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    Clinical Trial Results:
    A Phase III randomized, double blind, placebo-controlled study of BKM120 with fulvestrant, in postmenopausal women with hormone receptor-positive HER2-negative AI-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor based treatment

    Summary
    EudraCT number
    		 2012-002571-34
    Trial protocol
    		 AT   GB   DE   ES   NO   IT   SE   NL   GR   FI   HU   PL   BE   BG  
    Global end of trial date
    21 Sep 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Dec 2018
    First version publication date
    06 Oct 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Corrections for the number of participants for Outcome Measures n°5, 6 and 7

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CBKM120F2303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01633060
    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 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    21 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to determine whether treatment with buparlisib plus fulvestrant prolongs PFS based on local Investigator assessment compared to treatment with placebo plus fulvestrant. 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.nov for complete trial results.
    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
    03 Oct 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
    Argentina: 9
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 90
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Country: Number of subjects enrolled
    Lebanon: 5
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    432
    EEA total number of subjects
    332
    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)
    274
    From 65 to 84 years
    158
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 201 centers in 22 countries worldwide (Argentina, Austria, Belgium, Bulgaria, Canada, Colombia, Finland, France, Germany, Greece, Hungary, Italy, Republic of Korea, Lebanon, The Netherlands, Norway, Poland, Spain, Sweden, Thailand, UK and USA).

    Pre-assignment
    Screening details
    		 At least 420 patients were planned to be enrolled, randomized in a 2:1 ratio (two buparlisib, one placebo). A total of 432 patients were actually enrolled and analyzed (buparlisib arm: N=289; placebo arm: N=143). Not completed: in Randomization Phase=Randomized and not Treated; in Treatment Phase=Discontinued study treatment per Protocol.

    Period 1
    Period 1 title
    Randomization Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BKM120 100mg + Fulvestrant
    Arm description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Number of subjects in period 1
    		BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Started
    289
    143
    Completed
    288
    140
    Not completed
    1
    3
         Technical problem
    -
    1
         Protocol Deviation
    1
    2
    Period 2
    Period 2 title
    Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BKM120 100mg + Fulvestrant
    Arm description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Number of subjects in period 2
    		BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Started
    288
    140
    FAS - ctDNA PIK3CA Mutant
    100
    35
    FAS - ctDNA PIK3CA Non-mutant
    132
    81
    Safety Set (SS)
    288
    140
    Pharmacokinetic Analysis Set (PAS)
    63
    0
    Completed
    0
    0
    Not completed
    288
    140
         Adverse event, serious fatal
    4
    3
         Physician decision
    16
    7
         Adverse event, non-fatal
    24
    3
         Protocol Deviation
    1
    -
         Progressive Disease
    210
    120
         Study terminated by sponsor
    7
    3
         Subject/Guardian Decision
    25
    4
         Lost to follow-up
    1
    -
    Period 3
    Period 3 title
    Post-Treatment Efficacy Follow-Up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BKM120 100mg + Fulvestrant
    Arm description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Number of subjects in period 3
    		BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Started
    16
    2
    Completed
    0
    0
    Not completed
    16
    2
         Adverse event, serious fatal
    1
    -
         Physician decision
    1
    -
         Adverse event, non-fatal
    2
    -
         Progressive Disease
    10
    1
         Study terminated by sponsor
    1
    -
         Subject/Guardian Decision
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.

    Reporting group values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant Total
    Number of subjects
    		 289 143 432
    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)
    		 191 83 274
        From 65-84 years
    		 98 60 158
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.5 ± 9.76 61.5 ± 9.23 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 289 143 432
        Male
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 4 1 5
        Asian
    		 20 9 29
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 4 8
        White
    		 249 121 370
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 12 8 20

    End points

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    End points reporting groups
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.

    Primary: Progression Free Survival (PFS) based on Local Investigator assessment - Full Analysis Set (FAS)

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    End point title
    		 Progression Free Survival (PFS) based on Local Investigator assessment - Full Analysis Set (FAS)
    End point description
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. Patients were followed up for approximately every 6 weeks after randomization.
    End point type
    Primary
    End point timeframe
    Every 6 weeks after randomization up to a maximum of 4 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Months
        median (confidence interval 95%)
    3.9 (2.8 to 4.2)
    1.8 (1.5 to 2.8)
    Statistical analysis title
    		 Progression-Free survival (PFS)
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.53
         upper limit
    		 -
    Notes
    [1] - Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance

    Secondary: Overall Survival (OS) - Full Analysis Set (FAS)

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    End point title
    		 Overall Survival (OS) - Full Analysis Set (FAS)
    End point description
    Overall Survival (OS) is 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 known date patient alive. Patients were followed up approximately every 6 weeks after randomization and every 3 months during survival follow-up.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks after randomization up to a maximum of 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Months
        median (confidence interval 95%)
    21.2 (18.2 to 23.4)
    22.1 (17.3 to 999)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) by PIK3CA mutational status

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    End point title
    		 Progression Free Survival (PFS) by PIK3CA mutational status
    End point description
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. Patients were followed up for approximately every 6 weeks after randomization.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks after randomization up to a maximum of 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Months
    median (confidence interval 95%)
        FAS ctDNA PIK3CA mutant (n=100,35)|
    4.2 (2.8 to 6.7)
    1.6 (1.4 to 2.8)
        FAS ctDNA PIK3CA non-mutant (n=132,81)|
    3.9 (2.8 to 4.3)
    2.7 (1.5 to 3.6)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) by PIK3CA mutational status

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    End point title
    		 Overall Survival (OS) by PIK3CA mutational status
    End point description
    Overall Survival (OS) by PIK3CA mutational status based on ctDNA is 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 known date patient alive. Patients were followed up approximately every 6 weeks after randomization and every 3 months during survival follow-up.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks after randomization up to a maximum of 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Months
    median (confidence interval 95%)
        FAS ctDNA PIK3CA mutant (n=100,35)|
    21.8 (14.7 to 25.8)
    999 (14.5 to 999)
        FAS ctDNA PIK3CA non-mutant (n=132,81)|
    21.4 (17.3 to 999)
    21.4 (17.3 to 999)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) by PIK3CA mutational status

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    End point title
    		 Overall Response Rate (ORR) by PIK3CA mutational status
    End point description
    Overall Response Rate (ORR) is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator’s assessment according to RECIST 1.1. ORR was analyzed in the full population and by PIK3CA mutational status based on ctDNA. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Patients were followed up for the duration of the study and for approximately every 6 weeks after randomization.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks after randomization up to a maximum of 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Percentage of Participants
    number (confidence interval 95%)
        Full Analysis Set (FAS) (n=289,143)|
    7.6 (4.8 to 11.3)
    2.1 (0.4 to 6.0)
        FAS ctDNA PIK3CA mutant (n=100,35)|
    10.0 (4.9 to 17.6)
    0.0 (0.0 to 10.0)
        FAS ctDNA PIK3CA non-mutant (n=132,81)|
    7.6 (3.7 to 13.5)
    3.7 (0.8 to 10.4)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) by PIK3CA mutational status

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    End point title
    		 Clinical Benefit Rate (CBR) by PIK3CA mutational status
    End point description
    Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 14 or 24 weeks based on local investigator’s assessment according to RECIST 1.1. CBR was analyzed in the full population and by PIK3CA mutational status based on ctDNA. Patients were followed up for the duration of the study and approximately every 6 weeks after randomization.
    End point type
    Secondary
    End point timeframe
    Week 14, Week 24
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Percentage of Participants
    number (confidence interval 95%)
        CBR>=14wks(FAS) (n=289,143)|
    33.2 (27.8 to 39.0)
    20.3 (14.0 to 27.8)
        CBR>=24wks(FAS) (n=289,143)|
    24.6 (19.7 to 29.9)
    15.4 (9.9 to 22.4)
        CBR>=14wks(FAS ctDNA PIK3CA mutant)(n=100,35)|
    38.0 (28.5 to 48.3)
    14.3 (4.8 to 30.3)
        CBR>=24wks(FAS ctDNA PIK3CA mutant)(n=100,35)|
    30.0 (21.2 to 40.0)
    11.4 (3.2 to 26.7)
        CBR>=14wks(FAS ctDNA PIK3CA non-mutant)(n=132,81)|
    36.4 (28.2 to 45.2)
    21.0 (12.7 to 31.5)
        CBR>= 24wks(FAS ctDNA PIK3CA non-mutant)(n=132,81)
    25.8 (18.5 to 34.1)
    14.8 (7.9 to 24.4)
    No statistical analyses for this end point

    Secondary: Long-term safety and tolerability in the two treatment arms - Safety Set (SS)

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    End point title
    		 Long-term safety and tolerability in the two treatment arms - Safety Set (SS)
    End point description
    Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment to 30 days after last dose of study treatment, up to 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    288
    140
    Units: Percentage of participants
    number (not applicable)
        AEs|
    97.9
    92.9
        SAEs|
    25.7
    18.6
        Deaths|
    42.7
    48.6
    No statistical analyses for this end point

    Secondary: Plasma concentration-time profiles of BKM120 in combination with fulvestrant at Cycle 1 Day 1 - Pharmacokinetic Analysis Set (PAS)

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    End point title
    		 Plasma concentration-time profiles of BKM120 in combination with fulvestrant at Cycle 1 Day 1 - Pharmacokinetic Analysis Set (PAS) [2]
    End point description
    Plasma samples were collected from the first 100 BKM120-treated patients on Cycle 1 Day 1 (at 1h, 2h, and 6h post-dose and a recommended 9h post-dose sample).
    End point type
    Secondary
    End point timeframe
    C1D1 1 hour post dose, C1D1 2 hour post dose, C1D1 6 hour post dose and C1D1 9 hour post dose
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: BKM120 PK sampling only performed in BKM120 100mg + Fulvestrant treatment arm
    End point values
    		 BKM120 100mg + Fulvestrant
    Number of subjects analysed
    63
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        C1D1 - 1 hour post dose|
    425.178 ± 149.6
        C1D1 - 2 hour post dose|
    615.441 ± 70.9
        C1D1 - 6 hour post dose|
    314.094 ± 41.9
        C1D1 - 9 hour post dose|
    302.899 ± 58.3
    No statistical analyses for this end point

    Secondary: Predose trough concentration-time profile of BKM120 in combination with fulvestrant over time - Pharmacokinetic Analysis Set (PAS)

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    End point title
    		 Predose trough concentration-time profile of BKM120 in combination with fulvestrant over time - Pharmacokinetic Analysis Set (PAS) [3]
    End point description
    Pre-dose samples were collected for trough concentrations at Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1 and Cycle 4 Day 1.
    End point type
    Secondary
    End point timeframe
    C1D15, C2D1, C3D1 and C4D1
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: BKM120 PK sampling only performed in BKM120 100mg + Fulvestrant treatment arm
    End point values
    		 BKM120 100mg + Fulvestrant
    Number of subjects analysed
    63
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        C1D15|
    939.978 ± 36.8
        C2D1|
    880.074 ± 38.4
        C3D1|
    777.026 ± 131.0
        C4D1|
    1088.074 ± 27.0
    No statistical analyses for this end point

    Secondary: Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30 - Full Analysis Set (FAS)

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    End point title
    		 Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30 - Full Analysis Set (FAS)
    End point description
    The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6 (C2D15), Week 12 (C4D1), then every 8 weeks until discontinuation (a cycle [C] = 4 weeks).
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Months
    median (confidence interval 95%)
        EORTC QLQ-30 - Global QoL score|
    5.3 (4.4 to 8.1)
    6.3 (3.0 to 9.9)
        EORTC QLQ-30 - PF scale score|
    11.8 (8.1 to 999)
    10.1 (7.5 to 14.6)
        EORTC QLQ-30 - EF scale score|
    10.0 (6.2 to 999)
    10.0 (4.9 to 999)
        EORTC QLQ-30 - SF scale score|
    10.0 (6.2 to 20.2)
    11.5 (6.4 to 14.6)
    No statistical analyses for this end point

    Secondary: Time to Definitive deterioration of ECOG Performance Status from Baseline - Full Analysis Set (FAS)

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    End point title
    		 Time to Definitive deterioration of ECOG Performance Status from Baseline - Full Analysis Set (FAS)
    End point description
    The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. The ECOG Performance Scores has 5 grades: 0 = fully active, able to carry on all predisease performance without restriction, 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours, 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair and 5 = dead. Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.
    End point type
    Secondary
    End point timeframe
    Screening, Baseline (Cycle 1 Day 1) and then at day 1 of each cycle and at the EOT visit
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    289
    143
    Units: Months
        median (confidence interval 95%)
    18.3 (6.9 to 999)
    12.0 (6.4 to 14.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment (FPFT) until end of treatment exposure + 30 days safety follow.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "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
    19.1
    Reporting groups
    Reporting group title
    BKM120 100 mg@+ fulvestrant
    Reporting group description
    		 BKM120 100 mg@+ fulvestrant

    Reporting group title
    All@Patients
    Reporting group description
    		 All@Patients

    Reporting group title
    Placebo@+ fulvestrant
    Reporting group description
    		 Placebo@+ fulvestrant

    Serious adverse events
    		 BKM120 100 mg@+ fulvestrant All@Patients Placebo@+ fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 288 (25.69%)
    100 / 428 (23.36%)
    26 / 140 (18.57%)
         number of deaths (all causes)
    123
    191
    68
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 428 (0.47%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Facial pain
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 428 (0.47%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 428 (0.47%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Homicide
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 288 (2.43%)
    8 / 428 (1.87%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 288 (2.08%)
    6 / 428 (1.40%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    4 / 288 (1.39%)
    5 / 428 (1.17%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mood altered
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 288 (1.04%)
    3 / 428 (0.70%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 288 (1.74%)
    5 / 428 (1.17%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 288 (2.08%)
    6 / 428 (1.40%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electric injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord injury thoracic
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracardiac mass
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Horner's syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Resting tremor
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 288 (0.69%)
    3 / 428 (0.70%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vith nerve paralysis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 428 (0.47%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic atrophy
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 428 (0.47%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 288 (1.04%)
    4 / 428 (0.93%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Nausea
         subjects affected / exposed
    1 / 288 (0.35%)
    3 / 428 (0.70%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 288 (1.39%)
    5 / 428 (1.17%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 288 (0.35%)
    3 / 428 (0.70%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridial infection
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective thrombosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumonia
         subjects affected / exposed
    4 / 288 (1.39%)
    4 / 428 (0.93%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 428 (0.47%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 428 (0.23%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 428 (0.47%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    3 / 288 (1.04%)
    3 / 428 (0.70%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 428 (0.23%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 428 (0.47%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BKM120 100 mg@+ fulvestrant All@Patients Placebo@+ fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    271 / 288 (94.10%)
    384 / 428 (89.72%)
    113 / 140 (80.71%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    113 / 288 (39.24%)
    123 / 428 (28.74%)
    10 / 140 (7.14%)
         occurrences all number
    142
    154
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    108 / 288 (37.50%)
    122 / 428 (28.50%)
    14 / 140 (10.00%)
         occurrences all number
    141
    162
    21
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    26 / 288 (9.03%)
    31 / 428 (7.24%)
    5 / 140 (3.57%)
         occurrences all number
    31
    38
    7
    Weight decreased
         subjects affected / exposed
    27 / 288 (9.38%)
    34 / 428 (7.94%)
    7 / 140 (5.00%)
         occurrences all number
    30
    38
    8
    Vascular disorders
    Hot flush
         subjects affected / exposed
    10 / 288 (3.47%)
    21 / 428 (4.91%)
    11 / 140 (7.86%)
         occurrences all number
    11
    25
    14
    Hypertension
         subjects affected / exposed
    33 / 288 (11.46%)
    41 / 428 (9.58%)
    8 / 140 (5.71%)
         occurrences all number
    37
    45
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    35 / 288 (12.15%)
    45 / 428 (10.51%)
    10 / 140 (7.14%)
         occurrences all number
    44
    55
    11
    Dysgeusia
         subjects affected / exposed
    19 / 288 (6.60%)
    23 / 428 (5.37%)
    4 / 140 (2.86%)
         occurrences all number
    21
    25
    4
    Headache
         subjects affected / exposed
    27 / 288 (9.38%)
    42 / 428 (9.81%)
    15 / 140 (10.71%)
         occurrences all number
    33
    49
    16
    Tremor
         subjects affected / exposed
    18 / 288 (6.25%)
    18 / 428 (4.21%)
    0 / 140 (0.00%)
         occurrences all number
    19
    19
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    52 / 288 (18.06%)
    67 / 428 (15.65%)
    15 / 140 (10.71%)
         occurrences all number
    67
    83
    16
    Fatigue
         subjects affected / exposed
    69 / 288 (23.96%)
    94 / 428 (21.96%)
    25 / 140 (17.86%)
         occurrences all number
    78
    105
    27
    Oedema peripheral
         subjects affected / exposed
    18 / 288 (6.25%)
    20 / 428 (4.67%)
    2 / 140 (1.43%)
         occurrences all number
    18
    20
    2
    Pyrexia
         subjects affected / exposed
    20 / 288 (6.94%)
    28 / 428 (6.54%)
    8 / 140 (5.71%)
         occurrences all number
    21
    29
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 288 (5.56%)
    22 / 428 (5.14%)
    6 / 140 (4.29%)
         occurrences all number
    18
    24
    6
    Abdominal pain upper
         subjects affected / exposed
    23 / 288 (7.99%)
    27 / 428 (6.31%)
    4 / 140 (2.86%)
         occurrences all number
    27
    31
    4
    Constipation
         subjects affected / exposed
    29 / 288 (10.07%)
    42 / 428 (9.81%)
    13 / 140 (9.29%)
         occurrences all number
    30
    44
    14
    Diarrhoea
         subjects affected / exposed
    76 / 288 (26.39%)
    89 / 428 (20.79%)
    13 / 140 (9.29%)
         occurrences all number
    111
    126
    15
    Dry mouth
         subjects affected / exposed
    23 / 288 (7.99%)
    28 / 428 (6.54%)
    5 / 140 (3.57%)
         occurrences all number
    26
    31
    5
    Dyspepsia
         subjects affected / exposed
    29 / 288 (10.07%)
    31 / 428 (7.24%)
    2 / 140 (1.43%)
         occurrences all number
    30
    32
    2
    Nausea
         subjects affected / exposed
    100 / 288 (34.72%)
    124 / 428 (28.97%)
    24 / 140 (17.14%)
         occurrences all number
    123
    158
    35
    Stomatitis
         subjects affected / exposed
    32 / 288 (11.11%)
    38 / 428 (8.88%)
    6 / 140 (4.29%)
         occurrences all number
    36
    42
    6
    Vomiting
         subjects affected / exposed
    27 / 288 (9.38%)
    40 / 428 (9.35%)
    13 / 140 (9.29%)
         occurrences all number
    43
    57
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    27 / 288 (9.38%)
    36 / 428 (8.41%)
    9 / 140 (6.43%)
         occurrences all number
    30
    39
    9
    Dyspnoea
         subjects affected / exposed
    22 / 288 (7.64%)
    34 / 428 (7.94%)
    12 / 140 (8.57%)
         occurrences all number
    28
    41
    13
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    22 / 288 (7.64%)
    25 / 428 (5.84%)
    3 / 140 (2.14%)
         occurrences all number
    23
    26
    3
    Pruritus
         subjects affected / exposed
    25 / 288 (8.68%)
    29 / 428 (6.78%)
    4 / 140 (2.86%)
         occurrences all number
    37
    41
    4
    Rash
         subjects affected / exposed
    37 / 288 (12.85%)
    40 / 428 (9.35%)
    3 / 140 (2.14%)
         occurrences all number
    49
    52
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    51 / 288 (17.71%)
    66 / 428 (15.42%)
    15 / 140 (10.71%)
         occurrences all number
    62
    77
    15
    Depression
         subjects affected / exposed
    60 / 288 (20.83%)
    71 / 428 (16.59%)
    11 / 140 (7.86%)
         occurrences all number
    72
    84
    12
    Insomnia
         subjects affected / exposed
    26 / 288 (9.03%)
    37 / 428 (8.64%)
    11 / 140 (7.86%)
         occurrences all number
    26
    37
    11
    Mood altered
         subjects affected / exposed
    15 / 288 (5.21%)
    17 / 428 (3.97%)
    2 / 140 (1.43%)
         occurrences all number
    16
    19
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 288 (7.29%)
    33 / 428 (7.71%)
    12 / 140 (8.57%)
         occurrences all number
    25
    37
    12
    Back pain
         subjects affected / exposed
    27 / 288 (9.38%)
    38 / 428 (8.88%)
    11 / 140 (7.86%)
         occurrences all number
    32
    45
    13
    Bone pain
         subjects affected / exposed
    9 / 288 (3.13%)
    20 / 428 (4.67%)
    11 / 140 (7.86%)
         occurrences all number
    13
    26
    13
    Muscle spasms
         subjects affected / exposed
    21 / 288 (7.29%)
    26 / 428 (6.07%)
    5 / 140 (3.57%)
         occurrences all number
    24
    30
    6
    Pain in extremity
         subjects affected / exposed
    19 / 288 (6.60%)
    29 / 428 (6.78%)
    10 / 140 (7.14%)
         occurrences all number
    24
    36
    12
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    15 / 288 (5.21%)
    18 / 428 (4.21%)
    3 / 140 (2.14%)
         occurrences all number
    21
    24
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    47 / 288 (16.32%)
    56 / 428 (13.08%)
    9 / 140 (6.43%)
         occurrences all number
    53
    62
    9
    Hyperglycaemia
         subjects affected / exposed
    104 / 288 (36.11%)
    108 / 428 (25.23%)
    4 / 140 (2.86%)
         occurrences all number
    172
    177
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2013
    Amendment 1 issued after randomization of seven patients, introduced the following key changes: • Discontinuation of enrollment of patients with unknown PI3K pathway activation status • Modification of the definition of PI3K pathway activation status to no longer include PIK3CA mutation in exon 5 and phosphatase and tensin homolog mutation overall • Modification of the guidelines for management of selected AEs, including psychiatric disorders, hyperglycemia grade 2, transaminases, stomatitis and skin rash • Extension of the buparlisib/placebo interruption period to recover from an AE from 21 to 28 days before the patient had to be permanently discontinued from study treatment
    19 Dec 2013
    Amendment 2 issued after randomization of 34 patients, introduced the following key changes: • Removal of the co-primary endpoint of PFS in the PI3K pathway activated subpopulation • Removal of stratification of randomization by molecular PI3K status • Modification of guideline for management of skin rash • Addition of clarification of the definition of a light breakfast
    07 May 2015
    Amendment 3 issued after randomization of 260 patients, introduced the following key changes: • Addition of guidance to Investigators regarding management of liver toxicities • Additional clarification regarding the use of validated translations for patient-reported outcome measures in the study • Additional clarification regarding withdrawal of consent • Implementation of tumor assessments and collection of scans until disease progression irrespective of start of new anti-neoplastic therapy • Exclusion criteria number 27 was added to exclude enrollment of patients with an acute viral hepatitis or with a history of chronic or active Hepatitis B Virus or Hepatitis C Virus infection
    20 Aug 2015
    Amendment 4 issued after randomization of 315 patients, introduced the following key changes: • Addition of a secondary objective to assess efficacy of buparlisib plus fulvestrant vs. placebo plus fulvestrant in PIK3CA mutant and non-mutant patients based on ctDNA • Simplification of the dose reduction schedule for buparlisib/placebo. Prior to introduction of Amendment 4, the first dose reduction (i.e., dose level −1) was to a dose of 80 mg/day continuously. Subsequent to introduction of Amendment 4, dose level −1 was 100 mg/day 5 days out of 7
    07 Jun 2016
    Amendment 5 issued after randomization of 432 patients, introduced the following key changes: • Addition of clarification on the measures to follow when a patient exhibits suicidal ideation regardless of the response to question 9 of the PHQ-9 questionnaire • Addition of clarification that buparlisib/placebo can be administered with or without food

    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 primary efficacy analysis was completed by 23May16 (primary PFS analysis cutoff date). The study was later terminated and the final safety analysis was conducted up to 08Sep17. One CRF was collecting on 21Sep2017 for survival follow up (LPLV).
    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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