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    Clinical Trial Results:
    A Phase II randomized, double-blind placebo controlled, study of letrozole with or without alpelisib (BYL719) or buparlisib (BKM120), for the neo-adjuvant treatment of postmenopausal women with hormone receptor-positive HER2-negative breast cancer Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2013-001862-41
    Trial protocol
    		 ES   IT   AT   BE   DE   NL   CZ   BG  
    Global end of trial date
    08 Jul 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CBYL719A2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01923168
    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
    08 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the anti-tumor activity of alpelisib once daily plus letrozole versus letrozole alone in increasing the pathologic complete response (pCR) rate during neo-adjuvant treatment among postmenopausal subjects with hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 negative (HER2-negative) breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA wild type tumors based on tumor tissue. To assess the anti-tumor activity of alpelisib once daily plus letrozole versus letrozole alone in increasing the Objective Response Rate (ORR) during neo-adjuvant treatment among postmenopausal subjects with HR-positive, HER2-negative breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA wild type tumors based on tumor tissue. The primary objective of the study was considered met if either one or both of these two objectives
    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
    11 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 49
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hong Kong: 8
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Lebanon: 8
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 63
    Country: Number of subjects enrolled
    United States: 100
    Worldwide total number of subjects
    340
    EEA total number of subjects
    168
    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)
    187
    From 65 to 84 years
    152
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of approximately 320 patients were planned to be randomized: this was based on 60 patients per arm in each cohort (PIK3CA mutant and PIK3CA wild-type) for the alpelisib+letrozole and placebo+letrozole arms, plus the estimated number of patients randomized to buparlisib+letrozole arm at the time this arm was discontinued.

    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
    		 Alpelisib + Letrozole
    Arm description
    		 Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alpelisib
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alpelisib came in 50 mg and 200 mg tablets and was administered at a dose of 300 mg orally daily .

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was administered at a dose of 2.5 mg orally daily

    Arm title
    		 Buparlisib + Letrozole
    Arm description
    		 Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Buparlisib was administered at a dose of 100 mg orally daily in combination with Letrozole 2.5 mg orally daily.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was administered at a dose of 2.5 mg orally daily

    Arm title
    		 Placebo + Letrozole
    Arm description
    		 Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    came in 50 mg and 200 mg tablets.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was dosed at 2.5 mg orally daily.

    Number of subjects in period 1
    		Alpelisib + Letrozole Buparlisib + Letrozole Placebo + Letrozole
    Started
    131
    83
    126
    Completed
    94
    44
    109
    Not completed
    37
    39
    17
         Adverse event, serious fatal
    -
    -
    1
         Physician decision
    6
    9
    5
         Adverse event, non-fatal
    12
    12
    -
         Progressive disease
    4
    3
    7
         Subject/guardian decision
    14
    14
    4
         Protocol deviation
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alpelisib + Letrozole
    Reporting group description
    		 Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.

    Reporting group title
    Buparlisib + Letrozole
    Reporting group description
    		 Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.

    Reporting group title
    Placebo + Letrozole
    Reporting group description
    		 Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.

    Reporting group values
    		 Alpelisib + Letrozole Buparlisib + Letrozole Placebo + Letrozole Total
    Number of subjects
    		 131 83 126 340
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 69 40 78 187
        From 65-84 years
    		 61 43 48 152
        85 years and over
    		 1 0 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.3 ( 8.53 ) 65.2 ( 8.61 ) 63.1 ( 8.31 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 131 83 126 340
        Male
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 117 68 105 290
        Asian
    		 7 4 10 21
        Black or African American
    		 3 3 5 11
        Other
    		 3 6 3 12
        Unknown
    		 1 2 3 6

    End points

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    End points reporting groups
    Reporting group title
    Alpelisib + Letrozole
    Reporting group description
    		 Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily.

    Reporting group title
    Buparlisib + Letrozole
    Reporting group description
    		 Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily.

    Reporting group title
    Placebo + Letrozole
    Reporting group description
    		 Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.

    Primary: Pathological Complete Response (pCR) per Investigator assessment for alpelisib vs. Placebo for PIK3CA mutant cohort

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    End point title
    		 Pathological Complete Response (pCR) per Investigator assessment for alpelisib vs. Placebo for PIK3CA mutant cohort [1]
    End point description
    Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.
    End point type
    Primary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [1] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    60
    67
    Units: Percentage of Participants
        number (confidence interval 80%)
    1.7 (0.2 to 6.3)
    3.0 (0.8 to 7.7)
    Statistical analysis title
    		 pCR: Alpelisib vs Placebo - mutant cohort
    Comparison groups
    Alpelisib + Letrozole v Placebo + Letrozole
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.282
    Method
    		 Posterior mean diff. & credible interval
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 1.7
    Notes
    [2] - Bayesian double criteria

    Primary: Pathological Complete Response (pCR) per Investigator assessment for alpelisib vs. Placebo for PIK3CA wild-type cohort

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    End point title
    		 Pathological Complete Response (pCR) per Investigator assessment for alpelisib vs. Placebo for PIK3CA wild-type cohort [3]
    End point description
    Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.
    End point type
    Primary
    End point timeframe
    After 24 weeks of treatment
    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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    71
    59
    Units: Percentage of Participants
        number (confidence interval 80%)
    2.8 (0.8 to 7.3)
    1.7 (0.2 to 6.4)
    Statistical analysis title
    		 pCR: Alpelisib vs Placebo - wild-type cohort
    Comparison groups
    Alpelisib + Letrozole v Placebo + Letrozole
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.697
    Method
    		 Posterior mean difference
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 4.2
    Notes
    [4] - Bayesian double criteria

    Primary: Objective Response Rate per Investigator assessment according to RECIST 1.1 for alpelisib vs. placebo - PIK3CA mutant cohort

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    End point title
    		 Objective Response Rate per Investigator assessment according to RECIST 1.1 for alpelisib vs. placebo - PIK3CA mutant cohort [5]
    End point description
    Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator’s assessment according to RECIST 1.1.
    End point type
    Primary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [5] - 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: At protocol amendment 5 enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    60
    67
    Units: Percentage of Participants
        number (confidence interval 80%)
    43.3 (34.6 to 52.4)
    44.8 (36.5 to 53.3)
    Statistical analysis title
    		 ORR: Alpelisib vs Placebo - mutant cohort
    Comparison groups
    Alpelisib + Letrozole v Placebo + Letrozole
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.435
    Method
    		 Posterior mean diff. & credible interval
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -12.5
         upper limit
    		 9.7
    Notes
    [6] - Bayesian double criteria

    Primary: Objective Response Rate according to RECIST 1.1 per Investigator assessment for alpelisib vs. placebo - PIK3CA wild-type cohort

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    End point title
    		 Objective Response Rate according to RECIST 1.1 per Investigator assessment for alpelisib vs. placebo - PIK3CA wild-type cohort [7]
    End point description
    Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator’s assessment according to RECIST 1.1.
    End point type
    Primary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [7] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    71
    59
    Units: Percentage of Participants
        number (confidence interval 80%)
    63.4 (55.1 to 71.0)
    61.0 (51.8 to 69.6)
    Statistical analysis title
    		 ORR: Alpelisib vs Placebo - wild-type cohort
    Comparison groups
    Alpelisib + Letrozole v Placebo + Letrozole
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.611
    Method
    		 Posterior mean diff. & credible interval
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 13.2
    Notes
    [8] - Bayesian double criteria

    Secondary: pCR and Objective response rate according to RECIST 1.1 criteria per Investigator assessment for alpelisib vs. placebo in PIK3CA mutant cohort based on ctDNA

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    End point title
    		 pCR and Objective response rate according to RECIST 1.1 criteria per Investigator assessment for alpelisib vs. placebo in PIK3CA mutant cohort based on ctDNA [9]
    End point description
    pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [9] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Participants
    Notes
    [10] - No patients were analyzed for this endpoint
    [11] - No patients were analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: pCR and Objective response rate according to RECIST 1.1 criteria per Investigator assessment for alpelisib vs. placebo in PIK3CA wild-type cohort based on ctDNA

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    End point title
    		 pCR and Objective response rate according to RECIST 1.1 criteria per Investigator assessment for alpelisib vs. placebo in PIK3CA wild-type cohort based on ctDNA [12]
    End point description
    pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [12] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Participants
    Notes
    [13] - No patients were analyzed for this endpoint
    [14] - No patients were analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: Rate of breast conserving surgery for alpelisib vs. placebo - PIK3CA mutant cohort

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    End point title
    		 Rate of breast conserving surgery for alpelisib vs. placebo - PIK3CA mutant cohort [15]
    End point description
    Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [15] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    60
    67
    Units: Percentage of participants
    number (confidence interval 80%)
        Breast conserving surgery
    56.7 (47.6 to 65.4)
    50.7 (42.2 to 59.2)
        No Surgery
    15.0 (9.3 to 22.6)
    9.0 (4.8 to 15.2)
    No statistical analyses for this end point

    Secondary: Rate of breast conserving surgery for alpelisib vs. placebo - PIK3CA wild-type cohort

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    End point title
    		 Rate of breast conserving surgery for alpelisib vs. placebo - PIK3CA wild-type cohort [16]
    End point description
    Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [16] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    71
    59
    Units: Percentage of participants
    number (confidence interval 80%)
        Breast conserving surgery
    50.7 (42.5 to 58.9)
    62.7 (53.6 to 71.2)
        No Surgery
    18.3 (12.5 to 25.6)
    8.5 (4.5 to 15.2)
    No statistical analyses for this end point

    Secondary: Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA mutant cohort: responders as per pCR

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    End point title
    		 Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA mutant cohort: responders as per pCR [17]
    End point description
    Association between pCR and change in Ki67 from baseline to day 15 and baseline to surgery
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 and surgery (End of Treatment (EOT))
    Notes
    [17] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    1
    2
    Units: Percentage of positive cells
    median (full range (min-max))
        Baseline|
    5.0 (5 to 5)
    11.0 (5 to 17)
        C1D15: % change from Baseline (n=1,1)|
    -80.0 (-80 to -80)
    80.0 (80 to 80)
        EOT % change from Baseline (n= 0,0)|
    99.9 (99.9 to 99.9)
    99.9 (99.9 to 99.9)
    No statistical analyses for this end point

    Secondary: Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA mutant cohort: non-responders as per pCR

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    End point title
    		 Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA mutant cohort: non-responders as per pCR [18]
    End point description
    Association between pCR and change in Ki67 from baseline to day 15 and baseline to surgery
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Surgery (End of Treatment (EOT))
    Notes
    [18] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    59
    65
    Units: Percentage of positive cells
    median (full range (min-max))
        Baseline|
    14.0 (0 to 82)
    13.0 (3 to 89)
        C1D15 % change from Baseline (n=45,52)|
    -62.5 (-97 to 467)
    -60.0 (-96 to 733)
        EOT % change from Baseline (n= 34,49)|
    -51.2 (-94 to 400)
    -60.0 (-97 to 223)
    No statistical analyses for this end point

    Secondary: Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: responders as per pCR

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    End point title
    		 Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: responders as per pCR [19]
    End point description
    Association between pCR and changes in Ki67 from baseline to day 15 and baseline to surgery
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 and surgery (End of Treatment (EOT))
    Notes
    [19] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    2
    1
    Units: Percentage of positive cells
    median (full range (min-max))
        Baseline|
    16.5 (3 to 30)
    20.0 (20 to 20)
        C1D15: % change from Baseline (n =1,0)|
    -80.0 (-80 to -80)
    0 (0 to 0)
        EOT % change from Baseline (n= 2,0)|
    -45.0 (-90 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR

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    End point title
    		 Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR [20]
    End point description
    Association between pCR and changes in Ki67 from baseline to day 15 and baseline to surgery
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Surgery (End of Treatment (EOT))
    Notes
    [20] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    69
    58
    Units: Percentage of positive cells
    median (full range (min-max))
        Baseline|
    16.0 (3 to 60)
    18.0 (4 to 85)
        C1D15 % change from Baseline (n =51,47)|
    -60.0 (-97 to 220)
    -52.0 (-93 to 50)
        EOT % change from Baseline (n= 37,41)|
    -60.0 (-90 to 190)
    -71.1 (-100 to 250)
    No statistical analyses for this end point

    Secondary: Preoperative endocrine prognostic index (PEPI) as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort

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    End point title
    		 Preoperative endocrine prognostic index (PEPI) as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort [21]
    End point description
    PEPI response is defined as central PEPI score of 0 at surgery
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [21] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    60
    67
    Units: Number of participants
    1
    0
    No statistical analyses for this end point

    Secondary: Preoperative endocrine prognostic index (PEPI) as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort

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    End point title
    		 Preoperative endocrine prognostic index (PEPI) as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort [22]
    End point description
    PEPI response is defined as central PEPI score of 0 at surgery
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    Notes
    [22] - 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: At protocol amendment 5, enrollment to the buparlisib plus letrozole arm was discontinued and the assessment of the anti-tumor activity of buparlisib plus letrozole became an exploratory objective, hence the efficacy results are not reported for this arm.
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    71
    59
    Units: Number of participants
    1
    1
    No statistical analyses for this end point

    Secondary: Alpelisib PK parameters: AUC0-24, AUClast at cycle 1 day 1

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    End point title
    		 Alpelisib PK parameters: AUC0-24, AUClast at cycle 1 day 1 [23]
    End point description
    Summary of primary PK parameters for alpelisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [23] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole
    Number of subjects analysed
    5
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24 (n = 3)
    30800 ( 20.6 )
        AUClast
    27300 ( 68.6 )
    No statistical analyses for this end point

    Secondary: Alpelisib PK parameter: Cmax at cycle 1 day 1

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    End point title
    		 Alpelisib PK parameter: Cmax at cycle 1 day 1 [24]
    End point description
    Summary of primary PK parameters for alpelisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [24] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole
    Number of subjects analysed
    5
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3160 ( 25.3 )
    No statistical analyses for this end point

    Secondary: Alpelisib and PK parameter: Tmax at cycle 1 day 1

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    End point title
    		 Alpelisib and PK parameter: Tmax at cycle 1 day 1 [25]
    End point description
    Summary of primary PK parameters for alpelisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [25] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole
    Number of subjects analysed
    5
    Units: HR
        median (full range (min-max))
    2.93 (1 to 6)
    No statistical analyses for this end point

    Secondary: Alpelisib PK parameters: AUC0-24, AUClast at cycle 4 day 1

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    End point title
    		 Alpelisib PK parameters: AUC0-24, AUClast at cycle 4 day 1 [26]
    End point description
    Summary of primary PK parameters for alpelisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [26] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole
    Number of subjects analysed
    5
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24 (n = 2)
    38000 ( 13.2 )
        AUClast (n = 2)
    38000 ( 13.1 )
    No statistical analyses for this end point

    Secondary: Alpelisib PK parameter: Cmax at cycle 4 day 1

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    End point title
    		 Alpelisib PK parameter: Cmax at cycle 4 day 1 [27]
    End point description
    Summary of primary PK parameters for alpelisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [27] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole
    Number of subjects analysed
    5 [28]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3260 ( 26.7 )
    Notes
    [28] - n = 2
    No statistical analyses for this end point

    Secondary: Alpelisib PK parameter: Tmax at cycle 4 day 1

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    End point title
    		 Alpelisib PK parameter: Tmax at cycle 4 day 1 [29]
    End point description
    Summary of primary PK parameters for alpelisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [29] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole
    Number of subjects analysed
    5 [30]
    Units: hr
        median (full range (min-max))
    2.99 (2.98 to 3)
    Notes
    [30] - n = 2
    No statistical analyses for this end point

    Secondary: Letrozole and PK parameters: AUC0-24, AUClast at cycle 1 day 1

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    End point title
    		 Letrozole and PK parameters: AUC0-24, AUClast at cycle 1 day 1 [31]
    End point description
    Summary of primary PK parameters for Letrozole plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [31] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    5
    15
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        AUC0 - 24 (n = 3, 10)
    433 ( 36.3 )
    427 ( 28.8 )
        AUClast (n= 5, 14)
    314 ( 96.9 )
    347 ( 49.6 )
    No statistical analyses for this end point

    Secondary: Letrozole PK parameter: Cmax at cycle 1 day 1

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    End point title
    		 Letrozole PK parameter: Cmax at cycle 1 day 1 [32]
    End point description
    Summary of primary PK parameters for letrozole plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [32] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    5
    15 [33]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    30.2 ( 33.2 )
    28 ( 42.3 )
    Notes
    [33] - n =14
    No statistical analyses for this end point

    Secondary: Letrozole PK parameter: Tmax at cycle 1 day 1

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    End point title
    		 Letrozole PK parameter: Tmax at cycle 1 day 1 [34]
    End point description
    Summary of primary PK parameters for letrozole plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [34] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    5
    15
    Units: hr
        median (full range (min-max))
    1.03 (1 to 3)
    2.25 (1 to 24.5)
    No statistical analyses for this end point

    Secondary: Letrozole PK parameters: AUC0-24, AUClast at cycle 4 day 1

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    End point title
    		 Letrozole PK parameters: AUC0-24, AUClast at cycle 4 day 1 [35]
    End point description
    Summary of primary PK parameters for Letrozole plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [35] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    5
    15
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24 (n = 2, 8)
    1280 ( 18 )
    1810 ( 33.1 )
        AUClast (n = 2, 13)
    1280 ( 17.9 )
    1440 ( 66.7 )
    No statistical analyses for this end point

    Secondary: Letrozole PK parameter: Cmax at cycle 4 day 1

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    End point title
    		 Letrozole PK parameter: Cmax at cycle 4 day 1 [36]
    End point description
    Summary of primary PK parameters for letrozole plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [36] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    5 [37]
    15 [38]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    75.6 ( 6.84 )
    103 ( 30 )
    Notes
    [37] - n = 2
    [38] - n = 13
    No statistical analyses for this end point

    Secondary: Letrozole PK parameter: Tmax at cycle 4 day 1

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    End point title
    		 Letrozole PK parameter: Tmax at cycle 4 day 1 [39]
    End point description
    Summary of primary PK parameters for letrozole plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [39] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Alpelisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    5 [40]
    15 [41]
    Units: hr
        median (full range (min-max))
    2 (1 to 3)
    1.17 (1 to 6)
    Notes
    [40] - n = 2
    [41] - n = 13
    No statistical analyses for this end point

    Secondary: Buparlisib PK parameters: AUC0-24, AUClast at cycle 1 day 1

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    End point title
    		 Buparlisib PK parameters: AUC0-24, AUClast at cycle 1 day 1 [42]
    End point description
    Summary of primary PK parameters for Buparlisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [42] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Buparlisib + Letrozole
    Number of subjects analysed
    10
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24 (n = 8)|
    6420 ( 60 )
        AUClast (n = 9)|
    4820 ( 123 )
    No statistical analyses for this end point

    Secondary: Buparlisib PK parameter: Cmax at cycle 1 day 1

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    End point title
    		 Buparlisib PK parameter: Cmax at cycle 1 day 1 [43]
    End point description
    Summary of primary PK parameters for buparlisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [43] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Buparlisib + Letrozole
    Number of subjects analysed
    10 [44]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    760 ( 86.7 )
    Notes
    [44] - n = 9
    No statistical analyses for this end point

    Secondary: Buparlisib PK parameter: Tmax at cycle 1 day 1

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    End point title
    		 Buparlisib PK parameter: Tmax at cycle 1 day 1 [45]
    End point description
    Summary of primary PK parameters for buparlisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [45] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Buparlisib + Letrozole
    Number of subjects analysed
    10 [46]
    Units: hr
        median (full range (min-max))
    1.03 (0.5 to 3.5)
    Notes
    [46] - n = 9
    No statistical analyses for this end point

    Secondary: Buparlisib PK parameter: AUClast at cycle 4 day 1

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    End point title
    		 Buparlisib PK parameter: AUClast at cycle 4 day 1 [47]
    End point description
    Summary of primary PK parameters for Buparlisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [47] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Buparlisib + Letrozole
    Number of subjects analysed
    10 [48]
    Units: ng*hr/mL
        median (full range (min-max))
    10400 (10400 to 10400)
    Notes
    [48] - n = 1
    No statistical analyses for this end point

    Secondary: Buparlisb PK parameter: Cmax at cycle 4 day 1

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    End point title
    		 Buparlisb PK parameter: Cmax at cycle 4 day 1 [49]
    End point description
    Summary of primary PK parameters for buparlisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [49] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Buparlisib + Letrozole
    Number of subjects analysed
    10 [50]
    Units: ng/mL
        median (full range (min-max))
    610 (610 to 610)
    Notes
    [50] - n = 1
    No statistical analyses for this end point

    Secondary: Buparlisib PK parameter: Tmax at cycle 4 day 1

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    End point title
    		 Buparlisib PK parameter: Tmax at cycle 4 day 1 [51]
    End point description
    Summary of primary PK parameters for buparlisib plasma concentration
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    Notes
    [51] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 Buparlisib + Letrozole
    Number of subjects analysed
    10 [52]
    Units: hr
        median (full range (min-max))
    3 (3 to 3)
    Notes
    [52] - n = 1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are on-treatment events (from first dose of study treatment to last dose of study treatment + 30 days).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Alpelisib + Letrozole
    Reporting group description
    		 Alpelisib + Letrozole

    Reporting group title
    Buparlisib + Letrozole
    Reporting group description
    		 Buparlisib + Letrozole

    Reporting group title
    Placebo + Letrozole
    Reporting group description
    		 Placebo + Letrozole

    Serious adverse events
    		 Alpelisib + Letrozole Buparlisib + Letrozole Placebo + Letrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 130 (16.15%)
    22 / 81 (27.16%)
    6 / 125 (4.80%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 130 (0.00%)
    7 / 81 (8.64%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 130 (0.00%)
    6 / 81 (7.41%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 81 (2.47%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Iritis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 81 (2.47%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 81 (1.23%)
    0 / 125 (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
    Nausea
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 81 (3.70%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    3 / 130 (2.31%)
    2 / 81 (2.47%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 130 (1.54%)
    2 / 81 (2.47%)
    0 / 125 (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
    Skin necrosis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 81 (1.23%)
    0 / 125 (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
    Dehydration
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    7 / 130 (5.38%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 81 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    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
    		 Alpelisib + Letrozole Buparlisib + Letrozole Placebo + Letrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 130 (96.92%)
    80 / 81 (98.77%)
    106 / 125 (84.80%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 130 (6.15%)
    12 / 81 (14.81%)
    31 / 125 (24.80%)
         occurrences all number
    8
    12
    32
    Hypertension
         subjects affected / exposed
    16 / 130 (12.31%)
    10 / 81 (12.35%)
    8 / 125 (6.40%)
         occurrences all number
    24
    13
    16
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    21 / 130 (16.15%)
    16 / 81 (19.75%)
    17 / 125 (13.60%)
         occurrences all number
    23
    18
    20
    Chills
         subjects affected / exposed
    7 / 130 (5.38%)
    8 / 81 (9.88%)
    5 / 125 (4.00%)
         occurrences all number
    8
    9
    6
    Fatigue
         subjects affected / exposed
    53 / 130 (40.77%)
    30 / 81 (37.04%)
    42 / 125 (33.60%)
         occurrences all number
    60
    35
    46
    Mucosal dryness
         subjects affected / exposed
    7 / 130 (5.38%)
    2 / 81 (2.47%)
    0 / 125 (0.00%)
         occurrences all number
    7
    2
    0
    Oedema peripheral
         subjects affected / exposed
    9 / 130 (6.92%)
    4 / 81 (4.94%)
    4 / 125 (3.20%)
         occurrences all number
    10
    4
    4
    Pyrexia
         subjects affected / exposed
    12 / 130 (9.23%)
    1 / 81 (1.23%)
    3 / 125 (2.40%)
         occurrences all number
    14
    1
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    4 / 130 (3.08%)
    8 / 81 (9.88%)
    10 / 125 (8.00%)
         occurrences all number
    4
    9
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 130 (6.92%)
    8 / 81 (9.88%)
    9 / 125 (7.20%)
         occurrences all number
    9
    8
    9
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 130 (7.69%)
    16 / 81 (19.75%)
    10 / 125 (8.00%)
         occurrences all number
    12
    18
    11
    Depression
         subjects affected / exposed
    5 / 130 (3.85%)
    12 / 81 (14.81%)
    3 / 125 (2.40%)
         occurrences all number
    5
    14
    4
    Insomnia
         subjects affected / exposed
    15 / 130 (11.54%)
    8 / 81 (9.88%)
    17 / 125 (13.60%)
         occurrences all number
    16
    8
    17
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    14 / 130 (10.77%)
    49 / 81 (60.49%)
    3 / 125 (2.40%)
         occurrences all number
    17
    52
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 130 (8.46%)
    44 / 81 (54.32%)
    2 / 125 (1.60%)
         occurrences all number
    12
    54
    3
    Blood bilirubin increased
         subjects affected / exposed
    2 / 130 (1.54%)
    6 / 81 (7.41%)
    1 / 125 (0.80%)
         occurrences all number
    3
    6
    1
    Blood creatinine increased
         subjects affected / exposed
    12 / 130 (9.23%)
    1 / 81 (1.23%)
    4 / 125 (3.20%)
         occurrences all number
    12
    1
    6
    Blood glucose increased
         subjects affected / exposed
    12 / 130 (9.23%)
    3 / 81 (3.70%)
    2 / 125 (1.60%)
         occurrences all number
    17
    3
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 130 (3.85%)
    6 / 81 (7.41%)
    1 / 125 (0.80%)
         occurrences all number
    5
    6
    1
    Weight decreased
         subjects affected / exposed
    16 / 130 (12.31%)
    10 / 81 (12.35%)
    3 / 125 (2.40%)
         occurrences all number
    18
    10
    4
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 130 (1.54%)
    5 / 81 (6.17%)
    9 / 125 (7.20%)
         occurrences all number
    2
    5
    10
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 130 (2.31%)
    5 / 81 (6.17%)
    1 / 125 (0.80%)
         occurrences all number
    3
    5
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 130 (5.38%)
    22 / 81 (27.16%)
    19 / 125 (15.20%)
         occurrences all number
    8
    25
    22
    Dysgeusia
         subjects affected / exposed
    24 / 130 (18.46%)
    11 / 81 (13.58%)
    7 / 125 (5.60%)
         occurrences all number
    27
    12
    7
    Headache
         subjects affected / exposed
    26 / 130 (20.00%)
    10 / 81 (12.35%)
    16 / 125 (12.80%)
         occurrences all number
    31
    14
    19
    Memory impairment
         subjects affected / exposed
    2 / 130 (1.54%)
    5 / 81 (6.17%)
    2 / 125 (1.60%)
         occurrences all number
    2
    5
    2
    Paraesthesia
         subjects affected / exposed
    8 / 130 (6.15%)
    2 / 81 (2.47%)
    4 / 125 (3.20%)
         occurrences all number
    8
    2
    4
    Tremor
         subjects affected / exposed
    0 / 130 (0.00%)
    8 / 81 (9.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    10
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 130 (3.85%)
    5 / 81 (6.17%)
    6 / 125 (4.80%)
         occurrences all number
    5
    6
    7
    Eye disorders
    Vision blurred
         subjects affected / exposed
    9 / 130 (6.92%)
    3 / 81 (3.70%)
    0 / 125 (0.00%)
         occurrences all number
    9
    3
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 130 (2.31%)
    6 / 81 (7.41%)
    4 / 125 (3.20%)
         occurrences all number
    3
    6
    4
    Abdominal pain
         subjects affected / exposed
    7 / 130 (5.38%)
    5 / 81 (6.17%)
    4 / 125 (3.20%)
         occurrences all number
    9
    6
    4
    Abdominal pain upper
         subjects affected / exposed
    5 / 130 (3.85%)
    7 / 81 (8.64%)
    4 / 125 (3.20%)
         occurrences all number
    5
    7
    6
    Constipation
         subjects affected / exposed
    5 / 130 (3.85%)
    7 / 81 (8.64%)
    13 / 125 (10.40%)
         occurrences all number
    5
    11
    14
    Diarrhoea
         subjects affected / exposed
    66 / 130 (50.77%)
    29 / 81 (35.80%)
    19 / 125 (15.20%)
         occurrences all number
    106
    44
    26
    Dry mouth
         subjects affected / exposed
    14 / 130 (10.77%)
    5 / 81 (6.17%)
    4 / 125 (3.20%)
         occurrences all number
    15
    5
    4
    Dyspepsia
         subjects affected / exposed
    11 / 130 (8.46%)
    11 / 81 (13.58%)
    6 / 125 (4.80%)
         occurrences all number
    13
    12
    6
    Nausea
         subjects affected / exposed
    57 / 130 (43.85%)
    37 / 81 (45.68%)
    23 / 125 (18.40%)
         occurrences all number
    73
    43
    25
    Stomatitis
         subjects affected / exposed
    42 / 130 (32.31%)
    18 / 81 (22.22%)
    5 / 125 (4.00%)
         occurrences all number
    50
    19
    6
    Vomiting
         subjects affected / exposed
    23 / 130 (17.69%)
    6 / 81 (7.41%)
    6 / 125 (4.80%)
         occurrences all number
    30
    9
    6
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    28 / 130 (21.54%)
    3 / 81 (3.70%)
    7 / 125 (5.60%)
         occurrences all number
    28
    3
    7
    Dry skin
         subjects affected / exposed
    19 / 130 (14.62%)
    14 / 81 (17.28%)
    4 / 125 (3.20%)
         occurrences all number
    21
    15
    4
    Pruritus
         subjects affected / exposed
    22 / 130 (16.92%)
    18 / 81 (22.22%)
    9 / 125 (7.20%)
         occurrences all number
    23
    18
    10
    Rash
         subjects affected / exposed
    58 / 130 (44.62%)
    31 / 81 (38.27%)
    10 / 125 (8.00%)
         occurrences all number
    82
    45
    11
    Rash maculo-papular
         subjects affected / exposed
    22 / 130 (16.92%)
    9 / 81 (11.11%)
    3 / 125 (2.40%)
         occurrences all number
    26
    12
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 130 (8.46%)
    13 / 81 (16.05%)
    34 / 125 (27.20%)
         occurrences all number
    12
    13
    41
    Back pain
         subjects affected / exposed
    1 / 130 (0.77%)
    7 / 81 (8.64%)
    11 / 125 (8.80%)
         occurrences all number
    2
    8
    13
    Muscle spasms
         subjects affected / exposed
    13 / 130 (10.00%)
    5 / 81 (6.17%)
    5 / 125 (4.00%)
         occurrences all number
    16
    5
    5
    Musculoskeletal pain
         subjects affected / exposed
    2 / 130 (1.54%)
    4 / 81 (4.94%)
    7 / 125 (5.60%)
         occurrences all number
    2
    4
    8
    Myalgia
         subjects affected / exposed
    6 / 130 (4.62%)
    4 / 81 (4.94%)
    13 / 125 (10.40%)
         occurrences all number
    6
    4
    13
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    15 / 130 (11.54%)
    7 / 81 (8.64%)
    7 / 125 (5.60%)
         occurrences all number
    19
    9
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 130 (3.85%)
    5 / 81 (6.17%)
    13 / 125 (10.40%)
         occurrences all number
    5
    5
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    40 / 130 (30.77%)
    25 / 81 (30.86%)
    10 / 125 (8.00%)
         occurrences all number
    41
    28
    10
    Hyperglycaemia
         subjects affected / exposed
    69 / 130 (53.08%)
    38 / 81 (46.91%)
    8 / 125 (6.40%)
         occurrences all number
    116
    51
    17
    Hypokalaemia
         subjects affected / exposed
    9 / 130 (6.92%)
    1 / 81 (1.23%)
    0 / 125 (0.00%)
         occurrences all number
    9
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2013
    This protocol amendment was implemented before the inclusion of the first subject. • Revised the starting dose of alpelisib from 350 mg QD to 300 mg QD and corresponding dose reduction guidelines. • Changed study inclusion/exclusion criteria, concomitant medications, dose adjustments and follow up of toxicities. • Included additional analyses for safety. Administrative changes are made for clarification and typographical errors had been corrected.
    29 Jan 2015
    Amendment 2, issued when 76 subjects had been randomized in the study. •Revised the dosing schedule of buparlisib, from 100 mg QD to 100 mg QD 5 days on/2 days off. •Modified the guidelines for pneumonitis management that had been revised based on the Urgent Safety Measure released on 19-Dec-2014 following accumulation of pneumonitis cases up to nine (including three with fatal outcome) within the alpelisib development program. The most recent fatal case was reported from the CLJM716X2103 trial (alpelisib in combination with the anti-HER-3 monoclonal antibody LJM716).” •Modified and clarified some of the inclusion/exclusion criteria. •Updated clinical efficacy and safety data of both buparlisib and alpelisib as a result of new available data and in alignment with the latest Buparlisib and alpelisib Investigators’ Brochure updates. •Made administrative changes for clarification and typographical errors have been corrected.
    09 Feb 2015
    The main purpose of this protocol amendment was to correct a typo identified in Inclusion criteria #4 (“T1c-Tc” to “T1c-T3”) and #13 (formatting issues).
    20 Jul 2015
    This amendment was issued when 146 subjects had been randomized in the study. The main purpose of this amendment was to provide additional guidance to Investigators around management of liver toxicities.
    12 Feb 2016
    This amendment was issued when 241 subjects had been randomized in the study. Of these, 121 subjects had been randomized to buparlisib/buparlisib-placebo arms, and 120 subjects had been randomized to alpelisib/ alpelisib-placebo. The main purpose of this amendment was to introduce the following key changes: •Updated the clinical study protocol according to the decision made by the Sponsor on 22-Dec-2015 to stop permanently the accrual in the buparlisib/buparlisib-placebo treatment arms. •Changed the assessment of the anti-tumor activity of buparlisib/buparlisib-placebo plus letrozole into an exploratory objective. •Changed the ORR from being secondary to primary endpoint. •Changed the assessment of the anti-tumor activity of alpelisib plus letrozole versus letrozole alone on pCR and ORR by PIK3CA status based on circulating tumor DNA (ctDNA), from exploratory to secondary objective. •Stopped the conduct of the central review for pathological response. •Implemented regular safety review of unblinded data performed by a DMC •Updated the inclusion criteria with regards to baseline glucose metabolism parameters, potassium, and values of amylase and lipase. •Retired the exclusion criteria related to psychiatric disorders and viral hepatitis, and update the exclusion criterion on uncontrolled medical conditions. •Updated the safety monitoring and guidance for the management of hyperglycemia, skin toxicity, and pancreatitis •Revised and updated the Appendix 14-1 “List of concomitant medications” due to a recent re-classification of drugs with QT prolongation •Updated the language of some protocol sections as part of a general update implemented across the program (e.g. safety monitoring for liver toxicity; language for Adverse Eventsreporting)
    04 May 2016
    This protocol amendment was classified as non-substantial. The purpose of this protocol amendment was to correct formatting error of “Table 6-4: Cardiac QTC prolongation
    18 Oct 2016
    This amendment was issued when 325 subjects have been randomized in study. Of these, 204 subjects have been randomized to alpelisib/alpelisib-placebo. All 121 subjects randomized to buparlisib/buparlisib-placebo arm had discontinued study treatment. PIK3CA wild-type cohort enrollment was completed and 7 subjects remained to be enrolled in the PIK3CA mutant cohort. The main purpose of this amendment was to introduce the following key changes:  - Provided more detailed treatment guidance for AE of hyperglycemia and update on AE management for skin toxicity following an advisory-board meeting recommendation - Updated the general administration guidelines for alpelisib/placebo based on a food effect and acid reducing agents (ARA) drug-drug interaction (DDI) study: alpelisib must be taken with a meal regardless of composition or overall calorie intake. A staggered approach for co-administration of alpelisib with acid reducing agents is no longer required

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
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    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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