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    Clinical Trial Results:
    NeoPHOEBE: Pi3k inhibition in Her2 OverExpressing Breast cancEr: A phase II, randomized, parallel cohort, two stage, double-blind, placebo-controlled study of neoadjuvant trastuzumab versus trastuzumab + BKM120 in combination with weekly paclitaxel in HER2-positive, PIK3CA wild-type and PIK3CA mutant primary breast cancer

    Summary
    EudraCT number
    		 2012-000738-21
    Trial protocol
    		 AT   ES  
    Global end of trial date
    18 Feb 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Sep 2019
    First version publication date
    29 Jul 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CBKM120F2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01816594
    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
    18 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate efficacy, in terms of pathological complete response (pCR) rate, at the time of surgery in patients with HER2 overexpressing or amplified (HER2+) operable breast cancer randomized to trastuzumab plus BKM120 placebo (followed by trastuzumab plus BKM120 placebo and paclitaxel) OR trastuzumab plus BKM120 (followed by trastuzumab plus BKM120 and paclitaxel) separately for PIK3CA mutant and wild-type cohorts.
    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 Sep 2013
    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: 1
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Spain: 9
    Worldwide total number of subjects
    50
    EEA total number of subjects
    46
    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)
    43
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Planned: Minimum 128 patients (in case of early stopping of both cohorts), maximum: 220 patients (if both cohorts would have proceeded into stage 2), and 174 patients if one cohort would have stopped early.

    Pre-assignment
    Screening details
    		 Screened: 68 patients Randomized and analyzed (safety and efficacy): 50 patients

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab + BKM120 + paclitaxel
    Arm description
    		 BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.
    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
    BKM120 was to be administered on a once daily continuous dosing schedule and was dosed on a flat scale of mg/day and not adjusted to weight or body surface area.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    weekly paclitaxel (80 mg/m2 i.v.) for 12 weeks

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    trastuzumab was dosed at 4 mg/kg i.v. load followed by 2 mg/kg i.v. weekly for 6 weeks.

    Arm title
    		 Trastuzumab + BKM120 PBO + paclitaxel
    Arm description
    		 BKM120 placebo in combination with trastuzumab and paclitaxel
    Arm type
    		 Placebo

    Investigational medicinal product name
    BKM120 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BKM120 placebo was to be administered on a once daily continuous dosing schedule and was dosed on a flat scale of mg/day and not adjusted to weight or body surface area.

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    trastuzumab was dosed at 4 mg/kg i.v. load followed by 2 mg/kg i.v. weekly for 6 weeks.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    weekly paclitaxel (80 mg/m2 i.v.) for 12 weeks

    Number of subjects in period 1
    		Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Started
    25
    25
    Completed
    14
    23
    Not completed
    11
    2
         Consent withdrawn by subject
    1
    -
         Physician decision
    1
    -
         Adverse event, non-fatal
    9
    -
         Local Progress
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab + BKM120 + paclitaxel
    Reporting group description
    		 BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.

    Reporting group title
    Trastuzumab + BKM120 PBO + paclitaxel
    Reporting group description
    		 BKM120 placebo in combination with trastuzumab and paclitaxel

    Reporting group values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel Total
    Number of subjects
    		 25 25 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 21 22 43
        From 65-84 years
    		 4 3 7
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.1 ± 11.5 51.3 ± 11.2 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 25 25 50
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian/white
    		 21 24 45
        Asian/Oriental
    		 3 1 4
        Other
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab + BKM120 + paclitaxel
    Reporting group description
    		 BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.

    Reporting group title
    Trastuzumab + BKM120 PBO + paclitaxel
    Reporting group description
    		 BKM120 placebo in combination with trastuzumab and paclitaxel

    Subject analysis set title
    Trastuzumab + BKM120 + paclitaxel (PIK3CA wild type)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in the BKM120 in combination with trastuzumab and paclitaxel group with PIK3CA wild type.

    Subject analysis set title
    Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA wild type)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in the BKM120 Placebo in combination with trastuzumab and paclitaxel group with PIK3CA wild type.

    Subject analysis set title
    Trastuzumab + BKM120 + paclitaxel (PIK3CA mutant)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in the BKM120 in combination with trastuzumab and paclitaxel group with PIK3CA mutant.

    Subject analysis set title
    Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA mutant)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in the BKM120 Placebo in combination with trastuzumab and paclitaxel group with PIK3CA mutant.

    Subject analysis set title
    ER+ subjects (Trastuzumab + BKM120 + paclitaxel)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with a positive (+) Estrogen Receptor in the BKM120 group

    Subject analysis set title
    ER + subjects (Trastuzumab + BKM120 PBO + paclitaxel)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with a positive (+) Estrogen Receptor in the placebo group

    Subject analysis set title
    ER- subjects (Trastuzumab + BKM120 + paclitaxel)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with a negative (-) Estrogen Receptor in the BKM120 group

    Subject analysis set title
    ER- subjecst (Trastuzumab + BKM120 PBO + paclitaxel)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with a negative (-) Estrogen Receptor in the BKM120 PBO group.

    Primary: Pathological complete response (pCR) rate at the time of surgery - All subjects

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    End point title
    		 Pathological complete response (pCR) rate at the time of surgery - All subjects
    End point description
    Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast [ypT0]) is the number of subjects with pathological complete response (pCR) at the time of surgery. Subjects were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.
    End point type
    Primary
    End point timeframe
    week 18
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects
    number (confidence interval 95%)
        pCR yp T0/is - Yes (All subjects)
    32.0 (14.9 to 53.5)
    40.0 (21.1 to 61.3)
    Statistical analysis title
    		 All subjects - pCR
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.811
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Primary: Pathological complete response (pCR) rate at the time of surgery - PIK3CA wild type (WT)

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    End point title
    		 Pathological complete response (pCR) rate at the time of surgery - PIK3CA wild type (WT)
    End point description
    Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast [ypT0]) is the number of subjects with pathological complete response (pCR) at the time of surgery. Participants in this group were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.
    End point type
    Primary
    End point timeframe
    week 18
    End point values
    		 Trastuzumab + BKM120 + paclitaxel (PIK3CA wild type) Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA wild type)
    Number of subjects analysed
    21
    21
    Units: Percentage of subjects
    number (confidence interval 95%)
        pCR yp T0/is - Yes (PIK3CA wild type (wt))
    33.3 (14.6 to 57.0)
    42.9 (21.8 to 66.0)
    Statistical analysis title
    		 WT cohort- pCR
    Statistical analysis description
    wild type cohort
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel (PIK3CA wild type) v Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA wild type)
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Primary: Pathological complete response (pCR) rate at the time of surgery - PIK3CA mutant (MT)

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    End point title
    		 Pathological complete response (pCR) rate at the time of surgery - PIK3CA mutant (MT)
    End point description
    Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast [ypT0]) is the number of subjects with pathological complete response (pCR) at the time of surgery. Subjects in this group were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.
    End point type
    Primary
    End point timeframe
    Week 18
    End point values
    		 Trastuzumab + BKM120 + paclitaxel (PIK3CA mutant) Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA mutant)
    Number of subjects analysed
    4
    4
    Units: Percentage of subjects
    number (confidence interval 95%)
        pCR yp T0/is - Yes (PIK3CA mutant (mt)) (n= 4, 4)
    25.0 (0.6 to 80.6)
    25.0 (0.6 to 80.6)
    Statistical analysis title
    		 MT cohort- pCR
    Statistical analysis description
    mutant cohort
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel (PIK3CA mutant) v Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA mutant)
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.786
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Overall objective clinical response rate at the end of the biologic window (after week 6) compared to baseline (Key Secondary) - All subjects

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    End point title
    		 Overall objective clinical response rate at the end of the biologic window (after week 6) compared to baseline (Key Secondary) - All subjects
    End point description
    Percentage of Overall objective clinical response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria.
    End point type
    Secondary
    End point timeframe
    end of biologic window (after week 6)
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects with response
    number (confidence interval 95%)
        ORR (All subjects)
    56.0 (34.9 to 75.6)
    44.0 (24.4 to 65.1)
    Statistical analysis title
    		 All subjects - ORR
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.286
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Overall objective clinical response rate at the end of the biologic window (after week 6) compared to baseline (Key Secondary) - PIK3A wild type subjects

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    End point title
    		 Overall objective clinical response rate at the end of the biologic window (after week 6) compared to baseline (Key Secondary) - PIK3A wild type subjects
    End point description
    Percentage of Overall objective clinical response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria for the PIK31 wild type subjects.
    End point type
    Secondary
    End point timeframe
    end of biologic window (after week 6)
    End point values
    		 Trastuzumab + BKM120 + paclitaxel (PIK3CA wild type) Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA wild type)
    Number of subjects analysed
    21
    21
    Units: Percentage of subjects with response
    number (confidence interval 95%)
        ORR - WT subjects (n = 21, 21)
    61.9 (38.4 to 81.9)
    42.9 (21.8 to 66.0)
    Statistical analysis title
    		 WT cohort - ORR
    Statistical analysis description
    wild type cohort
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel (PIK3CA wild type) v Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA wild type)
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.177
    Method
    		 Fisher Exact (one sided)
    Confidence interval

    Secondary: Overall objective clinical response rate at the end of the biologic window (after week 6) compared to baseline (Key Secondary) - PIK3A mutant subjects

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    End point title
    		 Overall objective clinical response rate at the end of the biologic window (after week 6) compared to baseline (Key Secondary) - PIK3A mutant subjects
    End point description
    Percentage of Overall objective clinical response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria for the mutant subjects.
    End point type
    Secondary
    End point timeframe
    end of biologic window (after week 6)
    End point values
    		 Trastuzumab + BKM120 + paclitaxel (PIK3CA mutant) Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA mutant)
    Number of subjects analysed
    4
    4
    Units: Percentage of subjects with response
    number (confidence interval 95%)
        ORR - mt subjects (n = 4, 4)
    25.0 (0.6 to 80.6)
    50.0 (6.8 to 93.2)
    Statistical analysis title
    		 MT cohort - ORR
    Statistical analysis description
    mutant cohort
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel (PIK3CA mutant) v Trastuzumab + BKM120 Placebo + paclitaxel (PIK3CA mutant)
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.929
    Method
    		 Fisher Exact (one sided)
    Confidence interval

    Secondary: Rate of breast conserving surgery (most radical surgery)

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    End point title
    		 Rate of breast conserving surgery (most radical surgery)
    End point description
    Rate of subjects with breast conserving surgery. No breast surgery was considered as breast conservation surgery (BCS)
    End point type
    Secondary
    End point timeframe
    18 weeks
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    60.0 (38.7 to 78.9)
    68.0 (46.5 to 85.1)
    Statistical analysis title
    		 Rate of BCS
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.811
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: pCR ypT0 ypN0 per GBG definition

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    End point title
    		 pCR ypT0 ypN0 per GBG definition
    End point description
    pCR defined as no invasive and non-invasive (DCIS) residuals in breast and lymph nodes (ypT0, ypN0 [GBG definition]). If patient had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such patient was considered to be pN0 for both secondary pCR definitions.
    End point type
    Secondary
    End point timeframe
    week 18
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    20.0 (6.8 to 40.7)
    28.0 (12.1 to 49.4)
    Statistical analysis title
    		 pCR - GBG
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: pCR ypT0/is ypN0 per MD Anderson definition

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    End point title
    		 pCR ypT0/is ypN0 per MD Anderson definition
    End point description
    pCR defined as no invasive residuals in breast and lymph nodes (ypT0/Tis, ypN0 [MD Anderson definition]). If patient had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such patient was considered to be pN0 for both secondary pCR definitions.
    End point type
    Secondary
    End point timeframe
    week 18
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    32.0 (14.9 to 53.5)
    36.0 (18.0 to 57.5)
    Statistical analysis title
    		 pCR - MD Anderson
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.724
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Overall objective response rate (ORR) prior to surgery for all subjects

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    End point title
    		 Overall objective response rate (ORR) prior to surgery for all subjects
    End point description
    Number of Overall objective response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria. CR: Complete disappearance of all tumor signs in the breast as assessed by ultrasound or MRI. The response of the axillary nodes was not to be considered. PR: Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by ultrasound or MRI. In subjects with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes was not to be considered.
    End point type
    Secondary
    End point timeframe
    prior to surgery
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects with response
        number (confidence interval 95%)
    56.0 (34.9 to 75.6)
    76.0 (54.9 to 90.6)
    Statistical analysis title
    		 ORR prior to surgery
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.964
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Percentage of subjects with pCR rates by hormone receptor status - Positive Estrogen Receptor (ER+)

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    End point title
    		 Percentage of subjects with pCR rates by hormone receptor status - Positive Estrogen Receptor (ER+)
    End point description
    pCR defined as no invasive and non-invasive (DCIS) residuals in breast and lymph nodes (ypT0, ypN0 [GBG definition]); pCR defined as no invasive residuals in breast and lymph nodes (ypT0/Tis, ypN0 [MD Anderson definition]). If a subject had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such subject was considered to be pN0 for both secondary pCR definitions.
    End point type
    Secondary
    End point timeframe
    baseline, week 18
    End point values
    		 ER+ subjects (Trastuzumab + BKM120 + paclitaxel) ER + subjects (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects analysed
    16
    15
    Units: Percentage of subjects
        number (confidence interval 95%)
    31.3 (11.0 to 58.7)
    26.7 (7.8 to 55.1)
    Statistical analysis title
    		 ER+ subjects
    Statistical analysis description
    For ER+ subjects - pCR
    Comparison groups
    ER+ subjects (Trastuzumab + BKM120 + paclitaxel) v ER + subjects (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.546
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Percentage of subjects with pCR rates by hormone receptor status - Negative Estrogen Receptor (ER-)

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    End point title
    		 Percentage of subjects with pCR rates by hormone receptor status - Negative Estrogen Receptor (ER-)
    End point description
    pCR defined as no invasive and non-invasive (DCIS) residuals in breast and lymph nodes (ypT0, ypN0 [GBG definition]); pCR defined as no invasive residuals in breast and lymph nodes (ypT0/Tis, ypN0 [MD Anderson definition]). If a subject had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such subject was considered to be pN0 for both secondary pCR definitions.
    End point type
    Secondary
    End point timeframe
    baseline, week 18
    End point values
    		 ER- subjects (Trastuzumab + BKM120 + paclitaxel) ER- subjecst (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects analysed
    9
    10
    Units: Percentage of subjects
    number (confidence interval 95%)
        ER- subjects with pCR (N = 9, 10)
    33.3 (7.5 to 70.1)
    60.0 (26.2 to 87.8)
    Statistical analysis title
    		 ER- subjects
    Statistical analysis description
    For ER- subjects - pCR
    Comparison groups
    ER- subjects (Trastuzumab + BKM120 + paclitaxel) v ER- subjecst (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.949
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Percentage of subjects with objective response rates by hormone receptor status - Positive Estrogen Receptor (ER+)

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    End point title
    		 Percentage of subjects with objective response rates by hormone receptor status - Positive Estrogen Receptor (ER+)
    End point description
    Objective response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria. CR: Complete disappearance of all tumor signs in the breast as assessed by ultrasound or MRI. The response of the axillary nodes was not to be considered. PR: Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by ultrasound or MRI. In patients with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes was not to be considered.
    End point type
    Secondary
    End point timeframe
    baseline, week 18
    End point values
    		 ER+ subjects (Trastuzumab + BKM120 + paclitaxel) ER + subjects (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects analysed
    16
    15
    Units: Percentage of subjects
    number (confidence interval 95%)
        ER+ subjects with ORR (N = 16, 15)
    68.8 (41.3 to 89.0)
    33.3 (11.8 to 61.6)
    Statistical analysis title
    		 ER+ subjects
    Statistical analysis description
    For ER+ subjects - ORR
    Comparison groups
    ER+ subjects (Trastuzumab + BKM120 + paclitaxel) v ER + subjects (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Percentage of subjects with objective response rates by hormone receptor status - Negative Estrogen Receptor (ER-)

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    End point title
    		 Percentage of subjects with objective response rates by hormone receptor status - Negative Estrogen Receptor (ER-)
    End point description
    Objective response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria. CR: Complete disappearance of all tumor signs in the breast as assessed by ultrasound or MRI. The response of the axillary nodes was not to be considered. PR: Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by ultrasound or MRI. In subjects with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes was not to be considered.
    End point type
    Secondary
    End point timeframe
    baseline, week 18
    End point values
    		 ER- subjects (Trastuzumab + BKM120 + paclitaxel) ER- subjecst (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects analysed
    9
    10
    Units: Percentage of subjects
    number (confidence interval 95%)
        ER- subjects with ORR (N = 9, 10)
    33.3 (7.5 to 70.1)
    60.0 (26.2 to 87.8)
    Statistical analysis title
    		 ER- subjects
    Statistical analysis description
    For ER- subjects - ORR
    Comparison groups
    ER- subjects (Trastuzumab + BKM120 + paclitaxel) v ER- subjecst (Trastuzumab + BKM120 PBO + paclitaxel)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.949
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Secondary: Percentage of subjects with Remaining Ductal carcinoma in situ (DCIS) (ypTis)

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    End point title
    		 Percentage of subjects with Remaining Ductal carcinoma in situ (DCIS) (ypTis)
    End point description
    This included subjects at definitive surgery irrespective of lymph node status
    End point type
    Secondary
    End point timeframe
    18 weeks
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    12.0 (2.5 to 31.2)
    12.0 (2.5 to 31.2)
    Statistical analysis title
    		 For DCIS
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.666
    Method
    		 Fisher Exact (one -sided)
    Confidence interval

    Secondary: Percentage of subjects with node-negative disease at definitive surgery (ypN0)

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    End point title
    		 Percentage of subjects with node-negative disease at definitive surgery (ypN0)
    End point description
    Node-negative disease at definitive surgery (ypN0) were considered as binary variables of ‘response’ versus ‘non response’.
    End point type
    Secondary
    End point timeframe
    18 weeks
    End point values
    		 Trastuzumab + BKM120 + paclitaxel Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects analysed
    25
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    52.0 (31.3 to 72.2)
    60.0 (38.7 to 78.9)
    Statistical analysis title
    		 For Node-negative disease
    Statistical analysis description
    All subjects
    Comparison groups
    Trastuzumab + BKM120 + paclitaxel v Trastuzumab + BKM120 PBO + paclitaxel
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.803
    Method
    		 Fisher Exact (one-sided)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 19.1 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BKM120
    Reporting group description
    		 BKM120

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 BKM120 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 25 (32.00%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BKM120 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 25 (84.00%)
    19 / 25 (76.00%)
    Vascular disorders
    Hot flushes
         subjects affected / exposed
    5 / 25 (20.00%)
    7 / 25 (28.00%)
         occurrences all number
    5
    7
    Vascular disorders
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 25 (16.00%)
         occurrences all number
    1
    4
    Fatigue
         subjects affected / exposed
    13 / 25 (52.00%)
    14 / 25 (56.00%)
         occurrences all number
    13
    14
    Oedema
         subjects affected / exposed
    3 / 25 (12.00%)
    8 / 25 (32.00%)
         occurrences all number
    3
    8
    Other general disorders and administration site conditions
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Immune system disorders
    Allergic reactions
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    2 / 25 (8.00%)
    6 / 25 (24.00%)
         occurrences all number
    2
    6
    Epistaxis
         subjects affected / exposed
    0 / 25 (0.00%)
    5 / 25 (20.00%)
         occurrences all number
    0
    5
    Other respiratory and mediastinal disorders
         subjects affected / exposed
    5 / 25 (20.00%)
    6 / 25 (24.00%)
         occurrences all number
    5
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 25 (20.00%)
    3 / 25 (12.00%)
         occurrences all number
    5
    3
    Depression
         subjects affected / exposed
    6 / 25 (24.00%)
    8 / 25 (32.00%)
         occurrences all number
    6
    8
    Insomnia
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 25 (16.00%)
         occurrences all number
    3
    4
    Psychiatric disorders
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Decreased calcium
         subjects affected / exposed
    9 / 25 (36.00%)
    11 / 25 (44.00%)
         occurrences all number
    9
    11
    Decreased potassium
         subjects affected / exposed
    6 / 25 (24.00%)
    2 / 25 (8.00%)
         occurrences all number
    6
    2
    Decreased serum albumin
         subjects affected / exposed
    5 / 25 (20.00%)
    2 / 25 (8.00%)
         occurrences all number
    5
    2
    Decreased sodium
         subjects affected / exposed
    9 / 25 (36.00%)
    7 / 25 (28.00%)
         occurrences all number
    9
    7
    Increased ALT
         subjects affected / exposed
    21 / 25 (84.00%)
    18 / 25 (72.00%)
         occurrences all number
    21
    18
    Increased AP
         subjects affected / exposed
    6 / 25 (24.00%)
    6 / 25 (24.00%)
         occurrences all number
    6
    6
    Increased AST
         subjects affected / exposed
    19 / 25 (76.00%)
    9 / 25 (36.00%)
         occurrences all number
    19
    9
    Increased FPG
         subjects affected / exposed
    13 / 25 (52.00%)
    8 / 25 (32.00%)
         occurrences all number
    13
    8
    Increased GGT
         subjects affected / exposed
    8 / 25 (32.00%)
    7 / 25 (28.00%)
         occurrences all number
    8
    7
    Increased aPTT
         subjects affected / exposed
    5 / 25 (20.00%)
    6 / 25 (24.00%)
         occurrences all number
    5
    6
    Increased potassium
         subjects affected / exposed
    3 / 25 (12.00%)
    11 / 25 (44.00%)
         occurrences all number
    3
    11
    Increased serum creatinine
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Increased sodium
         subjects affected / exposed
    4 / 25 (16.00%)
    2 / 25 (8.00%)
         occurrences all number
    4
    2
    Increased total bilirubin
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Increased total cholesterol
         subjects affected / exposed
    14 / 25 (56.00%)
    14 / 25 (56.00%)
         occurrences all number
    14
    14
    Increased triglycerides
         subjects affected / exposed
    5 / 25 (20.00%)
    6 / 25 (24.00%)
         occurrences all number
    5
    6
    Increased uric acid
         subjects affected / exposed
    6 / 25 (24.00%)
    10 / 25 (40.00%)
         occurrences all number
    6
    10
    Injury, poisoning and procedural complications
    Injury and poisoning and procedural complications
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Cardiac disorders
    Cardiac disorders not yet listed
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 25 (36.00%)
    4 / 25 (16.00%)
         occurrences all number
    9
    4
    Headache
         subjects affected / exposed
    2 / 25 (8.00%)
    8 / 25 (32.00%)
         occurrences all number
    2
    8
    Other neurological disorder
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 25 (56.00%)
    16 / 25 (64.00%)
         occurrences all number
    14
    16
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    17 / 25 (68.00%)
    18 / 25 (72.00%)
         occurrences all number
    17
    18
    Leukopenia
         subjects affected / exposed
    11 / 25 (44.00%)
    15 / 25 (60.00%)
         occurrences all number
    11
    15
    Lymphopenia
         subjects affected / exposed
    11 / 25 (44.00%)
    8 / 25 (32.00%)
         occurrences all number
    11
    8
    Neutropenia
         subjects affected / exposed
    6 / 25 (24.00%)
    9 / 25 (36.00%)
         occurrences all number
    6
    9
    Thrombopenia
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 25 (0.00%)
         occurrences all number
    4
    0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Eye disorders
    Eye disorders
         subjects affected / exposed
    5 / 25 (20.00%)
    3 / 25 (12.00%)
         occurrences all number
    5
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 25 (16.00%)
         occurrences all number
    2
    4
    Constipation
         subjects affected / exposed
    4 / 25 (16.00%)
    7 / 25 (28.00%)
         occurrences all number
    4
    7
    Diarrhea
         subjects affected / exposed
    15 / 25 (60.00%)
    10 / 25 (40.00%)
         occurrences all number
    15
    10
    Dysgeusia
         subjects affected / exposed
    4 / 25 (16.00%)
    5 / 25 (20.00%)
         occurrences all number
    4
    5
    Dyspepsia
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 25 (16.00%)
         occurrences all number
    4
    4
    Mucositis
         subjects affected / exposed
    19 / 25 (76.00%)
    12 / 25 (48.00%)
         occurrences all number
    19
    12
    Nausea
         subjects affected / exposed
    11 / 25 (44.00%)
    8 / 25 (32.00%)
         occurrences all number
    11
    8
    Other gastrointestinal disorders
         subjects affected / exposed
    7 / 25 (28.00%)
    7 / 25 (28.00%)
         occurrences all number
    7
    7
    Upper abdominal pain
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 25 (4.00%)
         occurrences all number
    5
    1
    Vomiting
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 25 (72.00%)
    17 / 25 (68.00%)
         occurrences all number
    18
    17
    Dry skin
         subjects affected / exposed
    5 / 25 (20.00%)
    4 / 25 (16.00%)
         occurrences all number
    5
    4
    Erythema
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 25 (20.00%)
         occurrences all number
    3
    5
    Nail disorder
         subjects affected / exposed
    5 / 25 (20.00%)
    5 / 25 (20.00%)
         occurrences all number
    5
    5
    Other skin and subcutaneous tissue disorders
         subjects affected / exposed
    5 / 25 (20.00%)
    7 / 25 (28.00%)
         occurrences all number
    5
    7
    Pruritus
         subjects affected / exposed
    10 / 25 (40.00%)
    5 / 25 (20.00%)
         occurrences all number
    10
    5
    Rash maculo-papular
         subjects affected / exposed
    15 / 25 (60.00%)
    12 / 25 (48.00%)
         occurrences all number
    15
    12
    Rash other than macular-papular or NOS
         subjects affected / exposed
    8 / 25 (32.00%)
    8 / 25 (32.00%)
         occurrences all number
    8
    8
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 25 (28.00%)
    10 / 25 (40.00%)
         occurrences all number
    7
    10
    Bone pain
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 25 (20.00%)
         occurrences all number
    3
    5
    Myalgia
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 25 (20.00%)
         occurrences all number
    3
    5
    Other musculo-skeletal and connective tissue disorders
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Infections and infestations
    Fever without neutropenia
         subjects affected / exposed
    7 / 25 (28.00%)
    3 / 25 (12.00%)
         occurrences all number
    7
    3
    Infection
         subjects affected / exposed
    12 / 25 (48.00%)
    19 / 25 (76.00%)
         occurrences all number
    12
    19
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 25 (4.00%)
         occurrences all number
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2014
    The main purpose of the protocol amendment was to update and align the management of selected adverse events across the BKM120 program, specifically psychiatric disorders, hyperglycemia, stomatitis, skin rash and Posterior Reversible Encephalopathy Syndrome (PRES). In addition, changes for clarification purposes had been implemented to the inclusion/ exclusion criteria, definition of post-menopausal status and pregnancy testing requirements, visit evaluation schedule, and tumor tissue samples collected at baseline. Furthermore, the sections on clinical and pharmacokinetic experience with BKM120, and in combination with paclitaxel and trastuzumab as well as concomitant medication use had been updated to align with the latest Investigators Brochure (IB) Update (Version 6) and recently published data. Finally, the timepoints of the interim safety analyses reviews by the IDMC had been updated and a section describing the TRC had been added.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Oct 2014
    Study enrollment was suspended due to safety concerns (high rate of increased liver enzymes and high number of treatment discontinuations). Until then 50 patients were recruited. Patients who were under therapy were allowed to continue.
    29 Oct 2014

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