
    A Randomized Double-Blinded Phase II Study of Carboplatin/Paclitaxel/CT-322 versus Carboplatin/Paclitaxel/Bevacizumab as First-Line Treatment for Recurrent or Advanced Non-Small Cell Lung Cancer with Non-Squamous Histology

    Summary
    EudraCT number
    		 2008-007768-41
    Trial protocol
    		 GB   IT  
    Global end of trial date
    08 Nov 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2016
    First version publication date
    30 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA196-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00850577
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb International Corporation
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb Study Director, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Nov 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2011
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the progression free survival (PFS) of CT-322 versus bevacizumab in combination with carboplatin and paclitaxel in chemonaive subjects with recurrent or advanced non-small cell lung cancer with non-squamous histology.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 95
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Russian Federation: 34
    Country: Number of subjects enrolled
    South Africa: 36
    Worldwide total number of subjects
    255
    EEA total number of subjects
    73
    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)
    164
    From 65 to 84 years
    90
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 48 sites in 8 countries.

    Pre-assignment
    Screening details
    		 A total of 338 subjects were enrolled in the study, out of which 255 were randomized and treated (127 CT-322 arm, 128 Bevacizumab arm). 83 were not randomized because 3 experienced adverse events, 9 withdrew consent, 1 was lost to follow-up, 2 died, 64 no longer met study criteria, 1 for poor/non-compliance and 3 for other non-specified reasons

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paclitaxel/Carboplatin/CT-322
    Arm description
    		 Paclitaxel (200 mg/m2) and carboplatin (area under the plasma concentration versus time curve [AUC]=6) on Day 1 of a 21-day cycle, plus blinded CT-322 (2 mg/kg) weekly on Days 1, 8, and 15 of the 21-day cycle as an intravenous [IV] infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 was administered intravenously, over 3 hours on Day 1 of a 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin 10 mg/mL (AUC=6) was administered intravenously on day 1 of a 21 day cycle.

    Investigational medicinal product name
    CT-322
    Investigational medicinal product code
    Other name
    BMS-844203
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-322 2 mg/kg was administered intravenously weekly on Days 1,8, and 15 of the 21-day cycle

    Arm title
    		 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Arm description
    		 Paclitaxel (200 mg/m2) and carboplatin (AUC=6) on Day 1 of a 21-day cycle, plus blinded bevacizumab (15 mg/kg IV) on Day 1 and placebo (IV) on Day 8 and 15 of a 21-day cycle
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 was administered intravenously, over 3 hours on Day 1 of a 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin 10 mg/mL (AUC=6) was administered intravenously on day 1 of a 21 day cycle.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 15 mg/kg on Day 1 of a 21-day cycle

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Saline (Bevacizumab equivalent volume) was administered intravenously on Days 8 and 15 of a 21-day cycle

    Number of subjects in period 1
    		Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Started
    127
    128
    Completed
    0
    0
    Not completed
    127
    128
         Subject request to discontinue treatment
    5
    2
         Subject withdrew consent
    1
    -
         Consent withdrawn by subject
    -
    1
         Disease progression
    77
    63
         Study drug toxicity
    13
    20
         Adverse event, non-fatal
    9
    8
         Death
    7
    4
         Various other reasons
    3
    2
         Maximum clinical benefit
    -
    1
         On study therapy
    9
    24
         Subject no longer meets study criteria
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclitaxel/Carboplatin/CT-322
    Reporting group description
    		 Paclitaxel (200 mg/m2) and carboplatin (area under the plasma concentration versus time curve [AUC]=6) on Day 1 of a 21-day cycle, plus blinded CT-322 (2 mg/kg) weekly on Days 1, 8, and 15 of the 21-day cycle as an intravenous [IV] infusion.

    Reporting group title
    Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Reporting group description
    		 Paclitaxel (200 mg/m2) and carboplatin (AUC=6) on Day 1 of a 21-day cycle, plus blinded bevacizumab (15 mg/kg IV) on Day 1 and placebo (IV) on Day 8 and 15 of a 21-day cycle

    Reporting group values
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo Total
    Number of subjects
    		 127 128 255
    Age categorical
    Units: Subjects
        < 65 years
    		 87 77 164
        >= 65 years
    		 40 51 91
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.6 ( 9.33 ) 60.9 ( 10.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 50 57 107
        Male
    		 77 71 148

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel/Carboplatin/CT-322
    Reporting group description
    		 Paclitaxel (200 mg/m2) and carboplatin (area under the plasma concentration versus time curve [AUC]=6) on Day 1 of a 21-day cycle, plus blinded CT-322 (2 mg/kg) weekly on Days 1, 8, and 15 of the 21-day cycle as an intravenous [IV] infusion.

    Reporting group title
    Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Reporting group description
    		 Paclitaxel (200 mg/m2) and carboplatin (AUC=6) on Day 1 of a 21-day cycle, plus blinded bevacizumab (15 mg/kg IV) on Day 1 and placebo (IV) on Day 8 and 15 of a 21-day cycle

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to the time of disease progression (as assessed by CT/MRI scans) or death, whichever occurred first. The analysis was performed in all randomized subjects.
    End point type
    Primary
    End point timeframe
    Day of randomization to end of study
    End point values
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects analysed
    127
    128
    Units: Months
        median (confidence interval 95%)
    5.6 (4.2 to 6.4)
    6.8 (6 to 8.2)
    Statistical analysis title
    		 CT-322 Arm vs Bevacizumab Arm
    Comparison groups
    Paclitaxel/Carboplatin/CT-322 v Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.997
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 2.02

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time from randomization to death. The analysis was performed in all the subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Date of randomization to date of death
    End point values
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects analysed
    127
    128
    Units: Months
        median (confidence interval 95%)
    12.5 (10.2 to 15.7)
    15.2 (12.2 to 16.8)
    Statistical analysis title
    		 CT-322 Arm vs Bevacizumab Arm
    Comparison groups
    Paclitaxel/Carboplatin/CT-322 v Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.703
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.61

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Objective response rate was defined as the proportion of randomized subjects in each treatment arm, whose best response was complete response (CR) or partial response (PR). The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of study
    End point values
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects analysed
    127
    128
    Units: Percentage of subjects
        number (confidence interval 95%)
    25.2 (17.9 to 33.7)
    32.8 (24.8 to 41.7)
    Statistical analysis title
    		 CT-322 Arm vs Bevacizumab Arm
    Comparison groups
    Paclitaxel/Carboplatin/CT-322 v Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.9
         upper limit
    		 4.4

    Secondary: Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Grade 3 to 4 AEs, and Who Died During Treatment Period

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    End point title
    		 Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Grade 3 to 4 AEs, and Who Died During Treatment Period
    End point description
    AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not has a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalisation. Grade 3 to 4 AE were also reported. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to 30 days after the last dose of study treatment
    End point values
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Number of subjects analysed
    127
    128
    Units: Subjects
        SAEs (Any Grade)
    51
    48
        Drug-Related SAEs
    28
    24
        Grade 3/4 AEs
    104
    102
        Drug-Related Grade 3/4 AEs
    87
    83
        Deaths
    55
    57
        Deaths Within 30 Days of Last Study Dose
    10
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment to 30 days after the last dose of study treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Paclitaxel/Carboplatin/CT-322
    Reporting group description
    		 Paclitaxel (200 mg/m2) and carboplatin (area under the plasma concentration versus time curve [AUC]=6) on Day 1 of a 21-day cycle, plus blinded CT-322 (2 mg/kg) weekly on Days 1, 8, and 15 of the 21-day cycle as an intravenous [IV] infusion.

    Reporting group title
    Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Reporting group description
    		 Paclitaxel (200 mg/m2) and carboplatin (AUC=6) on Day 1 of a 21-day cycle, plus blinded bevacizumab (15 mg/kg IV) on Day 1 and placebo (IV) on Day 8 and 15 of a 21-day cycle

    Serious adverse events
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 127 (40.16%)
    48 / 128 (37.50%)
         number of deaths (all causes)
    10
    10
         number of deaths resulting from adverse events
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 127 (1.57%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (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
    Sudden death
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 127 (6.30%)
    5 / 128 (3.91%)
         occurrences causally related to treatment / all
    1 / 10
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 127 (1.57%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood amylase increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Monoparesis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    6 / 127 (4.72%)
    6 / 128 (4.69%)
         occurrences causally related to treatment / all
    7 / 7
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 127 (2.36%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 127 (2.36%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Corneal perforation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 127 (4.72%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 127 (4.72%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecalith
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ileal perforation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         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
    Arthralgia
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 127 (2.36%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         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 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligodipsia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Paclitaxel/Carboplatin/CT-322 Paclitaxel/Carboplatin/Bevacizumab/Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 127 (99.21%)
    125 / 128 (97.66%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 127 (23.62%)
    30 / 128 (23.44%)
         occurrences all number
    47
    40
    Hypotension
         subjects affected / exposed
    6 / 127 (4.72%)
    12 / 128 (9.38%)
         occurrences all number
    6
    13
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    59 / 127 (46.46%)
    54 / 128 (42.19%)
         occurrences all number
    126
    153
    Asthenia
         subjects affected / exposed
    13 / 127 (10.24%)
    33 / 128 (25.78%)
         occurrences all number
    35
    49
    Oedema peripheral
         subjects affected / exposed
    30 / 127 (23.62%)
    12 / 128 (9.38%)
         occurrences all number
    55
    19
    Chest pain
         subjects affected / exposed
    16 / 127 (12.60%)
    22 / 128 (17.19%)
         occurrences all number
    31
    35
    Pyrexia
         subjects affected / exposed
    15 / 127 (11.81%)
    18 / 128 (14.06%)
         occurrences all number
    18
    28
    Pain
         subjects affected / exposed
    10 / 127 (7.87%)
    19 / 128 (14.84%)
         occurrences all number
    14
    25
    Mucosal inflammation
         subjects affected / exposed
    14 / 127 (11.02%)
    15 / 128 (11.72%)
         occurrences all number
    15
    21
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    35 / 127 (27.56%)
    36 / 128 (28.13%)
         occurrences all number
    84
    96
    Cough
         subjects affected / exposed
    30 / 127 (23.62%)
    36 / 128 (28.13%)
         occurrences all number
    60
    72
    Dyspnoea
         subjects affected / exposed
    25 / 127 (19.69%)
    26 / 128 (20.31%)
         occurrences all number
    78
    48
    Dysphonia
         subjects affected / exposed
    6 / 127 (4.72%)
    18 / 128 (14.06%)
         occurrences all number
    7
    30
    Haemoptysis
         subjects affected / exposed
    10 / 127 (7.87%)
    10 / 128 (7.81%)
         occurrences all number
    18
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    24 / 127 (18.90%)
    27 / 128 (21.09%)
         occurrences all number
    27
    31
    Anxiety
         subjects affected / exposed
    9 / 127 (7.09%)
    16 / 128 (12.50%)
         occurrences all number
    9
    18
    Confusional state
         subjects affected / exposed
    2 / 127 (1.57%)
    8 / 128 (6.25%)
         occurrences all number
    2
    10
    Depression
         subjects affected / exposed
    3 / 127 (2.36%)
    8 / 128 (6.25%)
         occurrences all number
    4
    9
    Investigations
    Weight decreased
         subjects affected / exposed
    8 / 127 (6.30%)
    20 / 128 (15.63%)
         occurrences all number
    15
    21
    Platelet count decreased
         subjects affected / exposed
    5 / 127 (3.94%)
    8 / 128 (6.25%)
         occurrences all number
    13
    15
    Neutrophil count decreased
         subjects affected / exposed
    3 / 127 (2.36%)
    8 / 128 (6.25%)
         occurrences all number
    4
    17
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    20 / 127 (15.75%)
    33 / 128 (25.78%)
         occurrences all number
    69
    120
    Peripheral sensory neuropathy
         subjects affected / exposed
    31 / 127 (24.41%)
    23 / 128 (17.97%)
         occurrences all number
    106
    72
    Headache
         subjects affected / exposed
    17 / 127 (13.39%)
    25 / 128 (19.53%)
         occurrences all number
    33
    82
    Dizziness
         subjects affected / exposed
    11 / 127 (8.66%)
    22 / 128 (17.19%)
         occurrences all number
    24
    39
    Dysgeusia
         subjects affected / exposed
    14 / 127 (11.02%)
    16 / 128 (12.50%)
         occurrences all number
    29
    39
    Paraesthesia
         subjects affected / exposed
    13 / 127 (10.24%)
    17 / 128 (13.28%)
         occurrences all number
    25
    62
    Hypoaesthesia
         subjects affected / exposed
    4 / 127 (3.15%)
    7 / 128 (5.47%)
         occurrences all number
    17
    18
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    62 / 127 (48.82%)
    69 / 128 (53.91%)
         occurrences all number
    198
    256
    Anaemia
         subjects affected / exposed
    28 / 127 (22.05%)
    42 / 128 (32.81%)
         occurrences all number
    82
    97
    Thrombocytopenia
         subjects affected / exposed
    39 / 127 (30.71%)
    31 / 128 (24.22%)
         occurrences all number
    122
    65
    Leukopenia
         subjects affected / exposed
    9 / 127 (7.09%)
    21 / 128 (16.41%)
         occurrences all number
    37
    98
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    54 / 127 (42.52%)
    63 / 128 (49.22%)
         occurrences all number
    114
    135
    Diarrhoea
         subjects affected / exposed
    31 / 127 (24.41%)
    36 / 128 (28.13%)
         occurrences all number
    45
    58
    Constipation
         subjects affected / exposed
    38 / 127 (29.92%)
    32 / 128 (25.00%)
         occurrences all number
    54
    55
    Vomiting
         subjects affected / exposed
    29 / 127 (22.83%)
    32 / 128 (25.00%)
         occurrences all number
    49
    49
    Dyspepsia
         subjects affected / exposed
    12 / 127 (9.45%)
    21 / 128 (16.41%)
         occurrences all number
    16
    27
    Abdominal pain
         subjects affected / exposed
    9 / 127 (7.09%)
    13 / 128 (10.16%)
         occurrences all number
    12
    21
    Abdominal pain upper
         subjects affected / exposed
    6 / 127 (4.72%)
    7 / 128 (5.47%)
         occurrences all number
    7
    14
    Stomatitis
         subjects affected / exposed
    4 / 127 (3.15%)
    8 / 128 (6.25%)
         occurrences all number
    10
    20
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    50 / 127 (39.37%)
    56 / 128 (43.75%)
         occurrences all number
    66
    63
    Rash
         subjects affected / exposed
    16 / 127 (12.60%)
    16 / 128 (12.50%)
         occurrences all number
    22
    24
    Pruritus
         subjects affected / exposed
    9 / 127 (7.09%)
    8 / 128 (6.25%)
         occurrences all number
    10
    17
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    28 / 127 (22.05%)
    17 / 128 (13.28%)
         occurrences all number
    57
    34
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 127 (28.35%)
    38 / 128 (29.69%)
         occurrences all number
    117
    109
    Myalgia
         subjects affected / exposed
    17 / 127 (13.39%)
    26 / 128 (20.31%)
         occurrences all number
    47
    82
    Pain in extremity
         subjects affected / exposed
    14 / 127 (11.02%)
    27 / 128 (21.09%)
         occurrences all number
    34
    52
    Back pain
         subjects affected / exposed
    14 / 127 (11.02%)
    17 / 128 (13.28%)
         occurrences all number
    24
    20
    Bone pain
         subjects affected / exposed
    12 / 127 (9.45%)
    11 / 128 (8.59%)
         occurrences all number
    15
    14
    Musculoskeletal pain
         subjects affected / exposed
    7 / 127 (5.51%)
    14 / 128 (10.94%)
         occurrences all number
    10
    14
    Muscle spasms
         subjects affected / exposed
    2 / 127 (1.57%)
    7 / 128 (5.47%)
         occurrences all number
    2
    7
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 127 (8.66%)
    16 / 128 (12.50%)
         occurrences all number
    15
    21
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 127 (10.24%)
    8 / 128 (6.25%)
         occurrences all number
    19
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 127 (22.83%)
    30 / 128 (23.44%)
         occurrences all number
    39
    44
    Dehydration
         subjects affected / exposed
    11 / 127 (8.66%)
    8 / 128 (6.25%)
         occurrences all number
    16
    17
    Hypomagnesaemia
         subjects affected / exposed
    11 / 127 (8.66%)
    9 / 128 (7.03%)
         occurrences all number
    16
    15
    Hypokalaemia
         subjects affected / exposed
    6 / 127 (4.72%)
    8 / 128 (6.25%)
         occurrences all number
    11
    12
    Hyperglycaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    9 / 128 (7.03%)
         occurrences all number
    1
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jan 2009
    • Allowed for the collection and storage of blood samples for use in future exploratory pharmacogenetic research studies.
    06 Aug 2009
    • Updated drug administration and dose modification guidelines. • Provided additional guidance on symptoms and management of Reversible Posterior Leukoencephalopathy Syndrome (RPLS). • Added N-terminal brain natriuretic peptide (NT-BNP) as a tool for cardiac safety assessment. • Increased the number of participating countries and sites.
    25 Aug 2010
    • Increase number of participating sites • Update Exclusion Criteria • Update Packaging and Labeling, provide additional guidance on study drug preparation, start of first dose, dose modification criteria and unblinding criteria • Reinforce requirement for premedication for all subjects prior to infusion of paclitaxel and subsequent doses of blinded investigational drug if needed and update monitoring requirements for infusion reaction • Simplify blood sample collection times for PK and PD Biomarkers • Update definition of PFS • Correct some inconsistencies within the protocol
    03 Nov 2010
    • Update Exclusion criterion to align with new bevacizumab SmPC • Removal of FDG-PET measurements as exploratory objective • Removal NT-BNP as an additional tool for cardiac safety assessment

    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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