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    Clinical Trial Results:
    A randomized, double-blind, placebo controlled, Phase II/III study of BKM120 plus paclitaxel in patients with HER2 negative inoperable locally advanced or metastatic breast cancer, with or without PI3K pathway activation Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2011-005932-24
    Trial protocol
    		 AT   CZ   ES   NL   GB   BE   HU   IT   DE  
    Global end of trial date
    01 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2018
    First version publication date
    18 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBKM120F2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01572727
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 61324111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 61324111,
    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
    01 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine whether buparlisib once daily plus weeklypaclitaxel prolongs PFS as per local investigator assessment in patients with HER2- first lineinoperable LABC or MBC patients as compared to placebo plus paclitaxel in either all patients (fullpopulation) or the PI3K pathway activated subpopulation.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Aug 2012
    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
    Australia: 28
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Hong Kong: 8
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Spain: 74
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    United States: 82
    Worldwide total number of subjects
    416
    EEA total number of subjects
    189
    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)
    336
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Among 416 randomized patients, 405 patients received the study treatment. Of them, 403 patients had at least one post-baseline safety assessment.

    Pre-assignment
    Screening details
    		 A total of approximately 524 patients were to be randomized in a 1:1 ratio to one of the two treatment arms irrespective of the adaptation decision to continue in the full or PI3K pathway activated subpopulation. Randomization was stratified by PI3K activation and Hormone Receptor status.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BKM120 and paclitaxel
    Arm description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received study drug plus paclitaxel
    Arm type
    		 Experimental

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered once weekly at a dose of 80 mg/m2 iv in a 28-day cycle.

    Investigational medicinal product name
    burparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Buparlisib placebo were supplied as 100 mg and 50 mg hard gelatin capsules and was dosed on a flat scale og mg/day.

    Arm title
    		 Placebo and paclitaxel
    Arm description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received placebo plus paclitaxel
    Arm type
    		 Placebo

    Investigational medicinal product name
    burparlisib placebo
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Buparlisib placebo were supplied as 100 mg and 50 mg hard gelatin capsules and was dosed on a flat scale og mg/day.

    Number of subjects in period 1
    		BKM120 and paclitaxel Placebo and paclitaxel
    Started
    207
    209
    Completed
    0
    0
    Not completed
    207
    209
         Adverse event, serious fatal
    2
    2
         Physician decision
    23
    9
         Adverse event, non-fatal
    43
    15
         Study terminated by sponsor
    61
    83
         Untreated
    4
    7
         Lost to follow-up
    1
    1
         Progressive disease
    59
    82
         Parent/guardian decision
    14
    9
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BKM120 and paclitaxel
    Reporting group description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received study drug plus paclitaxel

    Reporting group title
    Placebo and paclitaxel
    Reporting group description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received placebo plus paclitaxel

    Reporting group values
    		 BKM120 and paclitaxel Placebo and paclitaxel Total
    Number of subjects
    		 207 209 416
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 172 164 336
        From 65-84 years
    		 35 45 80
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.1 ( 11.13 ) 55.6 ( 10.48 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 207 209 416
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    BKM120 and paclitaxel
    Reporting group description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received study drug plus paclitaxel

    Reporting group title
    Placebo and paclitaxel
    Reporting group description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received placebo plus paclitaxel

    Primary: Progression-free survival (PFS) assessed by local investigator’s assessment

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    End point title
    		 Progression-free survival (PFS) assessed by local investigator’s assessment
    End point description
    PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression or death due to any cause. PFS was based on local investigator assessment per RECIST criteria v1.1
    End point type
    Primary
    End point timeframe
    every 8 weeks after randomization Up to 3 months after end of Treatment
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    168
    170
    Units: Months
        median (confidence interval 95%)
    8 (7.2 to 9.2)
    9.2 (7.3 to 11)
    Statistical analysis title
    		 Statistical Analysis for PFS
    Comparison groups
    Placebo and paclitaxel v BKM120 and paclitaxel
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.68

    Secondary: overall survival by Kaplan-Meier estimate

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    End point title
    		 overall survival by Kaplan-Meier estimate
    End point description
    Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    every 8 weeks after randomization Up to 3 months after end of Treatment
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    207
    209
    Units: Months
        median (confidence interval 95%)
    29.5 (25 to 30)
    9999.9 (-99999.99 to 99999.99)
    No statistical analyses for this end point

    Secondary: overall response rate

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    End point title
    		 overall response rate
    End point description
    Percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1
    End point type
    Secondary
    End point timeframe
    every 8 weeks after randomization Up to 3 months after end of Treatment
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    168
    170
    Units: Percentage of participants
        number (confidence interval 95%)
    22.6 (16.5 to 29.7)
    27.1 (20.5 to 34.4)
    No statistical analyses for this end point

    Secondary: duration of response

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    End point title
    		 duration of response
    End point description
    time from the date of the first documented response (CR or PR, which had to be confirmed subsequently) to the date of the first radiologically documented disease progression or death due to disease
    End point type
    Secondary
    End point timeframe
    every 8 weeks after randomization Up to 3 months after end of Treatment
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        median (standard deviation)
    ( )
    ( )
    Notes
    [1] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    [2] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    No statistical analyses for this end point

    Secondary: time to response

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    End point title
    		 time to response
    End point description
    time from date of randomization until first documented response (CR or PR, which has to be confirmed subsequently).
    End point type
    Secondary
    End point timeframe
    every 8 weeks after randomization Up to 3 months after end of Treatment
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        number (not applicable)
    Notes
    [3] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    [4] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    No statistical analyses for this end point

    Secondary: clinical benefit rate (CBR)

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    End point title
    		 clinical benefit rate (CBR)
    End point description
    CBR was defined as the percentage of patients with an overall response of CR or PR or SD or non-CR/non-PD lasting more than 24 weeks based on local Investigator’s assessment according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    every 8 weeks after randomization Up to 3 months after end of Treatment
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    168
    170
    Units: Percentage of participants
        number (confidence interval 95%)
    26.2 (19.7 to 33.5)
    32.9 (25.9 to 40.6)
    No statistical analyses for this end point

    Secondary: Plasma concentration-time profiles of BKM120 - pharmacokinetics (PK)

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    End point title
    		 Plasma concentration-time profiles of BKM120 - pharmacokinetics (PK)
    End point description
    Summary statistics for PK: plasma concentration-time profiles of BKM120 and appropriate individual PK parameters based on population PK model , if deemed appropriate; each cycle = 28 days
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1, 15, 16, 22 and Cycle 2 day 1.
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: ng*day/mL
        median (standard deviation)
    ( )
    ( )
    Notes
    [5] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed.
    [6] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of ECOG performance status

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    End point title
    		 Time to definitive deterioration of ECOG performance status
    End point description
    Time to definitive deterioration of the ECOG performance status from baseline
    End point type
    Secondary
    End point timeframe
    every 4 weeks
    End point values
    		 BKM120 and paclitaxel Placebo and paclitaxel
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Months
        median (standard deviation)
    ( )
    ( )
    Notes
    [7] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    [8] - Futility criteria met at interim analysis, analysis on other secondary endpoints not analyzed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received placebo plus paclitaxel

    Reporting group title
    Buparlisib + Paclitaxel
    Reporting group description
    		 Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received study drug plus paclitaxel

    Serious adverse events
    		 Placebo + Paclitaxel Buparlisib + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 201 (20.90%)
    61 / 202 (30.20%)
         number of deaths (all causes)
    5
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    CANCER PAIN
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 201 (0.50%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENA CAVA THROMBOSIS
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 201 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACE OEDEMA
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    3 / 201 (1.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    LOCALISED OEDEMA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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
    3 / 201 (1.49%)
    7 / 202 (3.47%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    DIET NONCOMPLIANCE
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         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
    BREAST HAEMORRHAGE
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST ULCERATION
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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
    ASTHMA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 201 (0.50%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    ACUTE PSYCHOSIS
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANXIETY
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DELIRIUM
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL DISORDER
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSYCHOTIC DISORDER
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOCYTE COUNT INCREASED
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         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
    FALL
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST-TRAUMATIC PAIN
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ULNA FRACTURE
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ALTERED STATE OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRACHIAL PLEXOPATHY
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN COMPRESSION
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN OEDEMA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ENCEPHALOPATHY
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METABOLIC ENCEPHALOPATHY
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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
    2 / 201 (1.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    CATARACT
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OPTIC NEUROPATHY
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 201 (1.49%)
    5 / 202 (2.48%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULAR
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH PRURITIC
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN MASS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SWELLING FACE
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC SKIN ERUPTION
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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
    ABSCESS LIMB
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    5 / 201 (2.49%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    2 / 201 (1.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION SITE INFECTION
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMOCYSTIS JIROVECII INFECTION
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 201 (0.50%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         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
    1 / 201 (0.50%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    3 / 201 (1.49%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         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 / 201 (0.00%)
    1 / 202 (0.50%)
         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
    		 Placebo + Paclitaxel Buparlisib + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    188 / 201 (93.53%)
    196 / 202 (97.03%)
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    11 / 201 (5.47%)
    7 / 202 (3.47%)
         occurrences all number
    19
    8
    HYPERTENSION
         subjects affected / exposed
    10 / 201 (4.98%)
    17 / 202 (8.42%)
         occurrences all number
    13
    21
    LYMPHOEDEMA
         subjects affected / exposed
    16 / 201 (7.96%)
    7 / 202 (3.47%)
         occurrences all number
    18
    8
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    45 / 201 (22.39%)
    48 / 202 (23.76%)
         occurrences all number
    81
    75
    FATIGUE
         subjects affected / exposed
    64 / 201 (31.84%)
    67 / 202 (33.17%)
         occurrences all number
    93
    86
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    11 / 201 (5.47%)
    4 / 202 (1.98%)
         occurrences all number
    12
    5
    OEDEMA PERIPHERAL
         subjects affected / exposed
    50 / 201 (24.88%)
    21 / 202 (10.40%)
         occurrences all number
    61
    25
    PAIN
         subjects affected / exposed
    11 / 201 (5.47%)
    9 / 202 (4.46%)
         occurrences all number
    11
    10
    PYREXIA
         subjects affected / exposed
    19 / 201 (9.45%)
    29 / 202 (14.36%)
         occurrences all number
    21
    31
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    28 / 201 (13.93%)
    40 / 202 (19.80%)
         occurrences all number
    37
    46
    DYSPNOEA
         subjects affected / exposed
    21 / 201 (10.45%)
    26 / 202 (12.87%)
         occurrences all number
    24
    27
    EPISTAXIS
         subjects affected / exposed
    33 / 201 (16.42%)
    29 / 202 (14.36%)
         occurrences all number
    35
    37
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    16 / 201 (7.96%)
    12 / 202 (5.94%)
         occurrences all number
    18
    12
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    31 / 201 (15.42%)
    41 / 202 (20.30%)
         occurrences all number
    43
    47
    DEPRESSION
         subjects affected / exposed
    17 / 201 (8.46%)
    50 / 202 (24.75%)
         occurrences all number
    23
    58
    INSOMNIA
         subjects affected / exposed
    33 / 201 (16.42%)
    31 / 202 (15.35%)
         occurrences all number
    36
    31
    MOOD ALTERED
         subjects affected / exposed
    5 / 201 (2.49%)
    11 / 202 (5.45%)
         occurrences all number
    7
    13
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    12 / 201 (5.97%)
    35 / 202 (17.33%)
         occurrences all number
    14
    43
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    11 / 201 (5.47%)
    30 / 202 (14.85%)
         occurrences all number
    13
    44
    BLOOD GLUCOSE INCREASED
         subjects affected / exposed
    10 / 201 (4.98%)
    13 / 202 (6.44%)
         occurrences all number
    16
    29
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    12 / 201 (5.97%)
    7 / 202 (3.47%)
         occurrences all number
    14
    7
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    15 / 201 (7.46%)
    15 / 202 (7.43%)
         occurrences all number
    35
    39
    WEIGHT DECREASED
         subjects affected / exposed
    14 / 201 (6.97%)
    30 / 202 (14.85%)
         occurrences all number
    16
    34
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    14 / 201 (6.97%)
    10 / 202 (4.95%)
         occurrences all number
    43
    29
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    21 / 201 (10.45%)
    33 / 202 (16.34%)
         occurrences all number
    23
    36
    DYSGEUSIA
         subjects affected / exposed
    34 / 201 (16.92%)
    39 / 202 (19.31%)
         occurrences all number
    38
    40
    HEADACHE
         subjects affected / exposed
    37 / 201 (18.41%)
    35 / 202 (17.33%)
         occurrences all number
    48
    51
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    48 / 201 (23.88%)
    50 / 202 (24.75%)
         occurrences all number
    69
    59
    PARAESTHESIA
         subjects affected / exposed
    34 / 201 (16.92%)
    25 / 202 (12.38%)
         occurrences all number
    46
    29
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    31 / 201 (15.42%)
    31 / 202 (15.35%)
         occurrences all number
    39
    36
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    51 / 201 (25.37%)
    46 / 202 (22.77%)
         occurrences all number
    78
    64
    NEUTROPENIA
         subjects affected / exposed
    54 / 201 (26.87%)
    64 / 202 (31.68%)
         occurrences all number
    147
    149
    Eye disorders
    LACRIMATION INCREASED
         subjects affected / exposed
    17 / 201 (8.46%)
    12 / 202 (5.94%)
         occurrences all number
    18
    13
    VISION BLURRED
         subjects affected / exposed
    7 / 201 (3.48%)
    19 / 202 (9.41%)
         occurrences all number
    7
    20
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    22 / 201 (10.95%)
    27 / 202 (13.37%)
         occurrences all number
    26
    32
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    14 / 201 (6.97%)
    11 / 202 (5.45%)
         occurrences all number
    16
    12
    CONSTIPATION
         subjects affected / exposed
    38 / 201 (18.91%)
    47 / 202 (23.27%)
         occurrences all number
    55
    58
    DIARRHOEA
         subjects affected / exposed
    68 / 201 (33.83%)
    109 / 202 (53.96%)
         occurrences all number
    123
    191
    DRY MOUTH
         subjects affected / exposed
    10 / 201 (4.98%)
    12 / 202 (5.94%)
         occurrences all number
    11
    12
    DYSPEPSIA
         subjects affected / exposed
    15 / 201 (7.46%)
    23 / 202 (11.39%)
         occurrences all number
    18
    26
    NAUSEA
         subjects affected / exposed
    51 / 201 (25.37%)
    83 / 202 (41.09%)
         occurrences all number
    72
    126
    STOMATITIS
         subjects affected / exposed
    24 / 201 (11.94%)
    56 / 202 (27.72%)
         occurrences all number
    31
    77
    VOMITING
         subjects affected / exposed
    30 / 201 (14.93%)
    39 / 202 (19.31%)
         occurrences all number
    52
    67
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    104 / 201 (51.74%)
    103 / 202 (50.99%)
         occurrences all number
    105
    106
    DRY SKIN
         subjects affected / exposed
    13 / 201 (6.47%)
    28 / 202 (13.86%)
         occurrences all number
    15
    35
    ERYTHEMA
         subjects affected / exposed
    17 / 201 (8.46%)
    11 / 202 (5.45%)
         occurrences all number
    19
    13
    NAIL DISCOLOURATION
         subjects affected / exposed
    14 / 201 (6.97%)
    7 / 202 (3.47%)
         occurrences all number
    14
    7
    NAIL DISORDER
         subjects affected / exposed
    19 / 201 (9.45%)
    7 / 202 (3.47%)
         occurrences all number
    20
    8
    ONYCHOMADESIS
         subjects affected / exposed
    11 / 201 (5.47%)
    7 / 202 (3.47%)
         occurrences all number
    11
    8
    PRURITUS
         subjects affected / exposed
    30 / 201 (14.93%)
    32 / 202 (15.84%)
         occurrences all number
    35
    42
    RASH
         subjects affected / exposed
    43 / 201 (21.39%)
    86 / 202 (42.57%)
         occurrences all number
    62
    111
    RASH MACULO-PAPULAR
         subjects affected / exposed
    8 / 201 (3.98%)
    12 / 202 (5.94%)
         occurrences all number
    13
    19
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    32 / 201 (15.92%)
    23 / 202 (11.39%)
         occurrences all number
    37
    26
    BACK PAIN
         subjects affected / exposed
    22 / 201 (10.95%)
    21 / 202 (10.40%)
         occurrences all number
    25
    24
    BONE PAIN
         subjects affected / exposed
    14 / 201 (6.97%)
    10 / 202 (4.95%)
         occurrences all number
    17
    14
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    12 / 201 (5.97%)
    8 / 202 (3.96%)
         occurrences all number
    13
    9
    MYALGIA
         subjects affected / exposed
    27 / 201 (13.43%)
    22 / 202 (10.89%)
         occurrences all number
    35
    35
    PAIN IN EXTREMITY
         subjects affected / exposed
    40 / 201 (19.90%)
    27 / 202 (13.37%)
         occurrences all number
    51
    37
    Infections and infestations
    RHINITIS
         subjects affected / exposed
    9 / 201 (4.48%)
    11 / 202 (5.45%)
         occurrences all number
    10
    11
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    23 / 201 (11.44%)
    11 / 202 (5.45%)
         occurrences all number
    31
    12
    URINARY TRACT INFECTION
         subjects affected / exposed
    18 / 201 (8.96%)
    18 / 202 (8.91%)
         occurrences all number
    25
    21
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    26 / 201 (12.94%)
    64 / 202 (31.68%)
         occurrences all number
    32
    71
    HYPERGLYCAEMIA
         subjects affected / exposed
    22 / 201 (10.95%)
    82 / 202 (40.59%)
         occurrences all number
    58
    156
    HYPOKALAEMIA
         subjects affected / exposed
    6 / 201 (2.99%)
    19 / 202 (9.41%)
         occurrences all number
    7
    34

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2012
    The purpose of this protocol amendment was to add contraceptive guidance in alignment with the local summary of product characteristics for contraception recommendations after discontinuation of paclitaxel study drug.
    26 May 2013
    The main purpose of this protocol amendment was to update and align the management of selected AEs across the buparlisib program, specifically psychiatric disorders, hyperglycemia, stomatitis and skin rash, and to increase the permitted treatment interruption period for buparlisib/placebo from 21 to 28 days. Moreover, due to the very low frequency of PI3KCA mutations in exon5 and PTEN mutations overall in breast cancer, the definition of the PI3K pathway activation status (one of the two stratification factors) was modified and no longer included the above mentioned mutations.
    13 Sep 2013
    The main purpose of this protocol amendment was to convert the existing Phase II trial into a Phase II/III study by implementing an adaptive Phase II/III seamless design with a Bayesian decision tool for targeted therapy in oncology as described by Brannath W, Zuber E, Branson M, et al. (2009), in accordance with the published FDA guidelines on adaptive designs and enrichment strategies (FDA Guidance 2010 and 2012), and the EU 2007 reflection paper (CHMP/EWP/2459/02). Prior to implementation, scientific advice was sought and the planned amendment discussed with the FDA, EMA and PMDA

    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.
    The safety set included all randomized patients who received at least one dose of the study treatment (either buparlisib + paclitaxel or matching placebo + paclitaxel) and had at least one post-baseline safety assessment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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